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Lin X, Li X, Zhai Z, Zhang M. JAK-STAT pathway, type I/II cytokines, and new potential therapeutic strategy for autoimmune bullous diseases: update on pemphigus vulgaris and bullous pemphigoid. Front Immunol 2025; 16:1563286. [PMID: 40264772 PMCID: PMC12011800 DOI: 10.3389/fimmu.2025.1563286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/20/2025] [Indexed: 04/24/2025] Open
Abstract
Autoimmune Bullous Diseases (AIBDs), characterized by the formation of blisters due to autoantibodies targeting structural proteins, pose significant therapeutic challenges. Current treatments, often involving glucocorticoids or traditional immunosuppressants, are limited by their non-specificity and side effects. Cytokines play a pivotal role in AIBDs pathogenesis by driving inflammation and immune responses. The JAK-STAT pathway is central to the biological effects of various type I and II cytokines, making it an attractive therapeutic target. Preliminary reports suggest that JAK inhibitors may be a promising approach in PV and BP, but further clinical validation is required. In AIBDs, particularly bullous pemphigoid (BP) and pemphigus vulgaris (PV), JAK inhibitors have shown promise in modulating pathogenic cytokine signaling. However, the safety and selectivity of JAK inhibitors remain critical considerations, with the potential for adverse effects and the need for tailored treatment strategies. This review explores the role of cytokines and the JAK-STAT pathway in BP and PV, evaluating the therapeutic potential and challenges associated with JAK inhibitors in managing these complex disorders.
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Affiliation(s)
| | | | - Zhifang Zhai
- Department of Dermatology, The First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Mingwang Zhang
- Department of Dermatology, The First Affiliated Hospital, Army Medical University, Chongqing, China
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Juan HY, Sheu SJ, Hwang DK. Review of Janus Kinase Inhibitors as Therapies for Noninfectious Uveitis. J Ocul Pharmacol Ther 2025; 41:44-53. [PMID: 39315932 DOI: 10.1089/jop.2024.0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024] Open
Abstract
Uveitis remains one of the leading causes of blindness worldwide, with different etiologies requiring separate approaches to treatment. For over a decade, oral, topical, and local injection of corticosteroids as well as systemic conventional disease-modifying antirheumatic drugs (DMARDs) have remained the most effective treatment for noninfectious uveitis (NIU). Systemic administration of antitumor necrosis factor-α and other biological DMARDs have been used for treating cases that responded inadequately to conventional treatments. Unfortunately, some refractory patients still suffer from frequent attacks despite the combination of multiple treatments. Recently, there has been promising evidence for Janus kinase (JAK) inhibitors as the next-generation therapy for NIU. The JAK/signal transducers and activators of the transcription (STAT) signaling pathway mediate the downstream events involved in immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis by binding various ligands, such as cytokines, growth hormones, and growth factors. The mutation or loss of JAK/STAT components is implicated in autoimmune diseases, thus inhibition of such pathways has been an important area of research in therapeutic development.1 In this review, we provide a comprehensive overview of the efficacy and safety of JAK inhibitors for the management of NIU, with evidence from current trials and case reports.
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Affiliation(s)
- Hui Yu Juan
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Shwu-Jiuan Sheu
- Department of Ophthalmology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - De-Kuang Hwang
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Ophthalmology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Galan C, Lu G, Gill R, Li D, Liu Y, Huh JR, Hang S. RTF1 mediates epigenetic control of Th17 cell differentiation via H2B monoubiquitination. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:vkae043. [PMID: 40073106 PMCID: PMC11952878 DOI: 10.1093/jimmun/vkae043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/02/2024] [Indexed: 03/14/2025]
Abstract
A gene encoding the transcription factor RTF1 has been associated with an increased risk of ulcerative colitis (UC). In this study, we investigated its function in modulating T cells expressing interleukin-17A (Th17 cells), a cardinal cell type promoting intestinal inflammation. Our results indicate that Rtf1 deficiency disrupts the differentiation of Th17 cells, while leaving regulatory T cells (Treg) unaffected. Mechanistically, RTF1 facilitates histone H2B monoubiquitination (H2Bub1), which requires its histone modification domain (HMD), for supporting Th17 cell function. Impaired Th17 differentiation was also observed in cells lacking the H2Bub1 E3 ligase subunit RNF40, an enzyme known to physically interact with RTF1. Thus, our study underscores the essential role of RTF1 in H2Bub1-mediated epigenetic regulation of Th17 cell differentiation. Understanding this process will likely provide valuable insights into addressing Th17-associated inflammatory disorders. (Images were created with BioRender).
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Affiliation(s)
| | - Guangqing Lu
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, United States
| | - Richard Gill
- Genentech, Inc, South San Francisco, CA, United States
| | - Dun Li
- Genentech, Inc, South San Francisco, CA, United States
| | - Yifang Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, United States
| | - Jun R Huh
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, United States
- Bio2Q, Keio University, Tokyo, Japan
| | - Saiyu Hang
- Genentech, Inc, South San Francisco, CA, United States
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LaHue SC, Takegami N, Simmasalam R, Baqai A, Munoz E, Sikri A, de Courson TDB, Singhal NS, Eckalbar W, Langelier CR, Hendrickson CM, Calfee CS, Erle DJ, Krummel MF, Woodruff PG, Oskotsky T, Sirota M, Ferguson A, Douglas VC, Newman JC, Pleasure SJ, Wilson MR, COMET consortium, Singhal NS. Peripheral blood mononuclear cell transcriptomic trajectories reveal dynamic regulation of inflammatory actors in delirium. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.14.25322163. [PMID: 40034792 PMCID: PMC11875240 DOI: 10.1101/2025.02.14.25322163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Delirium is a neurologic syndrome characterized by inattention and cognitive impairment frequently encountered in the medically ill. Peripheral inflammation is a key trigger of delirium, but the patient-specific immune responses associated with delirium development and resolution are unknown. This retrospective cohort study of prospectively collected biospecimens examines RNA sequencing from peripheral blood mononuclear cells of adults hospitalized for COVID-19 to better understand patient-specific factors associated with delirium (n = 64). Longitudinal transcriptomic analyses highlight persistent immune dysregulation in delirium, marked by increasing expression trajectories of genes linked to innate immune pathways, including complement activation, cytokine production, and monocyte/macrophage recruitment. Genes involved adaptive immunity showed a declining trajectory over time in patients with delirium. Although corticosteroid treatment suppressed some aspects of immune hyperactivation, aberrant responses contributing to delirium were exacerbated. Delirium resolution was characterized by normalization of key transcripts such as CCL2 and innate immune markers. Novel associations with delirium were found in genes related to stress granule assembly and DUSP2 and KLF10, which mediate T-cell responses. These findings provide insights into the peripheral immune responses accompanying delirium and their modulation by corticosteroids. Future trials targeting aberrant inflammatory responses may mitigate the severe outcomes associated with delirium due to COVID19.
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Affiliation(s)
- Sara C. LaHue
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
- Weill Institute for Neurosciences, UCSF
- Buck Institute for Research on Aging, Novato, USA
| | - Naoki Takegami
- Weill Institute for Neurosciences, UCSF
- Department of Neurological Surgery, UCSF
- Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, USA
| | - Rubinee Simmasalam
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
| | - Abiya Baqai
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
| | - Elena Munoz
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
| | - Anya Sikri
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
| | | | - Nilika S. Singhal
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
| | - Walter Eckalbar
- Department of Medicine, UCSF
- UCSF CoLabs, UCSF
- Division of Pulmonary and Critical Care Medicine, UCSF
| | | | - Carolyn M. Hendrickson
- Department of Medicine, UCSF
- Division of Pulmonary and Critical Care Medicine, UCSF
- Zuckerberg San Francisco General Hospital and Trauma Center, USA
| | - Carolyn S. Calfee
- Department of Medicine, UCSF
- Division of Pulmonary and Critical Care Medicine, UCSF
| | - David J. Erle
- Department of Medicine, UCSF
- UCSF CoLabs, UCSF
- Division of Pulmonary and Critical Care Medicine, UCSF
| | | | - Prescott G. Woodruff
- Department of Medicine, UCSF
- Division of Pulmonary and Critical Care Medicine, UCSF
| | - Tomiko Oskotsky
- Bakar Computational Health Sciences Institute, UCSF
- Department of Pediatrics, UCSF
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, UCSF
- Department of Pediatrics, UCSF
| | - Adam Ferguson
- Weill Institute for Neurosciences, UCSF
- Department of Neurological Surgery, UCSF
- Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, USA
- San Francisco Veterans Affairs Medical Center, San Francisco, USA
| | - Vanja C. Douglas
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
- Weill Institute for Neurosciences, UCSF
| | - John C. Newman
- Buck Institute for Research on Aging, Novato, USA
- Department of Medicine, UCSF
- San Francisco Veterans Affairs Medical Center, San Francisco, USA
- Division of Geriatrics, UCSF
| | - Samuel J. Pleasure
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
- Weill Institute for Neurosciences, UCSF
| | - Michael R. Wilson
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
- Weill Institute for Neurosciences, UCSF
| | | | - Neel S. Singhal
- Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA
- San Francisco Veterans Affairs Medical Center, San Francisco, USA
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Adabi E, Charitidis FT, Thalheimer FB, Guaza-Lasheras M, Clarke C, Buchholz CJ. Enhanced conversion of T cells into CAR T cells by modulation of the MAPK/ERK pathway. Cell Rep Med 2025; 6:101970. [PMID: 39938523 PMCID: PMC11866553 DOI: 10.1016/j.xcrm.2025.101970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/20/2024] [Accepted: 01/22/2025] [Indexed: 02/14/2025]
Abstract
Delivery of chimeric antigen receptors (CARs) to T cells is usually mediated by lentiviral vectors (LVs), which can have broad tropism or be T cell targeted. To better understand the molecular events during CAR T cell generation, T cell transduction with four different LVs is followed by single-cell multi-omics analysis, distinguishing between transduced T cells and T cells with vector signal but no CAR. We find that only a fraction of the T cells that encounter vectors convert into CAR T cells. Single-cell transcriptome data reveal that interferon-stimulated genes are upregulated in non-transduced cells, whereas extracellular signal-regulated kinase (ERK)2 phosphatases are upregulated in CAR T cells. This expression pattern is evident in CAR T cells from healthy donors and patients. The role of the mitogen-activated protein kinase (MAPK)/ERK pathway in CAR T cell generation is confirmed by chemical inhibitors. These data provide molecular insights into T cell transduction with implications for improving CAR T cell generation.
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Affiliation(s)
- Elham Adabi
- Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany
| | - Filippos T Charitidis
- Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany
| | - Frederic B Thalheimer
- Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany; Hematology, Cell and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany; Frankfurt Cancer Institute (FCI), Goethe University, 60590 Frankfurt am Main, Germany
| | - Mar Guaza-Lasheras
- Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany
| | - Colin Clarke
- National Institute for Bioprocessing Research and Training, Fosters Avenue, A94 X099 Blackrock, Dublin, Ireland; School of Chemical and Bioprocess Engineering, University College Dublin, D04 V1W8 Belfield, Dublin, Ireland
| | - Christian J Buchholz
- Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Hessen, Germany; Frankfurt Cancer Institute (FCI), Goethe University, 60590 Frankfurt am Main, Germany; Deutsches Krebsforschungszentrum and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
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Liu C, Zhang Y, Zhao J, Zhang J, Meng Z, Yang Y, Xie Y, Jiao X, Liang B, Cao J, Wang Y. Vaping/e-cigarette-induced pulmonary extracellular vesicles contribute to exacerbated cardiomyocyte impairment through the translocation of ERK5. Life Sci 2024; 358:123195. [PMID: 39481834 DOI: 10.1016/j.lfs.2024.123195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/30/2024] [Accepted: 10/27/2024] [Indexed: 11/03/2024]
Abstract
AIMS The impact of e-cigarettes/vaping on cardiac function remains contradictory owing to insufficient direct evidence of interorgan communication. Extracellular vesicles (EVs) have protective or detrimental effects depending on pathological conditions, making it crucial to understand their role in lung-cardiac cell interactions mediated by vaping inhalation. METHODS AND KEY FINDINGS Pulmonary EVs were characterized from animals that underwent 12 weeks of nicotine inhalation (vaping component) (EVsNicotine) or vehicle control (EVsVehicle). EVsNicotine significantly increased in size and abundance compared with EVsVehicle. The direct effect of EVs Nicotine and EVs Vehicle on cardiomyocytes was then assessed in vitro and in vivo. EVs Nicotine led to a decrease in cardiac function as manifested by reduced cardiac contractility and impaired relaxation. EVs Nicotine induced increased levels of cleaved caspase-1 and cleaved caspase-11 in cardiomyocytes, indicating the promotion of pyroptosis. Meanwhile, EVsNicotine stimulated the secretion of fibrotic factors. Further analysis revealed that nicotine inhalation stimulated EVs Nicotine enriched with high levels of ERK5 (EVs Nicotine-ERK5). It was discovered that these EVs derived from pulmonary epithelial cells. Furthermore, inhibiting cardiac ERK5 blunted the EVs Nicotine-induced pyroptosis and fibrotic factor secretion. We further identified GATA4, a pro-pyroptosis transcription factor, as being activated through ERK5-dependent phosphorylation. SIGNIFICANCE Our research demonstrates that nicotine inhalation exacerbates cardiac injury through the activation of EVs derived from the lungs during e-cigarettes/vaping. Specifically, the EVs containing ERK5 play a crucial role in mediating the detrimental effects on cardiac function. This research provides new insights into the cardiac toxicity of vaping and highlights the role of EVs Nicotine-ERK5 in this process.
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Affiliation(s)
- Caihong Liu
- Department of Physiology, Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Yanwei Zhang
- Department of Cardiology, The First Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Jianli Zhao
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - John Zhang
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zhijun Meng
- Clinical Laboratory, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Yuhui Yang
- Department of Anesthesiology, Guangdong Medical University, Guangzhou 510182, Guangdong, China
| | - Yaoli Xie
- Department of Physiology, Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Xiangying Jiao
- Department of Physiology, Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Bin Liang
- Department of Physiology, Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, China; Department of Cardiology, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China
| | - Jimin Cao
- Department of Physiology, Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Yajing Wang
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Bellomo C, Furone F, Rotondo R, Ciscognetti I, Carpinelli M, Nicoletti M, D’Aniello G, Sepe L, Barone MV, Nanayakkara M. Role of Protein Tyrosine Phosphatases in Inflammatory Bowel Disease, Celiac Disease and Diabetes: Focus on the Intestinal Mucosa. Cells 2024; 13:1981. [PMID: 39682729 PMCID: PMC11640621 DOI: 10.3390/cells13231981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, such as cell growth, inflammation, differentiation, immune-mediated responses and oncogenic transformation. The aim of this review is to review the literature concerning the role of several PTPs-PTPN22, PTPN2, PTPN6, PTPN11, PTPσ, DUSP2, DUSP6 and PTPRK-at the level of the intestinal mucosa in inflammatory bowel disease (IBD), celiac disease (CeD) and type 1 diabetes (T1D) in both in vitro and in vivo models. The results revealed shared features, at the level of the intestinal mucosa, between these diseases characterized by alterations of different biological processes, such as proliferation, autoimmunity, cell death, autophagy and inflammation. PTPs are now actively studied to develop new drugs. Also considering the availability of organoids as models to test new drugs in personalized ways, it is very likely that soon these proteins will be the targets of useful drugs.
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Affiliation(s)
- Claudia Bellomo
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (C.B.); (F.F.); (I.C.); (M.C.); (M.N.)
| | - Francesca Furone
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (C.B.); (F.F.); (I.C.); (M.C.); (M.N.)
| | - Roberta Rotondo
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy;
| | - Ilaria Ciscognetti
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (C.B.); (F.F.); (I.C.); (M.C.); (M.N.)
| | - Martina Carpinelli
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (C.B.); (F.F.); (I.C.); (M.C.); (M.N.)
| | - Martina Nicoletti
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (C.B.); (F.F.); (I.C.); (M.C.); (M.N.)
| | - Genoveffa D’Aniello
- ELFID (European Laboratory for the Investigation of Food-Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Leandra Sepe
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy;
| | - Maria Vittoria Barone
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (C.B.); (F.F.); (I.C.); (M.C.); (M.N.)
- ELFID (European Laboratory for the Investigation of Food-Induced Diseases), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
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Guo S, Zeng M, Zhang C, Fan Y, Ran M, Song Z. Genome-wide characterization and comparative expression profiling of dual-specificity phosphatase genes in yellow catfish ( Pelteobagrus fulvidraco) after infection with exogenous Aeromonas hydrophila. Front Immunol 2024; 15:1481696. [PMID: 39606227 PMCID: PMC11598348 DOI: 10.3389/fimmu.2024.1481696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/15/2024] [Indexed: 11/29/2024] Open
Abstract
Introduction Dual-specificity phosphatases (DUSPs) are crucial regulators in many mammals, managing dephosphorylation and inactivation of mitogen-activated protein kinases (MAPKs) and playing essential roles in immune responses. However, their presence and functions in teleosts, like the yellow catfish (Pelteobagrus fulvidraco), remain unexplored. Methods In this study, eight pfDusp genes (pfDusp1-7 and pfDusp10) were identified in yellow catfish. We characterized their molecular features, conserved protein sequences, and chromosomal localization through genome-wide analyses, and we examined their expression patterns in immune responses. Results Our findings reveal two conserved motifs, Leu-Phe-Leu-Gly and Ala-Tyr-Leu-Met, within the DSPc domain of DUSP proteins. The genes were mapped across seven chromosomes without evidence of duplication. Comparative analysis showed high conservation of Dusp genes across vertebrates, with evolutionary analysis suggesting Dusp3 as a potential intermediate form. Dusp transcripts were significantly upregulated in the kidney post-A. hydrophila infection. Discussion These results suggest the involvement of Dusp genes in the immune response of yellow catfish to bacterial pathogens, providing insights into their evolutionary significance and potential applications in aquaculture and molecular breeding.
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Affiliation(s)
| | | | | | | | | | - Zhaobin Song
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College
of Life Sciences, Sichuan University, Chengdu, China
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Zhang X, Guo L, Tian W, Yang Y, Yin Y, Qiu Y, Wang W, Li Y, Zhang G, Zhao X, Wang G, Lin Z, Yang M, Zhao W, Lu D. CD36+ Proinflammatory Macrophages Interact with ZCCHC12+ Tumor Cells in Papillary Thyroid Cancer Promoting Tumor Progression and Recurrence. Cancer Immunol Res 2024; 12:1621-1639. [PMID: 39178310 DOI: 10.1158/2326-6066.cir-23-1047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/28/2024] [Accepted: 08/21/2024] [Indexed: 08/25/2024]
Abstract
Local recurrence and distal metastasis negatively impact the survival and quality of life in patients with papillary thyroid cancer (PTC). Therefore, identifying potential biomarkers and therapeutic targets for PTC is clinically crucial. In this study, we performed a multiomics analysis that identified a subset of CD36+ proinflammatory macrophages within the tumor microenvironment of PTC. The recruitment of CD36+ macrophages to premalignant regions strongly correlated with unfavorable outcomes in PTC, and the presence of tumor-infiltrating CD36+ macrophages was determined to be a risk factor for recurrence. The CD36+ macrophages exhibited interactions with metabolically active ZCCHC12+ tumor cells. By secreting SPP1, the CD36+ macrophages activated the PI3K-AKT signaling pathway, thereby promoting proliferation of the cancer cells. Dysregulation of iodine metabolism was closely related to the acquisition of the pro-inflammatory phenotype in macrophages. Iodine supplementation inhibited the activation of proinflammatory signaling and impeded the development of CD36+ macrophages by enhancing DUSP2 expression. Overall, our findings shed light on the intricate cross-talk between CD36+ macrophages and ZCCHC12+ tumor cells, providing valuable insights for the treatment and prognosis of PTC.
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Affiliation(s)
- Xin Zhang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Limei Guo
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Wenyu Tian
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Ying Yang
- Department of Blood Transfusion, Peking University People's Hospital, Beijing, P.R. China
| | - Yue Yin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Yaruo Qiu
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Weixuan Wang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Yang Li
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Guangze Zhang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Xuyang Zhao
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Guangxi Wang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Zhiqiang Lin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
| | - Meng Yang
- Department of General Surgery, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Wei Zhao
- Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Dan Lu
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing, P.R. China
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She Z, Dong H, Li Y, Chen P, Zhou C, Wang W, Jia Z, Shi Q. MiRNA29a-3p negatively regulates ISL1-Integrin β1 axis to suppress gastric cancer progression. Exp Cell Res 2024; 443:114288. [PMID: 39490753 DOI: 10.1016/j.yexcr.2024.114288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 09/22/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
Insulin gene enhancer protein 1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is closely related to the development of several cancers. We previously found that abnormally high ISL1 expression is involved in gastric cancer (GC) metastasis. However, the specific role of ISL1 and its regulatory mechanisms in GC metastasis warrant elucidation. In this study, we found that ISL1 is highly expressed in GC tissues and positively correlated with GC development, promoting cell migration and invasion in vivo and in vitro. Moreover, miRNA29a-3p can target ISL1 and thus inhibit GC cell migration. Furthermore, ISL1 upregulates ITGB1 by binding to its enhancer; nevertheless, ISL1-ITGB1 axis expression can be regulated using miRNA29a-3p. In GC cell nuclei, ISL1 and annexin A2 (ANXA2) form a transcriptional activator complex at the ITGB1 enhancer, thus promoting ITGB1 expression. In GC cell cytoplasm, the ISL1-ANXA2 complex synergistically activates matrix metalloproteinases, thus promoting cell migration. In conclusion, ISL1 is a potential therapeutic target for GC.
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Affiliation(s)
- Ziwei She
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China
| | - Haosheng Dong
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, Yunnan Province, 650118, PR China
| | - Yang Li
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, Yunnan Province, 650118, PR China
| | - Ping Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China
| | - Chunyan Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China
| | - Weiping Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Zhuqing Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Qiong Shi
- Department of Clinical Laboratory, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, Yunnan Province, 650118, PR China.
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11
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Liang Y, Li Y, Lee C, Yu Z, Chen C, Liang C. Ulcerative colitis: molecular insights and intervention therapy. MOLECULAR BIOMEDICINE 2024; 5:42. [PMID: 39384730 PMCID: PMC11464740 DOI: 10.1186/s43556-024-00207-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/13/2024] [Indexed: 10/11/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.
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Affiliation(s)
- Yuqing Liang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yang Li
- Department of Respiratory, Sichuan Integrative Medicine Hospital, Chengdu, 610042, China
| | - Chehao Lee
- Department of Traditional Chinese Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Ziwei Yu
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Chongli Chen
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Chao Liang
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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12
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Jin Y, Liu B, Li Q, Meng X, Tang X, Jin Y, Yin Y. PAC1 constrains type 2 inflammation through promotion of CGRP signaling in ILC2s. J Clin Invest 2024; 134:e180109. [PMID: 39287985 PMCID: PMC11527444 DOI: 10.1172/jci180109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 09/11/2024] [Indexed: 09/19/2024] Open
Abstract
Dysfunction of group 2 innate lymphoid cells (ILC2s) plays an important role in the development of type 2 inflammation-related diseases such as asthma and pulmonary fibrosis. Notably, neural signals are increasingly recognized as pivotal regulators of ILC2s. However, how ILC2s intrinsically modulate their responsiveness to these neural signals is still largely unknown. Here, using single-cell RNA-Seq, we found that the immune-regulatory molecule phosphatase of activated cells 1 (PAC1) selectively promoted the signaling of the neuropeptide calcitonin gene-related peptide (CGRP) in ILC2s in a cell-intrinsic manner. Genetic ablation of PAC1 in ILC2s substantially impaired the inhibitory effect of CGRP on proliferation and IL-13 secretion. PAC1 deficiency significantly exacerbated allergic airway inflammation induced by Alternaria alternata or papain in mice. Moreover, in human circulating ILC2s, the expression level of PAC1 was also significantly negatively correlated with the number of ILC2s and their expression level of IL13. Mechanistically, PAC1 was necessary for ensuring the expression of CGRP response genes by influencing chromatin accessibility. In summary, our study demonstrated that PAC1 is an important regulator of ILC2 responses, and we propose that PAC1 is a potential target for therapeutic interventions in type 2 inflammation-related diseases.
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Affiliation(s)
- Yuan Jin
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Bowen Liu
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- School of Medicine, Chinese University of Hong Kong (Shenzhen), Guangdong, China
| | - Qiuyu Li
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Xiangyan Meng
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiaowei Tang
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yan Jin
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- School of Medicine, Chinese University of Hong Kong (Shenzhen), Guangdong, China
- Peking-Tsinghua Joint Center for Life Sciences, Beijing, China
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, China
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13
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Han L, Sun X, Kong J, Li J, Feng K, Bai Y, Wang X, Zhu Z, Yang F, Chen Q, Zhang M, Yue B, Wang X, Fu L, Chen Y, Yang Q, Wang S, Xin Q, Sun N, Zhang D, Zhou Y, Gao Y, Zhao J, Jiang Y, Guo R. Multi-omics analysis reveals a feedback loop amplifying immune responses in acute graft-versus-host disease due to imbalanced gut microbiota and bile acid metabolism. J Transl Med 2024; 22:746. [PMID: 39113144 PMCID: PMC11308528 DOI: 10.1186/s12967-024-05577-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024] Open
Abstract
Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.
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Affiliation(s)
- Lijie Han
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianlei Sun
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jingjing Kong
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jin Li
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Kai Feng
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanliang Bai
- Department of Hematology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, China
| | - Xianjing Wang
- Department of Hematology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Zhenhua Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fengyuan Yang
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Qingzhou Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengmeng Zhang
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Baohong Yue
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoqian Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Liyan Fu
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yaoyao Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qiankun Yang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shuya Wang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qingxuan Xin
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Nannan Sun
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Danfeng Zhang
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yiwei Zhou
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanxia Gao
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junwei Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Yong Jiang
- Henan Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine and Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Rongqun Guo
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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14
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Li H, Wang S, Yang Z, Meng X, Niu M. Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors. Bioact Mater 2024; 36:376-412. [PMID: 38544737 PMCID: PMC10965438 DOI: 10.1016/j.bioactmat.2024.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/25/2024] [Accepted: 03/03/2024] [Indexed: 11/25/2024] Open
Abstract
The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.
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Affiliation(s)
- Hao Li
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Shuai Wang
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianwei Meng
- Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Meng Niu
- China Medical University, Shenyang, China
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15
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Maura F, Coffey DG, Stein CK, Braggio E, Ziccheddu B, Sharik ME, Du MT, Tafoya Alvarado Y, Shi CX, Zhu YX, Meermeier EW, Morgan GJ, Landgren O, Bergsagel PL, Chesi M. The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans. Nat Commun 2024; 15:3844. [PMID: 38714690 PMCID: PMC11076575 DOI: 10.1038/s41467-024-48091-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 04/15/2024] [Indexed: 05/10/2024] Open
Abstract
Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic MYC activation in the germinal center of genetically engineered Vk*MYC mice is sufficient to induce plasma cell tumors in which a variety of secondary mutations are spontaneously acquired and selected over time. Analysis of 119 Vk*MYC myeloma reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC. In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors.
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Affiliation(s)
| | - David G Coffey
- Division of Myeloma, University of Miami, Miami, FL, USA
| | - Caleb K Stein
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Esteban Braggio
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | | | - Meaghen E Sharik
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Megan T Du
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Yuliza Tafoya Alvarado
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Chang-Xin Shi
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Yuan Xiao Zhu
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Erin W Meermeier
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Gareth J Morgan
- Myeloma Research Program, NYU Langone, Perlmutter Cancer Center, New York, NY, USA
| | - Ola Landgren
- Division of Myeloma, University of Miami, Miami, FL, USA
| | - P Leif Bergsagel
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Marta Chesi
- Department of Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.
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16
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Wørzner K, Zimmermann J, Buhl R, Desoi A, Christensen D, Dietrich J, Nguyen NDNT, Lindenstrøm T, Woodworth JS, Alhakeem RS, Yu S, Ødum N, Mortensen R, Ashouri JF, Pedersen GK. Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype. J Autoimmun 2024; 144:103174. [PMID: 38377868 DOI: 10.1016/j.jaut.2024.103174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 01/17/2024] [Accepted: 01/31/2024] [Indexed: 02/22/2024]
Abstract
In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell. Whilst ATRA was previously found to broadly reduce Th17 responses, we found that antigen formulated in ATRA-containing cationic liposomes only inhibited Th17 cells in an antigen-specific manner and not when combined with an irrelevant antigen. Furthermore, this approach shifted existing Th17 cells away from IL-17A expression and transcriptomic analysis of sorted Th17 lineage cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, vaccination with myelin-specific (MOG) antigen in ATRA-containing liposomes reduced Th17 responses and alleviated disease. This highlights the potential of therapeutic vaccination for changing the phenotype of existing Th17 cells in the context of immune mediated diseases.
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Affiliation(s)
- Katharina Wørzner
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark.
| | - Julie Zimmermann
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Regitze Buhl
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Anna Desoi
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Dennis Christensen
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Jes Dietrich
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | | | - Thomas Lindenstrøm
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Joshua S Woodworth
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | | | - Steven Yu
- Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, USA
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Denmark
| | - Rasmus Mortensen
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark
| | - Judith F Ashouri
- Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, USA.
| | - Gabriel K Pedersen
- Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Denmark
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17
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Zhang H, Shi Y, Lin C, He C, Wang S, Li Q, Sun Y, Li M. Overcoming cancer risk in inflammatory bowel disease: new insights into preventive strategies and pathogenesis mechanisms including interactions of immune cells, cancer signaling pathways, and gut microbiota. Front Immunol 2024; 14:1338918. [PMID: 38288125 PMCID: PMC10822953 DOI: 10.3389/fimmu.2023.1338918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Inflammatory bowel disease (IBD), characterized primarily by gastrointestinal inflammation, predominantly manifests as Crohn's disease (CD) and ulcerative colitis (UC). It is acknowledged that Inflammation plays a significant role in cancer development and patients with IBD have an increased risk of various cancers. The progression from inflammation to carcinogenesis in IBD is a result of the interplay between immune cells, gut microbiota, and carcinogenic signaling pathways in epithelial cells. Long-term chronic inflammation can lead to the accumulation of mutations in epithelial cells and the abnormal activation of carcinogenic signaling pathways. Furthermore, Immune cells play a pivotal role in both the acute and chronic phases of IBD, contributing to the transformation from inflammation to tumorigenesis. And patients with IBD frequently exhibit dysbiosis of the intestinal microbiome. Disruption of the gut microbiota and subsequent immune dysregulation are central to the pathogenesis of both IBD and colitis associated colorectal cancer (CAC). The proactive management of inflammation combined with regular endoscopic and tumor screenings represents the most direct and effective strategy to prevent the IBD-associated cancer.
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Affiliation(s)
- Haonan Zhang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yulu Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chanchan Lin
- Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Chengcheng He
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shanping Wang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingyuan Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Sun
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingsong Li
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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18
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Ono E, Lenief V, Lefevre MA, Cuzin R, Guironnet-Paquet A, Mosnier A, Nosbaum A, Nicolas JF, Vocanson M. Topical corticosteroids inhibit allergic skin inflammation but are ineffective in impeding the formation and expansion of resident memory T cells. Allergy 2024; 79:52-64. [PMID: 37539746 DOI: 10.1111/all.15819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/28/2023] [Accepted: 05/23/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND Tissue-resident memory T (TRM ) cells are detrimental in allergic contact dermatitis (ACD), in which they contribute to the chronicity and severity of the disease. METHODS We assessed the impact of a standard topical corticosteroid (TCS) treatment, triamcinolone acetonide (TA), on the formation, maintenance and reactivation of epidermal TRM cells in a preclinical model of ACD to 2,4-dinitrofluorobenzene. TA 0.01% was applied at different time points of ACD response and we monitored skin inflammation and tracked CD8+ CD69+ CD103+ TRM by flow cytometry and RNA sequencing. RESULTS The impact of TA on TRM formation depended on treatment regimen: (i) in a preventive mode, that is, in sensitized mice before challenge, TA transiently inhibited the infiltration of effector T cells and the accumulation of TRM upon hapten challenge. In contrast, (ii) in a curative mode, that is, at the peak of the ACD response, TA blocked skin inflammation but failed to prevent the formation of TRM . Finally, (iii) in a proactive mode, that is, on previous eczema lesions, TA had no effect on the survival of skin TRM , but transiently inhibited their reactivation program upon allergen reexposure. Indeed, specific TRM progressively regained proliferative functions upon TA discontinuation and expanded in the tissue, leading to exaggerated iterative responses. Interestingly, TRM re-expansion correlated with the decreased clearance of hapten moieties from the skin induced by repeated TA applications. CONCLUSIONS Our results demonstrate that TCS successfully treat ACD inflammation, but are mostly ineffective in impeding the formation and expansion of allergen-specific TRM , which certainly restricts the induction of lasting tolerance in patients with chronic dermatitis.
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Affiliation(s)
- Emi Ono
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Vanina Lenief
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Marine-Alexia Lefevre
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Roxane Cuzin
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Aurélie Guironnet-Paquet
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
- Etablissement Français du Sang (EFS) Auvergne Rhône-Alpes, Apheresis Unit, Hôpital Lyon Sud, Pierre Bénite, France
| | - Amandine Mosnier
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Audrey Nosbaum
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
- Allergology and Clinical Immunology Department, Lyon Sud University Hospital, Pierre Bénite, France
| | - Jean-Francois Nicolas
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
- Allergology and Clinical Immunology Department, Lyon Sud University Hospital, Pierre Bénite, France
| | - Marc Vocanson
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
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Herrera-De La Mata S, Ramírez-Suástegui C, Mistry H, Castañeda-Castro FE, Kyyaly MA, Simon H, Liang S, Lau L, Barber C, Mondal M, Zhang H, Arshad SH, Kurukulaaratchy RJ, Vijayanand P, Seumois G. Cytotoxic CD4 + tissue-resident memory T cells are associated with asthma severity. MED 2023; 4:875-897.e8. [PMID: 37865091 PMCID: PMC10964988 DOI: 10.1016/j.medj.2023.09.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 07/02/2023] [Accepted: 09/18/2023] [Indexed: 10/23/2023]
Abstract
BACKGROUND Patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling that is refractory to corticosteroid treatment. CD4+ TH2 cells play a central role in orchestrating asthma pathogenesis, and biologic therapies targeting their cytokine pathways have had promising outcomes. However, not all patients respond well to such treatment, and their effects are not always durable nor reverse airway remodeling. This observation raises the possibility that other CD4+ T cell subsets and their effector molecules may drive airway inflammation and remodeling. METHODS We performed single-cell transcriptome analysis of >50,000 airway CD4+ T cells isolated from bronchoalveolar lavage samples from 30 patients with mild and severe asthma. FINDINGS We observed striking heterogeneity in the nature of CD4+ T cells present in asthmatics' airways, with tissue-resident memory T (TRM) cells making a dominant contribution. Notably, in severe asthmatics, a subset of CD4+ TRM cells (CD103-expressing) was significantly increased, comprising nearly 65% of all CD4+ T cells in the airways of male patients with severe asthma when compared to mild asthma (13%). This subset was enriched for transcripts linked to T cell receptor activation (HLA-DRB1, HLA-DPA1) and cytotoxicity (GZMB, GZMA) and, following stimulation, expressed high levels of transcripts encoding for pro-inflammatory non-TH2 cytokines (CCL3, CCL4, CCL5, TNF, LIGHT) that could fuel persistent airway inflammation and remodeling. CONCLUSIONS Our findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand the heterogeneity of this disease. FUNDING This research was funded by the NIH.
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Affiliation(s)
| | | | - Heena Mistry
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton Foundation Trust, Southampton SO16 6YD, UK; The David Hide Asthma and Allergy Research Centre, St. Mary's Hospital, Newport PO30 5TG, Isle of Wight, UK
| | | | - Mohammad A Kyyaly
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; The David Hide Asthma and Allergy Research Centre, St. Mary's Hospital, Newport PO30 5TG, Isle of Wight, UK
| | - Hayley Simon
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Shu Liang
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Laurie Lau
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton Foundation Trust, Southampton SO16 6YD, UK
| | - Clair Barber
- National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton Foundation Trust, Southampton SO16 6YD, UK
| | | | - Hongmei Zhang
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN 38152, USA
| | - Syed Hasan Arshad
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton Foundation Trust, Southampton SO16 6YD, UK; The David Hide Asthma and Allergy Research Centre, St. Mary's Hospital, Newport PO30 5TG, Isle of Wight, UK
| | - Ramesh J Kurukulaaratchy
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton Foundation Trust, Southampton SO16 6YD, UK; The David Hide Asthma and Allergy Research Centre, St. Mary's Hospital, Newport PO30 5TG, Isle of Wight, UK.
| | - Pandurangan Vijayanand
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK.
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20
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Taha M, Elazab ST, Abdelbagi O, Saati AA, Babateen O, Baokbah TAS, Qusty NF, Mahmoud ME, Ibrahim MM, Badawy AM. Phytochemical analysis of Origanum majorana L. extract and investigation of its antioxidant, anti-inflammatory and immunomodulatory effects against experimentally induced colitis downregulating Th17 cells. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116826. [PMID: 37348796 DOI: 10.1016/j.jep.2023.116826] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/09/2023] [Accepted: 06/19/2023] [Indexed: 06/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Origanum majorana L. is a member of the Lamiaceae family and is commonly used in Egyptian cuisine as a seasoning and flavor enhancer. It is also recognized as a well-known traditional medicine in Egypt and is widely used for treating abdominal colic due to its antispasmodic properties. However, the protective effects of Origanum majorana L. against ulcerative colitis and its underlying mechanisms remain unclear. AIM OF THE STUDY This study aimed to identify the biologically active components present in methanol extracts of Origanum majorana L. using gas chromatography/mass spectrometry (GC/MS). Additionally, it aimed to investigate the therapeutic effects of these extracts on acetic acid-induced ulcerative colitis and elucidate the potential mechanisms involved. MATERIALS AND METHODS We conducted a GC-MS analysis of the methanolic extract obtained from Origanum majorana L. Thirty-two male rats were included in the study and divided into four experimental groups, with eight rats in each group: sham, UC, UC + O. majorana, and UC sulfasalazine. After euthanizing the rats, colon tissue samples were collected for gross and microscopic examinations, assessment of oxidative stress, and molecular evaluation. GC-MS analysis identified 15 components in the extracts. Pretreatment with O. majorana L. extract and sulfasalazine significantly improved the disease activity index (DAI) and resulted in notable improvements in macroscopic and microscopic colon findings. Additionally, both treatments demonstrated preventive effects against colonic oxidative damage by reducing the levels of malondialdehyde (MDA) and increasing the levels of the antioxidant systems superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), which operate through the Nrf2/HO-1 signaling pathway. Moreover, these treatments downregulated the colonic inflammatory cascade by inhibiting NFκB, TNFα, IL-1β, IL6, IL23, IL17, COX-2, and iNOS, subsequently leading to downregulation of the JAK2/STAT3 signaling pathway and a decrease in the Th17 cell response. Furthermore, a reduction in the number of apoptotic epithelial cells that expressed caspase-3 was observed. CONCLUSION pretreatment with O. majorana L. extract significantly ameliorated acetic acid-induced ulcerative colitis. This effect could be attributed to the protective, antioxidant, anti-inflammatory, and anti-apoptotic properties of the extract.
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Affiliation(s)
- Medhat Taha
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt; Department of Anatomy, Al- Qunfudah Medical College, Umm Al-Qura University, Al-Qunfudhah, 28814, Saudi Arabia.
| | - Sara T Elazab
- Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Omer Abdelbagi
- Department of Pathology, Qunfudah Faculty of Medicine, Umm-Al-Qura University, Kingdom of Saudi Arabia, Makka, 24382, Saudi Arabia
| | - Abdullah A Saati
- Department of Community Medicine and Pilgrims Healthcare, Faculty of Medicine, Umm Al-Qura University, Makkah, 24382, Saudi Arabia
| | - Omar Babateen
- Department of Physiology, Faculty of Medicine, Umm Al-Qura University, Makkah, 24382, Saudi Arabia
| | - Tourki A S Baokbah
- Department of Medical Emergency Services, College of Health Sciences-AlQunfudah, Umm Al-Qura University, Al-Qunfudah, 28814, Saudi Arabia
| | - Naeem F Qusty
- Medical Laboratories Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, 24382, Saudi Arabia
| | - Mohamed Ezzat Mahmoud
- Histology Department, Damietta Faculty of Medicine, Al-Azhar University, Damietta, 34711, Egypt
| | - Mohie Mahmoud Ibrahim
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Alaa M Badawy
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
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21
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Zou F, Rao T, Chen W, Song T, Li T, Hu W, Li L, Yu W, Cheng F. DUSP2 affects bladder cancer prognosis by down-regulating MEK/ERK and P38 MAPK signaling pathways through PTPN7. Cell Signal 2023; 112:110893. [PMID: 37739277 DOI: 10.1016/j.cellsig.2023.110893] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 09/17/2023] [Accepted: 09/19/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND As one of the leading causes of cancer death worldwide, bladder cancer (BCa) ranks 12th in incidence rate. Dual Specific Phosphatase 2 (DUSP2) is a member of the bispecific protein phosphatase subfamily. DUSP2 is closely related to the prognosis of cancer, but the role of DUSP2 in bladder cancer is still unclear. This study aims to explore how DUSP2 affects the prognosis of bladder cancer and clarify the important mechanism in bladder cancer. METHODS Bioinformatics and experiments have detected the anti-tumor effect of DUSP2. Construct a DUSP2 overexpression cell model, and then use protein blotting experiments to verify the efficiency of transfection. The effects of DUSP2 on proliferation, metastasis, apoptosis, epithelial mesenchymal transition (EMT) and immune invasion of bladder cancer cells were detected in vitro or in vivo. In addition, the mechanism of DUSP2 regulating MEK/ERK through PTPN7 pathway and P38 MAPK inhibiting the progression of bladder cancer was also discussed. RESULTS The expression of DUSP2 was down regulated in bladder cancer samples and cell lines. The overexpression of DUSP2 inhibits the proliferation, metastasis and immune microenvironment of bladder cancer cells. In addition, we confirmed that DUSP2 regulates MEK/ERK and P38 MAPK through PTPN7 pathway to inhibit the progression of bladder cancer. CONCLUSION DUSP2 inhibits the progression of bladder cancer by regulating PTPN7. These results suggest that DUSP2/PTPN7/MEK/ERK pathway may become a new therapeutic target for bladder cancer.
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Affiliation(s)
- Fan Zou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wu Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Tianbao Song
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Tongjie Li
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430026, China
| | - Weimin Hu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Linzhi Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Weimin Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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22
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Khantakova JN, Sennikov SV. T-helper cells flexibility: the possibility of reprogramming T cells fate. Front Immunol 2023; 14:1284178. [PMID: 38022605 PMCID: PMC10646684 DOI: 10.3389/fimmu.2023.1284178] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/12/2023] [Indexed: 12/01/2023] Open
Abstract
Various disciplines cooperate to find novel approaches to cure impaired body functions by repairing, replacing, or regenerating cells, tissues, or organs. The possibility that a stable differentiated cell can reprogram itself opens the door to new therapeutic strategies against a multitude of diseases caused by the loss or dysfunction of essential, irreparable, and specific cells. One approach to cell therapy is to induce reprogramming of adult cells into other functionally active cells. Understanding the factors that cause or contribute to T cell plasticity is not only of clinical importance but also expands the knowledge of the factors that induce cells to differentiate and improves the understanding of normal developmental biology. The present review focuses on the advances in the conversion of peripheral CD4+ T cells, the conditions of their reprogramming, and the methods proposed to control such cell differentiation.
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Affiliation(s)
- Julia N. Khantakova
- Department of Molecular Immunology, Federal State Budgetary Scientific Institution “Research Institute of Fundamental and Clinical Immunology” (RIFCI), Novosibirsk, Russia
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23
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Xu Z, Huang Y, Meese T, Van Nevel S, Holtappels G, Vanhee S, Bröker BM, Li Z, de Meester E, De Ruyck N, Van Zele T, Gevaert P, Van Nieuwerburgh F, Zhang L, Shamji MH, Wen W, Zhang N, Bachert C. The multi-omics single-cell landscape of sinus mucosa in uncontrolled severe chronic rhinosinusitis with nasal polyps. Clin Immunol 2023; 256:109791. [PMID: 37769787 DOI: 10.1016/j.clim.2023.109791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/03/2023]
Abstract
Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with elevated levels of type 2 inflammatory cytokines and raised immunoglobulin concentrations in nasal polyp tissue. By using single-cell RNA sequencing, transcriptomics, surface proteomics, and T cell and B cell receptor sequencing, we found the predominant cell types in nasal polyps were shifted from epithelial and mesenchymal cells to inflammatory cells compared to nasal mucosa from healthy controls. Broad expansions of CD4 T effector memory cells, CD4 tissue-resident memory T cells, CD8 T effector memory cells and all subtypes of B cells in nasal polyp tissues. The T and B cell receptor repertoires were skewed in NP. This study highlights the deviated immune response and remodeling mechanisms that contribute to the pathogenesis of uncontrolled severe CRSwNP. CLINICAL IMPLICATIONS: We identified differences in the cellular compositions, transcriptomes, proteomes, and deviations in the immune profiles of T cell and B cell receptors as well as alterations in the intercellular communications in uncontrolled severe CRSwNP patients versus healthy controls, which might help to define potential therapeutic targets in the future.
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Affiliation(s)
- Zhaofeng Xu
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Yanran Huang
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium; Department of Allergy, Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, PR China; Beijing key laboratory of nasal diseases, Beijing Institute of Otolaryngology, Beijing, PR China
| | - Tim Meese
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Sharon Van Nevel
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | | | - Stijn Vanhee
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium; VIB-UGent, Center for Inflammation Research, Gent 9052, Belgium
| | - Barbara M Bröker
- Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
| | - Zhengqi Li
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China
| | - Ellen de Meester
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Natalie De Ruyck
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Thibaut Van Zele
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Philip Gevaert
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Filip Van Nieuwerburgh
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Luo Zhang
- Department of Allergy, Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, PR China; Beijing key laboratory of nasal diseases, Beijing Institute of Otolaryngology, Beijing, PR China
| | - Mohamed H Shamji
- National Heart and Lung Institute, Imperial College London, and NIHR Imperial Biomedical Research Centre, United Kingdom
| | - Weiping Wen
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
| | - Nan Zhang
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium.
| | - Claus Bachert
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium; Clinic for ENT diseases and head and neck surgery, University Clinic Münster, Münster, Germany; Division of ENT diseases, CLINTEC, Karolinska Institute, Stockholm, Sweden.
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Li W, Ling Z, Wang J, Su Z, Lu J, Yang X, Cheng B, Tao X. ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus. Biochem Pharmacol 2023; 216:115767. [PMID: 37634599 DOI: 10.1016/j.bcp.2023.115767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 08/29/2023]
Abstract
Oral lichen planus (OLP) is a T cell-mediated autoimmune disease of oral mucosa concerning with the redox imbalance. Although glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) is critical to T cell differentiation, the exact mechanism remains ambiguous. Here, we elucidate a novel regulatory mechanism of ASCT2-mediated uptake in the differentiation and proliferation of T cells through maintaining redox balance in OLP. The results of immunohistochemistry (IHC) showed that both ASCT2 and glutaminase (GLS) were obviously upregulated compared to controls in OLP. Moreover, correlation analyses indicated that ASCT2 expression was significantly related to GLS level. Interestingly, the upregulation of glutamine metabolism in epithelial layer was consistent with that in lamina propria. Functional assays in vitro revealed the positive association between glutamine metabolism and lymphocytes infiltration. Additionally, multiplex immunohistochemistry (mIHC) uncovered a stronger colocalization among ASCT2 and CD4 and IFN-γ, which was further demonstrated by human Th1 differentiation assay in vitro. Mechanistically, targeting glutamine uptake through interference with ASCT2 using L-γ-Glutamyl-p-nitroanilide (GPNA) decreased the glutamine uptake of T cells and leaded to the accumulation of intracellular reactive oxygen species (ROS), which promoted dual specificity phosphatase 2 (DUSP2/PAC1) expression through activation of early growth response 1 (EGR1) to induce dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and inhibit Th1 differentiation in turn. These results demonstrated that glutamine uptake mediated by ASCT2 induced Th1 differentiation by ROS-EGR1-PAC1 pathway, and restoring the redox dynamic balance through targeting ASCT2 may be a potential treatment for T cell-mediated autoimmune diseases.
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Affiliation(s)
- Wei Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Zihang Ling
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Jinmei Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Zhangci Su
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Jingyi Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xi Yang
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, China.
| | - Bin Cheng
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
| | - Xiaoan Tao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
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25
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Guo M, Wang X. Pathological mechanism and targeted drugs of ulcerative colitis: A review. Medicine (Baltimore) 2023; 102:e35020. [PMID: 37713856 PMCID: PMC10508406 DOI: 10.1097/md.0000000000035020] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/09/2023] [Indexed: 09/17/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with abdominal pain, diarrhea, and mucopurulent stools as the main symptoms. Its incidence is increasing worldwide, and traditional treatments have problems such as immunosuppression and metabolic disorders. In this article, the etiology and pathogenesis of ulcerative colitis are reviewed to clarify the targeted drugs of UC in the latest research. Our aim is to provide more ideas for the clinical treatment and new drug development of UC, mainly by analyzing and sorting out the relevant literature on PubMed, summarizing and finding that it is related to the main genetic, environmental, immune and other factors, and explaining its pathogenesis from the NF-κB pathway, PI3K/Akt signaling pathway, and JAK/STAT signaling pathway, and obtaining anti-TNF-α monoclonal antibodies, integrin antagonists, IL-12/IL-23 antagonists, novel UC-targeted drugs such as JAK inhibitors and SIP receptor agonists. We believe that rational selection of targeted drugs and formulation of the best dosing strategy under the comprehensive consideration of clinical evaluation is the best way to treat UC.
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Affiliation(s)
- Meitong Guo
- Changchun University of Chinese Medicine, Changchun City, China
| | - Xiaoyan Wang
- Jilin Academy of Chinese Medicine, Chaoyang District, China
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Hu X, Jiao F, Deng J, Zhou Z, Chen S, Liu C, Liu Z, Guo F. Intestinal Epithelial Cell-specific Deletion of Cytokine-inducible SH2-containing Protein Alleviates Experimental Colitis in Ageing Mice. J Crohns Colitis 2023; 17:1278-1290. [PMID: 36881790 DOI: 10.1093/ecco-jcc/jjad041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Indexed: 03/09/2023]
Abstract
BACKGROUND AND AIMS The incidence of inflammatory bowel disease [IBD] in the elderly has increased in recent years. However, the mechanisms underlying the ageing-related IBD susceptibility remain elusive. Cytokine-inducible SH2-containing protein [CISH] is involved in regulating metabolism, the expansion of intestinal tuft cells and type-2 innate lymphoid cells, and ageing-related airway inflammation. Here, we investigated the role of CISH in ageing-related colitis susceptibility. METHODS CISH and phosphorylated signal transducer and activator of transcription-3 [p-STAT3] levels were evaluated in the colons of ageing mice and older ulcerative colitis [UC] patients. Mice with intestinal epithelial cell-specific knockout of Cish [CishΔIEC] and Cish-floxed mice were administered dextran sodium sulphate [DSS] or trinitrobenzene sulphonic acid [TNBS] to induce colitis. Colonic tissues were analysed in quantitative real-time polymerase chain reaction, immunoblotting, immunohistochemical, and histological staining experiments. Differentially expressed genes from colonic epithelia were analysed by RNA sequencing. RESULTS Ageing increased the severity of DSS-induced colitis and the expression of colonic epithelial CISH in mice. CishΔIEC prevented DSS- or TNBS-induced colitis in middle-aged mice but not in young mice. RNA-sequencing analysis revealed that CishΔIEC significantly suppressed DSS-induced oxidative stress and proinflammatory responses. During ageing in the CCD841 cell model, knockdown of CISH decreased ageing-induced oxidative stress and proinflammatory responses, whereas these effects were compromised by knocking down or inhibiting STAT3. The increase in CISH expression was higher in the colonic mucosa of older patients with UC than in that of healthy controls. CONCLUSIONS CISH might be a proinflammatory regulator in ageing; therefore, targeted therapy against CISH may provide a novel strategy for treating ageing-related IBD.
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Affiliation(s)
- Xiaoming Hu
- Zhongshan Hospital, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Fuxin Jiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jiali Deng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ziheng Zhou
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shanghai Chen
- Zhongshan Hospital, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Changqin Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Zhanju Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Feifan Guo
- Zhongshan Hospital, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
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Liu X, Chen J, Liu L. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway. Open Life Sci 2023; 18:20220649. [PMID: 37483429 PMCID: PMC10358749 DOI: 10.1515/biol-2022-0649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/11/2023] [Accepted: 05/31/2023] [Indexed: 07/25/2023] Open
Abstract
One of the most severe side effects of systemic lupus erythematosus (SLE) is lupus nephritis (LN). To search for potential therapeutic targets in SLE is crucial for the progression of SLE. In this study, we selected C57BL/6J mice as controls and MRL/lpr mice as an LN model and obtained dual specificity phosphatase 2 (DUSP2)-overexpressed mice by injecting AAV-DUSP2 plasmid into the tail vein. Then, proteinuria, urea nitrogen, dsDNA and TNF-α, IL-6, and IL-1β levels were measured in each group of mice. In addition, renal histopathological damage was assessed by hematoxylin-eosin. Finally, STAT3 phosphorylation levels were detected by Western blot assay. The results showed that DUSP2 could reduce proteinuria, urea nitrogen, dsDNA and TNF-α, IL-6, and IL-1β levels and improve renal tissue injury in mice with LN. Mechanistically, DUSP2 inhibited STAT3 phosphorylation. These results demonstrated that DUSP2 played a role in ameliorating LN, which provided potential targets for LN research.
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Affiliation(s)
- Xingzhong Liu
- Department of Clinical Laboratory, Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, Sichuan, Chengdu Province, 611135, China
| | - Jie Chen
- Department of Nephrology, Wuhan Third Hospital, 241 Pengliuyang Road, Wuhan, Hubei Province, 430074, China
| | - Lu Liu
- Pediatric Clinic, Wuhan Third Hospital, Wuhan, Hubei Province, 430074, China
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Zhang Y, Kong R, Yang W, Hu K, Zhao Z, Li L, Geng X, Liu L, Chen H, Xiao P, Liu D, Luo Y, Chen H, Hu J, Sun B. DUSP2 recruits CSNK2A1 to suppress AKT1-mediated apoptosis resistance under hypoxic microenvironment in pancreatic cancer. Cancer Lett 2023:216288. [PMID: 37390887 DOI: 10.1016/j.canlet.2023.216288] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/23/2023] [Accepted: 06/23/2023] [Indexed: 07/02/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic tumor microenvironment (TME), which aids tumor progression, drug resistance, and immune evasion. Dual-specificity phosphatase 2 (DUSP2), a member of the mitogen-activated protein kinase phosphatase family, regulates pancreatic cancer metastasis. However, its role in the hypoxic TME in PDAC remains unknown. We explored the role of DUSP2 by simulating the hypoxic TME. DUSP2 significantly promoted apoptosis in PDAC both in vitro and in vivo, mainly through AKT1 rather than ERK1/2. Mechanistically, DUSP2 competed with AKT1 to bind to casein kinase 2 alpha 1 (CSNK2A1) and inhibited the phosphorylation of AKT1, which plays a crucial role in apoptosis resistance. Interestingly, aberrant activation of AKT1 resulted in an increase in the ubiquitin E3 ligase tripartite motif-containing 21 (TRIM21), which binds to and mediates the ubiquitination-dependent proteasomal degradation of DUSP2. Overall, we identified CSNK2A1 as a novel binding partner of DUSP2 that promotes PDAC apoptosis through CSN2KA1/AKT1 in an ERK1/2-independent manner. Activation of AKT1 also mediated proteasomal degradation of DUSP2 via the AKT1/TRIM21 positive feedback loop. We propose increasing the level of DUSP2 as a potential therapeutic strategy for PDAC.
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Affiliation(s)
- Yangyang Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Rui Kong
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Wenbo Yang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Keyi Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Zhongjie Zhao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Xinglong Geng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Liwei Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Hongze Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Peng Xiao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Danxi Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Yan Luo
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Hua Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China
| | - Jisheng Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China.
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, China.
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Wei C, Wang Y, Hu C. Bioinformatic analysis and experimental validation of the potential gene in the airway inflammation of steroid-resistant asthma. Sci Rep 2023; 13:8098. [PMID: 37208441 DOI: 10.1038/s41598-023-35214-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 05/15/2023] [Indexed: 05/21/2023] Open
Abstract
Steroid-resistant asthma is a troublesome clinical problem in public health. The pathogenesis of steroid-resistant asthma is complex and remains to be explored. In our work, the online Gene Expression Omnibus microarray dataset GSE7368 was used to explore differentially expressed genes (DEGs) between steroid-resistant asthma patients and steroid-sensitive asthma patients. Tissue-specific gene expression of DEGs was analyzed using BioGPS. The enrichment analyses were performed using GO, KEGG, and GSEA analysis. The protein-protein interaction network and key gene cluster were constructed using STRING, Cytoscape, MCODE, and Cytohubba. A steroid-resistant neutrophilic asthma mouse model was established using lipopolysaccharide (LPS) and ovalbumin (OVA). An LPS-stimulated J744A.1 macrophage model was prepared to validate the underlying mechanism of the interesting DEG gene using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 66 DEGs were identified, most of which were present in the hematologic/immune system. Enrichment analysis displayed that the enriched pathways were the IL-17 signaling pathway, MAPK signal pathway, Toll-like receptor signaling pathway, and so on. DUSP2, as one of the top upregulated DEGs, has not been clearly demonstrated in steroid-resistant asthma. In our study, we observed that the salubrinal administration (DUSP2 inhibitor) reversed neutrophilic airway inflammation and cytokine responses (IL-17A, TNF-α) in a steroid-resistant asthma mouse model. We also found that salubrinal treatment reduced inflammatory cytokines (CXCL10 and IL-1β) in LPS-stimulated J744A.1 macrophages. DUSP2 may be a candidate target for the therapy of steroid-resistant asthma.
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Affiliation(s)
- Chaochao Wei
- Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Haikou, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Affiliated Hainan Hospital of Hainan Medical University, Haikou, People's Republic of China
- Department of Oncology, Xiangya Hospital Central South University, Changsha, People's Republic of China
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, People's Republic of China
| | - Yang Wang
- Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Chengping Hu
- Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
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30
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Hu Z, Jiang Z, Yang Z, Liu L, Zhu Z, Jin Y, Yin Y. Development of a modularized aptamer targeting the nuclear T-cell suppressor PAC1. Analyst 2023; 148:2616-2625. [PMID: 37191022 DOI: 10.1039/d3an00011g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Aptamers associated with cancer targeting therapy are commonly focused on cell membrane proteins; however, the study of intracellular, particularly, nuclear proteins is limited. The nuclear phosphatase PAC1 has been reported to be a potential T cell-related immunotherapeutic target. Here, we identified an aptamer, designated as PA5, with high affinity and specificity for PAC1 through the systematic evolution of ligands by exponential enrichment (SELEX) procedure. We then developed a dual-module aptamer PAC1-AS consisting of a cell-internalizing module and a targeting module, which can recognize PAC1 in the nucleus under physiological conditions. This modularized aptamer raises the possibility of manipulating endosomes and provides insights into the exploration and development of an efficient cancer immunotherapy approach.
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Affiliation(s)
- Zixi Hu
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
| | - Zhongyu Jiang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
| | - Zeliang Yang
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
| | - Liang Liu
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
| | - Zhenyu Zhu
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
| | - Yan Jin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
| | - Yuxin Yin
- Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
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31
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Kim MH, Lee CW. Phosphatase Ssu72 Is Essential for Homeostatic Balance Between CD4 + T Cell Lineages. Immune Netw 2023; 23:e12. [PMID: 37179750 PMCID: PMC10166661 DOI: 10.4110/in.2023.23.e12] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/01/2022] [Accepted: 12/21/2022] [Indexed: 05/15/2023] Open
Abstract
Ssu72, a dual-specificity protein phosphatase, not only participates in transcription biogenesis, but also affects pathophysiological functions in a tissue-specific manner. Recently, it has been shown that Ssu72 is required for T cell differentiation and function by controlling multiple immune receptor-mediated signals, including TCR and several cytokine receptor signaling pathways. Ssu72 deficiency in T cells is associated with impaired fine-tuning of receptor-mediated signaling and a defect in CD4+ T cell homeostasis, resulting in immune-mediated diseases. However, the mechanism by which Ssu72 in T cells integrates the pathophysiology of multiple immune-mediated diseases is still poorly elucidated. In this review, we will focus on the immunoregulatory mechanism of Ssu72 phosphatase in CD4+ T cell differentiation, activation, and phenotypic function. We will also discuss the current understanding of the correlation between Ssu72 in T cells and pathological functions which suggests that Ssu72 might be a therapeutic target in autoimmune disorders and other diseases.
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Affiliation(s)
- Min-Hee Kim
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
| | - Chang-Woo Lee
- Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
- SKKU Institute for Convergence, Sungkyunkwan University, Suwon 16419, Korea
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32
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Xin J. Critical signaling pathways governing colitis-associated colorectal cancer: Signaling, therapeutic implications, and challenges. Dig Liver Dis 2023; 55:169-177. [PMID: 36002360 DOI: 10.1016/j.dld.2022.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 07/05/2022] [Accepted: 08/03/2022] [Indexed: 02/01/2023]
Abstract
Long-term colitis in people with inflammatory bowel disease (IBD) may lead to colon cancer called colitis-associated colorectal cancer (CAC). Since the advent of preclinical prototypes of CAC, various immunological messaging cascades have been identified as implicated in developing this disease. The toll-like receptor (TLR)s, Janus kinase (JAK)-signal transducer and activator of transcription (STAT), Nuclear factor-kappa B (NF-κB), mammalian target of rapamycin complex (mTOR), autophagy, and oxidative stress are only a few of the molecular mechanisms that have been recognized as major components to CAC progression. These pathways may also represent attractive medicinal candidates for the prevention and management of CAC. CAC signaling mechanisms at the molecular level and how their dysregulation may cause illness are summarized in this comprehensive overview.
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Affiliation(s)
- Jiang Xin
- Department of Gastrointestinal Surgery, The Third People's hospital of Qingdao, 266000, China.
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Qiu S, Xie L, Lu C, Gu C, Xia Y, Lv J, Xuan Z, Fang L, Yang J, Zhang L, Li Z, Wang W, Xu H, Li B, Xu Z. Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:296. [PMID: 36217165 PMCID: PMC9549645 DOI: 10.1186/s13046-022-02499-8] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/21/2022] [Indexed: 11/07/2022]
Abstract
Background Liver metastasis (LM) is a major obstacle to the prognosis of gastric cancer (GC) patients, but the molecular mechanism underlying gastric cancer liver metastasis (GC-LM) remains unknown. Exosomes have been identified as an important mediator of communication between tumor cells and the microenvironment. Therefore, we sought to investigate the effects of primary GC cells on the liver microenvironment and the role of exosomal microRNAs (exo-miRNA) in GC-LM. Methods Sequential differential centrifugation, transmission electron microscopy and NanoSight analysis were used to extract and characterize exosomes. MicroRNA sequencing in GC-derived exosomes and mRNA sequencing in PMA-treated THP-1 cells were used to identify differentially expressed miRNAs in exosomes and the functional targets of exosomal miR-519a-3p (exo-miR-519a-3p) in macrophages, respectively. Tracing and internalization of exosomes and transfer of exo-miR-519a-3p were observed by immunofluorescence. Tubule formation assays, aortic ring assays, and exosome-educated GC-LM model were used to investigate the roles of GC-derived exosomes and exo-miR-519a-3p in angiogenesis and GC-LM. Luciferase reporter assay, qRT-PCR, Western blot, ELISA, flow cytometry and immunofluorescence were used to investigate the regulatory mechanism of exo-miR-519a-3p at GC-LM. Results The expression level of miR-519a-3p in serum exosomes was significantly higher in GC-LM patients than in patients without LM, and high expression of exo-miR-519a-3p indicates a worse prognosis. GC-derived exosomes are mainly accumulated in the liver and internalized by intrahepatic macrophages. Mechanistically, exo-miR-519a-3p activates the MAPK/ERK pathway by targeting DUSP2, thereby causing M2-like polarization of macrophages. M2-like polarized macrophages accelerate GC-LM by inducing angiogenesis and promoting intrahepatic premetastatic niche formation. Conclusions Our results indicate that exo-miR-519a-3p plays a critical role in mediating crosstalk between primary GC cells and intrahepatic macrophages and is a potential therapeutic target for GC-LM. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02499-8.
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Affiliation(s)
- Shengkui Qiu
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,grid.440642.00000 0004 0644 5481Department of General Surgery, The First People’s Hospital of Nantong, The Second Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu Province China
| | - Li Xie
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Chen Lu
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Chao Gu
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Yiwen Xia
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Jialun Lv
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Zhe Xuan
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Lang Fang
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Jing Yang
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Lu Zhang
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Zheng Li
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Weizhi Wang
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Hao Xu
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,grid.89957.3a0000 0000 9255 8984Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166 Jiangsu Province China
| | - Bowen Li
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
| | - Zekuan Xu
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,grid.89957.3a0000 0000 9255 8984Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166 Jiangsu Province China
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Ejima A, Abe S, Shimba A, Sato S, Uehata T, Tani-ichi S, Munakata S, Cui G, Takeuchi O, Hirai T, Kato S, Ikuta K. Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production in Th2 Cells. THE JOURNAL OF IMMUNOLOGY 2022; 209:1083-1094. [DOI: 10.4049/jimmunol.2200294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 07/12/2022] [Indexed: 01/04/2023]
Abstract
Abstract
Asthma is more common in females than males after adolescence. However, the mechanism of the sex bias in the prevalence of asthma remains unknown. To test whether sex steroid hormones have some roles in T cells during development of asthma, we analyzed airway inflammation in T cell–specific androgen receptor (AR)– and estrogen receptor (ER)–deficient mice. T cell–specific AR-deficient male mice developed severer house dust mite–induced allergic airway inflammation than did control male mice, whereas T cell–specific ERα- and ERβ-deficient female mice exhibited a similar degree of inflammation as for control female mice. Furthermore, administration of dihydrotestosterone reduced cytokine production of Th2 cells from control, but not AR-deficient, naive T cells. Transfer of OT-II transgenic AR-deficient Th2 cells into wild-type mice induced severer allergic airway inflammation by OVA than transfer of control Th2 cells. Gene expression profiling suggested that the expression of genes related with cell cycle and Th2 differentiation was elevated in AR-deficient Th2 cells, whereas expression of dual specificity phosphatase (DUSP)-2, a negative regulator of p38, was downregulated. In addition, a chromatin immunoprecipitation assay suggested that AR bound to an AR motif in the 5′ untranslated region of the Dusp2 gene in Th2 cells. Furthermore, the Dusp2 promoter with a wild-type AR motif, but not a mutated motif, was transactivated by dihydrotestosterone in a reporter assay. Finally, forced expression of DUSP-2 by retrovirus vector reduced IL-4 expression in Th2 cells. Thus, these results suggest that androgen signaling suppresses cytokine production of Th2 cells by inducing DUSP-2, explaining, in part, the sex bias of asthma after adolescence.
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Affiliation(s)
- Aki Ejima
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- †Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Shinya Abe
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Akihiro Shimba
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- ‡Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Sato
- §Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takuya Uehata
- ¶Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shizue Tani-ichi
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- ‡Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoru Munakata
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- †Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Guangwei Cui
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Osamu Takeuchi
- ¶Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toyohiro Hirai
- §Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shigeaki Kato
- ‖Graduate School of Life Science and Engineering, Iryo Sosei University, Iwaki, Japan
- #Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, Japan; and
- **School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Koichi Ikuta
- *Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Zhang L, Zhang B, Li L, Ye Y, Wu Y, Yuan Q, Xu W, Wen X, Guo X, Nian S. Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer. J Cancer Res Clin Oncol 2022; 149:2243-2258. [PMID: 36107246 DOI: 10.1007/s00432-022-04326-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022]
Abstract
In response to prolonged stimulation by tumour antigens, T cells gradually become exhausted. There is growing evidence that exhausted T cells not only lose their potent effector functions but also express multiple inhibitory receptors. Checkpoint blockade (CPB) therapy can improve cancer by reactivating exhausted effector cell function, leading to durable clinical responses, but further improvements are needed given the limited number of patients who benefit from treatment, even with autoimmune complications. Here, we suggest, based on recent advances that tumour antigens are the primary culprits of exhaustion, followed by some immune cells and cytokines that also play an accomplice role in the exhaustion process, and we also propose that chronic stress-induced hypoxia and hormones also play an important role in promoting T-cell exhaustion. Understanding the classification of exhausted CD8+ T-cell subpopulations and their functions is important for the effectiveness of immune checkpoint blockade therapies. We mapped the differentiation of T-cell exhausted subpopulations by changes in transcription factors, indicating that T-cell exhaustion is a dynamic developmental process. Finally, we summarized the novel immune checkpoints associated with depletion in recent years and combined them with bioinformatics to construct a web of exhaustion-related immune checkpoints with the aim of finding novel therapeutic targets associated with T-cell exhaustion in malignant tumours, aiming to revive the killing ability of exhausted T cells and restore anti-tumour immunity through combined targeted immunotherapy.
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Affiliation(s)
- Lulu Zhang
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Bo Zhang
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Lin Li
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Yingchun Ye
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Yuchuan Wu
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Qing Yuan
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Wenfeng Xu
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, People's Republic of China
| | - Xue Wen
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China
| | - Xiyuan Guo
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China.
- Division of Clinical Chemistry, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Siji Nian
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China.
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36
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JAK-STAT Signaling Pathway in Non-Infectious Uveitis. Biochem Pharmacol 2022; 204:115236. [PMID: 36041544 DOI: 10.1016/j.bcp.2022.115236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 11/22/2022]
Abstract
Non-infectious uveitis (NIU) refers to various intraocular inflammatory disorders responsible for severe visual loss. Cytokines participate in the regulation of ocular homeostasis and NIU pathological processes. Cytokine receptors transmit signals by activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. Increasing evidence from human NIU and experimental models reveals the involvement of the JAK-STAT signaling pathway in NIU pathogenesis. Several small-molecule drugs that potentially inhibit multiple cytokine-dependent pathways are under investigation for treating autoimmune diseases, implicating possible applications for NIU treatment. This review summarizes the current understanding of the diverse roles of the JAK-STAT signaling pathway in ocular homeostasis and NIU pathology, providing a rationale for targeting JAKs and STATs for NIU treatment. Moreover, available evidence for the safety and efficacy of JAK inhibitors for refractory uveitis and potential approaches for treatment optimization are discussed.
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37
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Resilient T-cell responses in patients with advanced cancers. Int J Hematol 2022; 117:634-639. [PMID: 35864292 DOI: 10.1007/s12185-022-03424-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/21/2022] [Accepted: 07/04/2022] [Indexed: 10/17/2022]
Abstract
Although cancer burden in patients with advanced disease results in many failed prior therapies, some patients still achieve durable responses to immunotherapy implying that remnant and resilient cytotoxic T cells are present in these responders. Since patients with more resilient T cells are likely to benefit from immunotherapy, it will be important to determine how resilient T cells in patients can be identified and to define the mechanisms by which tumor-reactive resilient T cells can be generated. In this review, we summarized recent advances in research on resilient T cells in patients with advanced cancers and proposed future research directions. From there, we expect to leverage this knowledge to generate or expand the resilient T cells in patients who do not respond to initial immunotherapy and convert them into responders.
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Song J, Xu X, He S, Wang N, Bai Y, Li B, Zhang S. Exosomal hsa_circ_0017252 attenuates the development of gastric cancer via inhibiting macrophage M2 polarization. Hum Cell 2022; 35:1499-1511. [PMID: 35796939 DOI: 10.1007/s13577-022-00739-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 06/15/2022] [Indexed: 01/07/2023]
Abstract
Gastric cancer (GC) is an aggressive malignant tumor of the digestive system, with high morbidity rates. We previously demonstrated that miR-17-5p can modify tumorigenesis in GC. In addition, other studies have shown that circRNAs can regulate GC progression by sponging various miRNAs. However, the association between circRNAs and miR-17-5p in GC has not yet been explored. Hence, this study aimed to explore the possible interactions between various circRNAs and miR-17-5p using a dual-luciferase assay. CCK-8 was used to determine cell viability, and a Transwell assay was used to measure cell invasion and migration. Gene expression was assessed using quantitative reverse transcription PCR (RT-qPCR), and exosomes were identified using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Annexin V/PI staining was also used to detect cell apoptosis. These investigations collectively revealed that miR-17-5p is a target of the circRNA hsa_circ_0017252 and hsa_circ_0017252 is significantly downregulated in GC tissues. In addition, the overexpression of hsa_circ_0017252 inhibited GC cell migration by sponging of miR-17-5p, and GC cell-secreted exosomal hsa_circ_0017252 effectively inhibited macrophage M2-like polarization, which in turn suppressed GC cell invasion. Notably, exosomes containing hsa_circ_0017252 also suppressed GC tumor growth in vivo. Thus, our data suggest that the overexpression of hsa_circ_0017252 suppresses GC malignancy by sponging miR-17-5p. In addition, exosomal hsa_circ_0017252 excreted from GC cells attenuated GC progression by suppressing macrophage M2-like polarization. These findings improve our basic understanding of GC and open a novel avenue for developing more effective GC treatments.
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Affiliation(s)
- Jin Song
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China.,Beijing Institute of Chinese Medicine, Beijing, 100010, China
| | - Xiaolong Xu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China.,Beijing Institute of Chinese Medicine, Beijing, 100010, China
| | - Shasha He
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China.,Beijing Institute of Chinese Medicine, Beijing, 100010, China
| | - Ning Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China.,Beijing Institute of Chinese Medicine, Beijing, 100010, China
| | - Yunjing Bai
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China.,Beijing Institute of Chinese Medicine, Beijing, 100010, China
| | - Bo Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China. .,Beijing Institute of Chinese Medicine, Beijing, 100010, China.
| | - Shengsheng Zhang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23 Back Street, Art Museum, Beijing, 100010, China.
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Xiong J, Ran L, Zhu Y, Wang Y, Wang S, Wang Y, Lan Q, Han W, Liu Y, Huang Y, He T, Li Y, Liu L, Zhao J, Yang K. DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury. Am J Cancer Res 2022; 12:5069-5085. [PMID: 35836796 PMCID: PMC9274747 DOI: 10.7150/thno.72291] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/25/2022] [Indexed: 02/07/2023] Open
Abstract
Rationale: Acute kidney injury (AKI) is pathologically characterized by renal tubular epithelial cell (RTEC) death and interstitial inflammation, while their pathogenesis remains incompletely understood. Dual-specificity phosphatase 2 (DUSP2) recently emerges as a crucial regulator of cell death and inflammation in a wide range of diseases, but its roles in renal pathophysiology are largely unknown. Methods: The expression of DUSP2 in the kidney was characterized by histological analysis in renal tissues from patients and mice with AKI. The role and mechanism of DUSP2-mediated inhibition of tubular epithelial cell pyroptosis in AKI were evaluated both in vivo and in vitro, and confirmed in RTEC-specific deletion of DUSP2 mice. Results: Here, we show that DUSP2 is enriched in RTECs in the renal tissue of both human and mouse and mainly positions in the nucleus. Further, we reveal that loss-of-DUSP2 in RTECs not only is a common feature of human and murine AKI but also positively contributes to AKI pathogenesis. Especially, RTEC-specific deletion of DUSP2 sensitizes mice to AKI by promoting RTEC pyroptosis and the resultant interstitial inflammation. Mechanistic studies show that gasdermin D (GSDMD), which mediates RTEC pyroptosis, is identified as a transcriptional target of activated STAT1 during AKI, whereas DUSP2 as a nuclear phosphatase deactivates STAT1 to restrict GSDMD-mediated RTEC pyroptosis. Importantly, DUSP2 overexpression in RTECs via adeno-associated virus-mediated gene transfer significantly ameliorates AKI. Conclusion: Our findings demonstrate a hitherto unrecognized role of DUSP2-STAT1 axis in regulating RTEC pyroptosis in AKI, highlighting that DUSP2-STAT1 axis is an attractive therapeutic target for AKI.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Jinghong Zhao
- ✉ Corresponding authors: Ke Yang, PhD, or Jinghong Zhao, MD, PhD, Department of Nephrology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China. E-mail: or . Tel: +86-023- 68774321; Fax: +86-023- 68774321
| | - Ke Yang
- ✉ Corresponding authors: Ke Yang, PhD, or Jinghong Zhao, MD, PhD, Department of Nephrology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China. E-mail: or . Tel: +86-023- 68774321; Fax: +86-023- 68774321
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40
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Fan LM, Zhang YQ, Chen YP, Chen LL, Xu WH, Nan LH, Xu W, Lu B, Wang Y, Chu KD, Zhang JP. Cryptotanshinone ameliorates dextran sulfate sodium-induced murine acute and chronic ulcerative colitis via suppressing STAT3 activation and Th17 cell differentiation. Int Immunopharmacol 2022; 108:108894. [DOI: 10.1016/j.intimp.2022.108894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/18/2022] [Accepted: 05/23/2022] [Indexed: 11/25/2022]
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41
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Xu H, Yu AL, Zhao DP, Meng GY, Wang L, Shan M, Hu NX, Liu YL. Ursolic acid inhibits Th17 cell differentiation via STAT3/RORγt pathway and suppresses Schwann cell-mediated Th17 cell migration by reducing CXCL9/10 expression. Innate Immun 2022; 28:155-163. [PMID: 35548957 PMCID: PMC9189552 DOI: 10.1177/17534259221094559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/24/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Th17 cells represent important immune cells. Ursolic acid (UA) can regulate immune cell activities. This study was aimed to explore the effects of UA on Th17 cell differentiation and Schwann cell(SCs)-mediated migration and the potential mechanism. Naïve CD4+ T cells were isolated from rat peripheral blood, induced for Th17 cell differentiation, and treated with UA. The proportion of Th17 cells was detected by flow cytometry assay. SCs were co-cultured with Th17 cells. Th17 cell migration was detected by Transwell assay. The molecule expression was determined by Western blot and qRT-PCR. UA inhibited the Th17 cell differentiation and suppressed the STAT3/RORγt pathway. STAT3 overexpression up-regulated p-STAT3 and RORγt expression and promoted Th17 cell differentiation under the UA treatment. In LPS- and IFN-γ-stimulated-SCs, UA suppressed the expression of chemokines CXCL9/10, but had no significant effect of CCL20 expression. The expression CXCL9/10 receptor CXCR3 was higher in Th17 cells than that in Treg cells, while the expression CCL20 receptor CCR6 was lower in Th17 cells than that in Treg cells. UA, anti-CXCR3, and anti-CCR6 treatment inhibited SCs-mediated Th17 cell migration, and anti-CXCR3 exerted stronger inhibitory effect than Anti-CCR6. UA inhibited Th17 cell differentiation through STAT3/RORγt pathway and suppressed Th17 cell migration through down-regulating CXCL9/10 expression in SCs.
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Affiliation(s)
- Hua Xu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong, China
- Department of Neurology, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Ai-ling Yu
- Department of Neurology, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Da-peng Zhao
- Department of Neurology, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Guang-yuan Meng
- Clinical laboratory, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Ling Wang
- Department of Hematology, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Min Shan
- Department of Neurology, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Nai-xia Hu
- Department of Neurology, Taian City Central Hospital, Taian 271000, Shandong, China
| | - Yun-lin Liu
- Department of Neurology, Taian City Central Hospital, Taian 271000, Shandong, China
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42
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Simmons JD, Dill-McFarland KA, Stein CM, Van PT, Chihota V, Ntshiqa T, Maenetje P, Peterson GJ, Benchek P, Nsereko M, Velen K, Fielding KL, Grant AD, Gottardo R, Mayanja-Kizza H, Wallis RS, Churchyard G, Boom WH, Hawn TR. Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion. mSphere 2022; 7:e0015922. [PMID: 35695527 PMCID: PMC9241521 DOI: 10.1128/msphere.00159-22] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/10/2022] [Indexed: 11/20/2022] Open
Abstract
Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR], <0.1). The distinct monocyte transcriptional response to M. tuberculosis among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of M. tuberculosis intracellular infection. IMPORTANCE After heavy M. tuberculosis exposure, the events that determine why some individuals resist TST/IGRA conversion are poorly defined. Enrichment of the TNF signaling gene set among RSTR monocytes from multiple distinct cohorts suggests an important role for the monocyte TNF response in determining this alternative immune outcome. These TNF responses to M. tuberculosis among RSTRs may contribute to antimicrobial programs that result in early clearance or the priming of alternative (gamma interferon-independent) cellular responses.
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Affiliation(s)
- Jason D. Simmons
- TB Research & Training Center, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Kimberly A. Dill-McFarland
- TB Research & Training Center, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Catherine M. Stein
- Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Phu T. Van
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Violet Chihota
- School of Public Health, University of Witwatersrand, Johannesburg, South Africa
- The Aurum Institute, Parktown, South Africa
| | | | | | - Glenna J. Peterson
- TB Research & Training Center, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Penelope Benchek
- Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Mary Nsereko
- Uganda-CWRU Research Collaboration, Kampala, Uganda
| | | | - Katherine L. Fielding
- School of Public Health, University of Witwatersrand, Johannesburg, South Africa
- TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Alison D. Grant
- School of Public Health, University of Witwatersrand, Johannesburg, South Africa
- TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Africa Health Research Institute, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa
| | - Raphael Gottardo
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | | | - Gavin Churchyard
- School of Public Health, University of Witwatersrand, Johannesburg, South Africa
- The Aurum Institute, Parktown, South Africa
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - W. Henry Boom
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Thomas R. Hawn
- TB Research & Training Center, Department of Medicine, University of Washington, Seattle, Washington, USA
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43
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Liu H, Wu W, Sun G, Chia T, Cao L, Liu X, Guan J, Fu F, Yao Y, Wu Z, Zhou S, Wang J, Lu J, Kuang Z, Wu M, He L, Shao Z, Wu D, Chen B, Xu W, Wang Z, He K. Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity. Cell Rep Med 2022; 3:100660. [PMID: 35732156 PMCID: PMC9245059 DOI: 10.1016/j.xcrm.2022.100660] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/26/2022] [Accepted: 05/20/2022] [Indexed: 11/29/2022]
Abstract
Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.
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Affiliation(s)
- Huisi Liu
- Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Weiwei Wu
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Gangyu Sun
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Tiongsun Chia
- Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Lei Cao
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Xiaodan Liu
- Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Jian Guan
- Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Fenggen Fu
- Department of Antibody Discovery and Protein Engineering, Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Ying Yao
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Zhihai Wu
- Department of Antibody Discovery and Protein Engineering, Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Shuaixiang Zhou
- Department of Antibody Discovery and Protein Engineering, Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Jie Wang
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Jia Lu
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Zhihui Kuang
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Min Wu
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Luan He
- Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Zhiyuan Shao
- Department of Antibody Discovery and Protein Engineering, Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Dongdong Wu
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Bingliang Chen
- Department of Pharmacology and Preclinical Studies, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China
| | - Wenqing Xu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Zhizhi Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
| | - Kaijie He
- Department of Immunology, Innovent Guoqing Academy, Innovent Biologics (Suzhou) Co., Ltd., Suzhou, China.
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Pan J, Zhou L, Zhang C, Xu Q, Sun Y. Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy. Signal Transduct Target Ther 2022; 7:177. [PMID: 35665742 PMCID: PMC9166240 DOI: 10.1038/s41392-022-01038-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/28/2022] [Accepted: 05/25/2022] [Indexed: 11/09/2022] Open
Abstract
Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the "double-edged sword" function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.
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Affiliation(s)
- Jie Pan
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Lisha Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Chenyang Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China.
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
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45
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Liu B, Jin Y, Yang J, Han Y, Shan H, Qiu M, Zhao X, Liu A, Jin Y, Yin Y. Extracellular vesicles from lung tissue drive bone marrow neutrophil recruitment in inflammation. J Extracell Vesicles 2022; 11:e12223. [PMID: 35595717 PMCID: PMC9122834 DOI: 10.1002/jev2.12223] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 04/14/2022] [Accepted: 04/16/2022] [Indexed: 11/11/2022] Open
Abstract
Extracellular vesicles (EVs) are single-membrane vesicles that play an essential role in long-range intercellular communications. EV investigation has been explored largely through cell-culture systems, but it remains unclear how physiological EVs exert homeostatic or pathological functions in vivo. Here, we report that lung EVs promote chemotaxis of neutrophils in bone marrow through delivery of double stranded DNA (dsDNA). We have identified and characterized EVs containing dsDNA collected from both human and murine lung tissues using newly developed approaches. Our analysis of EV proteomics together with single-cell RNA sequencing data reveals that type II alveolar epithelial cells are the main source of the lung EVs. Furthermore, we demonstrate that the lung EVs accumulate in bone marrow and enhance neutrophil recruitment under inflammation conditions. Moreover, lung EV-DNA stimulates neutrophils to release the chemokines CXCL1 and CXCL2 via DNA-TLR9 signalling. Our findings establish a molecular basis of lung EVs in enhancement of host immune response to bacterial infection and provide new insights into understanding of vesicle-mediated systematic communications.
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Affiliation(s)
- Bowen Liu
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yuan Jin
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Jingyi Yang
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yue Han
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Shan
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Mantang Qiu
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Xuyang Zhao
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Anhang Liu
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yan Jin
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumour Systems Biology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China.,Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, China
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46
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Shetty A, Tripathi SK, Junttila S, Buchacher T, Biradar R, Bhosale S, Envall T, Laiho A, Moulder R, Rasool O, Galande S, Elo L, Lahesmaa R. A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. Nucleic Acids Res 2022; 50:4938-4958. [PMID: 35511484 PMCID: PMC9122603 DOI: 10.1093/nar/gkac256] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 03/30/2022] [Accepted: 04/19/2022] [Indexed: 12/21/2022] Open
Abstract
Th17 cells are essential for protection against extracellular pathogens, but their aberrant activity can cause autoimmunity. Molecular mechanisms that dictate Th17 cell-differentiation have been extensively studied using mouse models. However, species-specific differences underscore the need to validate these findings in human. Here, we characterized the human-specific roles of three AP-1 transcription factors, FOSL1, FOSL2 and BATF, during early stages of Th17 differentiation. Our results demonstrate that FOSL1 and FOSL2 co-repress Th17 fate-specification, whereas BATF promotes the Th17 lineage. Strikingly, FOSL1 was found to play different roles in human and mouse. Genome-wide binding analysis indicated that FOSL1, FOSL2 and BATF share occupancy over regulatory regions of genes involved in Th17 lineage commitment. These AP-1 factors also share their protein interacting partners, which suggests mechanisms for their functional interplay. Our study further reveals that the genomic binding sites of FOSL1, FOSL2 and BATF harbour hundreds of autoimmune disease-linked SNPs. We show that many of these SNPs alter the ability of these transcription factors to bind DNA. Our findings thus provide critical insights into AP-1-mediated regulation of human Th17-fate and associated pathologies.
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Affiliation(s)
| | | | | | | | - Rahul Biradar
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Santosh D Bhosale
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- Department of Biochemistry and Molecular Biology, Protein Research Group, University of Southern Denmark, Campusvej 55, Odense M, DK 5230, Denmark
| | - Tapio Envall
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
| | - Asta Laiho
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Robert Moulder
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Omid Rasool
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research (IISER), Pune 411008, India
- Department of Life Sciences, Shiv Nadar University, Delhi-NCR
| | - Laura L Elo
- Correspondence may also be addressed to Laura Elo. Tel: +358 29 450 2090;
| | - Riitta Lahesmaa
- To whom correspondence should be addressed. Tel: +358 29 450 2415;
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47
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Shahin T, Mayr D, Shoeb MR, Kuehn HS, Hoeger B, Giuliani S, Gawriyski LM, Petronczki ÖY, Hadjadj J, Bal SK, Zoghi S, Haimel M, Jimenez Heredia R, Boutboul D, Triebwasser MP, Rialland-Battisti F, Costedoat Chalumeau N, Quartier P, Tangye SG, Fleisher TA, Rezaei N, Romberg N, Latour S, Varjosalo M, Halbritter F, Rieux-Laucat F, Castanon I, Rosenzweig SD, Boztug K. Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation. Blood Adv 2022; 6:2444-2451. [PMID: 34920454 PMCID: PMC9006292 DOI: 10.1182/bloodadvances.2021006367] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/06/2021] [Indexed: 11/20/2022] Open
Abstract
Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.
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Affiliation(s)
- Tala Shahin
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Daniel Mayr
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | | | - Hye Sun Kuehn
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Birgit Hoeger
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Sarah Giuliani
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
| | - Lisa M. Gawriyski
- Proteomics Unit, Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Özlem Yüce Petronczki
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Jérôme Hadjadj
- Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM Unité Mixte de Recherche (UMR) 1163, Institut Imagine, Université de Paris, Paris, France
| | - Sevgi Köstel Bal
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Samaneh Zoghi
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran
| | - Matthias Haimel
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Raul Jimenez Heredia
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - David Boutboul
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Institut Imagine, Université de Paris, Paris, France
| | - Michael P. Triebwasser
- Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Fanny Rialland-Battisti
- Pediatric Onco-Hematology Department, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Nathalie Costedoat Chalumeau
- Internal Medicine, Cochin Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP) Centre, Université de Paris, Paris, France
| | - Pierre Quartier
- Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM Unité Mixte de Recherche (UMR) 1163, Institut Imagine, Université de Paris, Paris, France
- Department of Paediatric Immuno-Haematology and Rheumatology, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France
| | - Stuart G. Tangye
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; and
| | - Thomas A. Fleisher
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran
| | - Neil Romberg
- Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Institut Imagine, Université de Paris, Paris, France
| | - Markku Varjosalo
- Proteomics Unit, Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | | | - Frédéric Rieux-Laucat
- Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM Unité Mixte de Recherche (UMR) 1163, Institut Imagine, Université de Paris, Paris, France
| | - Irinka Castanon
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
| | - Sergio D. Rosenzweig
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Kaan Boztug
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
- St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
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48
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Cheung KL, Jaganathan A, Hu Y, Xu F, Lejeune A, Sharma R, Caescu CI, Meslamani J, Vincek A, Zhang F, Lee K, Zaware N, Qayum AA, Ren C, Kaplan MH, He JC, Xiong H, Zhou MM. HIPK2 directs cell type-specific regulation of STAT3 transcriptional activity in Th17 cell differentiation. Proc Natl Acad Sci U S A 2022; 119:e2117112119. [PMID: 35344430 PMCID: PMC9168845 DOI: 10.1073/pnas.2117112119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/11/2022] [Indexed: 12/25/2022] Open
Abstract
SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.
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Affiliation(s)
- Ka Lung Cheung
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Anbalagan Jaganathan
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Yuan Hu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Feihong Xu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Alannah Lejeune
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Rajal Sharma
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Cristina I. Caescu
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Jamel Meslamani
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Adam Vincek
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Fan Zhang
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Kyung Lee
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Nilesh Zaware
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Amina Abdul Qayum
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Chunyan Ren
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Mark H. Kaplan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - John Cijiang He
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Huabao Xiong
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ming-Ming Zhou
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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49
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Liu J, Kumar S, Hong J, Huang ZM, Paez D, Castillo M, Calvo M, Chang HW, Cummins DD, Chung M, Yeroushalmi S, Bartholomew E, Hakimi M, Ye CJ, Bhutani T, Matloubian M, Gensler LS, Liao W. Combined Single Cell Transcriptome and Surface Epitope Profiling Identifies Potential Biomarkers of Psoriatic Arthritis and Facilitates Diagnosis via Machine Learning. Front Immunol 2022; 13:835760. [PMID: 35309349 PMCID: PMC8924042 DOI: 10.3389/fimmu.2022.835760] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/03/2022] [Indexed: 11/13/2022] Open
Abstract
Early diagnosis of psoriatic arthritis (PSA) is important for successful therapeutic intervention but currently remains challenging due, in part, to the scarcity of non-invasive biomarkers. In this study, we performed single cell profiling of transcriptome and cell surface protein expression to compare the peripheral blood immunocyte populations of individuals with PSA, individuals with cutaneous psoriasis (PSO) alone, and healthy individuals. We identified genes and proteins differentially expressed between PSA, PSO, and healthy subjects across 30 immune cell types and observed that some cell types, as well as specific phenotypic subsets of cells, differed in abundance between these cohorts. Cell type-specific gene and protein expression differences between PSA, PSO, and healthy groups, along with 200 previously published genetic risk factors for PSA, were further used to perform machine learning classification, with the best models achieving AUROC ≥ 0.87 when either classifying subjects among the three groups or specifically distinguishing PSA from PSO. Our findings thus expand the repertoire of gene, protein, and cellular biomarkers relevant to PSA and demonstrate the utility of machine learning-based diagnostics for this disease.
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Affiliation(s)
- Jared Liu
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Sugandh Kumar
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Julie Hong
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Zhi-Ming Huang
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Diana Paez
- Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, CA, United States
| | - Maria Castillo
- Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, CA, United States
| | - Maria Calvo
- Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, CA, United States
| | - Hsin-Wen Chang
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Daniel D. Cummins
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Mimi Chung
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Samuel Yeroushalmi
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Erin Bartholomew
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Marwa Hakimi
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Chun Jimmie Ye
- Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, CA, United States
- Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, United States
- Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, United States
- Institute of Computational Health Sciences, University of California at San Francisco, San Francisco, CA, United States
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, United States
- Chan Zuckerberg Biohub, San Francisco, CA, United States
| | - Tina Bhutani
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
| | - Mehrdad Matloubian
- Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, CA, United States
- Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, University of California at San Francisco, San Francisco, CA, United States
| | - Lianne S. Gensler
- Division of Rheumatology, Department of Medicine, University of California at San Francisco, San Francisco, CA, United States
| | - Wilson Liao
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, United States
- Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, United States
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50
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Millrine D, Jenkins RH, Hughes STO, Jones SA. Making sense of IL-6 signalling cues in pathophysiology. FEBS Lett 2022; 596:567-588. [PMID: 34618359 PMCID: PMC9673051 DOI: 10.1002/1873-3468.14201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022]
Abstract
Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine-receptor cross-reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomized by studies of Jak-STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signal-dependent cytokine responses. Here, a regulatory interplay between STAT transcription factors and their convergence to specific genomic enhancers support the fine-tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin-6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes.
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Affiliation(s)
- David Millrine
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
- Present address:
Medical Research Council Protein Phosphorylation and Ubiquitylation UnitSir James Black CentreSchool of Life SciencesUniversity of Dundee3rd FloorDundeeUK
| | - Robert H. Jenkins
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
| | - Stuart T. O. Hughes
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
| | - Simon A. Jones
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
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