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El-Howati A, Edmans JG, Santocildes-Romero ME, Madsen LS, Murdoch C, Colley HE. A Tissue-Engineered Model of T-Cell-Mediated Oral Mucosal Inflammatory Disease. J Invest Dermatol 2025; 145:1447-1458.e3. [PMID: 39366520 DOI: 10.1016/j.jid.2024.07.038] [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: 05/07/2024] [Revised: 07/03/2024] [Accepted: 07/18/2024] [Indexed: 10/06/2024]
Abstract
T-cell-mediated oral mucocutaneous inflammatory conditions, including oral lichen planus, are common, but development of new treatments aimed at relieving symptoms and controlling oral lichen planus progression is hampered by the lack of experimental models. In this study, we developed a tissue-engineered oral mucosal equivalent containing polarized T-cells to replicate oral lichen planus pathogenesis. Peripheral blood CD4+ and CD8+ T-cells were isolated, activated, and polarized into T helper 1 and cytotoxic T cells. Oral mucosal equivalents were constructed by culturing oral keratinocytes on an oral fibroblast-populated hydrogel to produce a stratified squamous epithelium. Oral mucosal equivalent stimulated with IFN-γ and TNF-α or medium from T helper 1 cells caused increased secretion of inflammatory cytokines and chemokines. A model of T-cell-mediated inflammatory disease was developed by combining oral mucosal equivalent on top of a T helper 1 and cytotoxic T-cell-containing hydrogel, followed by epithelial stimulation with IFN-γ and TNF-α. T-cell recruitment toward the epithelium was associated with increased secretion of T-cell chemoattractants CCL5, CXCL9, and CXCL10. Histological assessment showed tissue damage associated with cleaved caspase-3 and altered laminin-5 expression. Treatment with inhibitors directed against Jak, KCa3.1 channels, or clobetasol in solution and through a mucoadhesive patch prevented cytokine and chemokine release and tissue damage. This disease model has potential to probe for mechanisms of pathogenesis or as a test platform for novel therapeutics or treatment modalities.
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Affiliation(s)
- Asma El-Howati
- School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom; Department of Oral Medicine, Faculty of Dentistry, University of Benghazi, Benghazi, Libya
| | - Jake G Edmans
- School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom; Department of Chemistry, University of Sheffield, Sheffield, United Kingdom
| | | | | | - Craig Murdoch
- School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom; Insigneo Institute, University of Sheffield, Sheffield, United Kingdom.
| | - Helen E Colley
- School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom; Insigneo Institute, University of Sheffield, Sheffield, United Kingdom
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2
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O'Reilly ML, Wulf MJ, Connors TM, Jin Y, Bearoff F, Hai N, Bouyer J, Kortagere S, Zhong Y, Bethea JR, Tom VJ. NF-κB inhibition attenuates sympathetic hyperreflexia and concomitant development of autonomic dysreflexia and immune dysfunction after spinal cord injury. Commun Biol 2025; 8:787. [PMID: 40404889 PMCID: PMC12098895 DOI: 10.1038/s42003-025-08237-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 05/15/2025] [Indexed: 05/24/2025] Open
Abstract
Heightened sympathetic reflexes (sympathetic hyperreflexia, SH) post-high-level spinal cord injury (SCI) detrimentally impact effector organs, resulting in peripheral immune dysfunction and cardiovascular disease, two leading causes of morbidity and mortality in SCI. We previously found that an activated neuroimmune system after SCI contributes to intraspinal plasticity in the spinal sympathetic reflex (SSR) circuit, underlying SH. We hypothesize that activation of NF-κB, a key regulator of inflammation, in spinal cord below-SCI contributes to driving SSR circuit plasticity, resulting in SH-associated autonomic dysreflexia (AD) and peripheral immune dysfunction. Here, we demonstrate inhibition of central NF-κB signaling via intrathecal delivery of dimethylamino parthenolide (DMAPT) significantly decreases SH post-complete transection of thoracic spinal segment 3 in adult rats. This included reduced AD severity that was associated with decreased interneuron recruitment into the SSR circuit after SCI. We also observed intrathecal DMAPT-treatment improved survival post-SCI that corresponded with normalized numbers of splenic regulatory T-cells. These findings underscore central NF-κB signaling as a key component driving SH after SCI.
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Affiliation(s)
- Micaela L O'Reilly
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Mariah J Wulf
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Theresa M Connors
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Ying Jin
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Frank Bearoff
- Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Nan Hai
- School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Julien Bouyer
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Sandhya Kortagere
- Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Yinghui Zhong
- School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - John R Bethea
- Department of Anatomy and Cell Biology, George Washington University, Washington, DC, USA
| | - Veronica J Tom
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
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3
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Ho MFS, Farkas O, Faria AV, Plemel JR, Kerr BJ. A recent history of immune cell sex differences in the peripheral nervous system in persistent pain states. Brain Behav Immun 2025; 128:766-775. [PMID: 40345628 DOI: 10.1016/j.bbi.2025.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 04/23/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025] Open
Abstract
Pain is entwined with inflammation, and biological sex often influences mechanisms of the immune system. Due to possible differences in inflammatory mechanisms, women are predisposed to autoimmune diseases and chronic pain. Despite sex as a critical variable in clinical cases of autoimmune conditions and its pain comorbidities, fundamental investigations have long underrepresented female subjects in their studies. Fundamental research in the 2010s, however, identified a binary sex specific mechanism for pain in rodents: male pain is microglia-driven while female pain is T cell-driven. Since then, studies have expanded in neuro-immunology to indicate that the sex differences and immune cells involved in these processes take on more elaborate roles when expanded to other causal modalities and anatomical levels of neuropathic and inflammatory pain. In this mini-review, we highlight updated roles for macrophages, T cells, and B cells in the peripheral nervous system during persistent pain conditions: neuropathic pain and inflammatory pain. We discuss sex similarities and sex differences in these cell types. By parsing out the sex specific roles of immune cells in persistent pain states, we may be better positioned to find immune-based therapies that can effectively target chronic pain in sex-biased autoimmune conditions.
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Affiliation(s)
- Madelene Faye S Ho
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Olivia Farkas
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Andre Vilela Faria
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Jason R Plemel
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Medicine, Division of Neurology, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Bradley J Kerr
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Physiology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
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4
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Kashkoulinejad Kouhi T. Exosome-mediated communication between T cells and dendritic cells: Implications for therapeutic strategies. Cytokine 2025; 189:156914. [PMID: 40073808 DOI: 10.1016/j.cyto.2025.156914] [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: 10/05/2024] [Revised: 02/16/2025] [Accepted: 03/07/2025] [Indexed: 03/14/2025]
Abstract
Cell communication is crucial for coordinating physiological functions in multicellular organisms, with exosomes playing a significant role. Exosomes mediate intercellular communication by transporting proteins, lipids, and nucleic acids between cells. These small, membrane-bound vesicles, derived from the endosomal pathway, are integral to various biological processes, including signal transmission and cellular behavior modulation. Recent advances highlight the potential of exosomes, especially dendritic cell-derived exosomes (DEXs), for diagnostic and therapeutic applications, particularly in cancer immunotherapy. DEXs are distinguished by their ability to present antigens and stimulate immune responses more effectively than exosomes from other cell types. They carry a cargo rich in immunostimulatory molecules and MHC-peptide complexes, which facilitate robust T-cell activation and enhance tumor-specific immune responses. The unique properties of DEXs, such as their ability to cross biological barriers and resist tumor-induced immunosuppression, position them as promising candidates for therapeutic applications. Here, I review the reports on the bidirectional interaction between dendritic cells and T cells through exosomes and their role in medicine.
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Affiliation(s)
- Tahereh Kashkoulinejad Kouhi
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; CTOAM | Cancer Treatment Options & Management, Vancouver, British Columbia, Canada.
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5
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Nour MA, Rajabivahid M, Mehdi MSS, Tahmasebi S, Dashtgol SN, Dehghani-Ghorbi M, Vanan AG, Ghorbaninezhad F. A new era in melanoma immunotherapy: focus on DCs metabolic reprogramming. Cancer Cell Int 2025; 25:149. [PMID: 40234886 PMCID: PMC12001691 DOI: 10.1186/s12935-025-03781-3] [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: 12/11/2024] [Accepted: 04/03/2025] [Indexed: 04/17/2025] Open
Abstract
Melanoma, being one of the most dangerous forms of skin cancer, is characterized by its aggressive and metastatic nature, with the potential to develop resistance to various treatments. This resistance makes the disease challenging to treat, emphasizing the need for new treatment strategies. Within the tumor microenvironment (TME), melanoma cells exploit metabolic shifts, particularly glycolysis, to create an immunosuppressive TME that prevents dendritic cells (DCs) from functioning properly. Essential metabolic alterations such as lactate and lipid accumulation, and lack of tryptophan disrupt DC maturation, antigen presentation, and T cell activation. In recent years, melanoma immunotherapy has increasingly focused on reprogramming the metabolism of DCs. This review paper aims to provide insights into the metabolic suppression of melanoma-associated DCs, allowing the design of therapeutic strategies based on metabolic interventions to promote or restore DC function. This contribution reviews the metabolic reprogramming of DCs as a new approach for melanoma immunotherapy.
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Affiliation(s)
- Mina Afrashteh Nour
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mansour Rajabivahid
- Department of Internal Medicine, Valiasr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Marjan Sadat Seyed Mehdi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepideh Nasirzadeh Dashtgol
- Department of Medical Laboratory Sciences, School of Paramedical Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Mahmoud Dehghani-Ghorbi
- Hematology-Oncology Department, Imam Hossein Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ahmad Ghorbani Vanan
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farid Ghorbaninezhad
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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6
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Salminen A. Cooperation between inhibitory immune checkpoints of senescent cells with immunosuppressive network to promote immunosenescence and the aging process. Ageing Res Rev 2025; 106:102694. [PMID: 39984130 DOI: 10.1016/j.arr.2025.102694] [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: 11/22/2024] [Revised: 12/30/2024] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
The accumulation of senescent cells within tissues promotes the aging process by remodelling the functions of the immune system. For many years, it has been known that senescent cells secrete pro-inflammatory cytokines and chemokines, a phenotype called the senescence-associated secretory phenotype (SASP). Chemokines and colony-stimulating factors stimulate myelopoiesis and recruit myeloid cells into aging tissues. Interestingly, recent studies have demonstrated that senescent cells are not only secretory but they also express an increased level of ligand proteins for many inhibitory immune checkpoint receptors. These ligands represent "don't eat me" markers in senescent cells and moreover, they are able to induce an exhaustion of many immune cells, such as surveying natural killer (NK) cells, cytotoxic CD8+ T cells, and macrophages. The programmed cell death protein-1 (PD-1) and its ligand PD-L1 represent the best known inhibitory immune checkpoint pathway. Importantly, the activation of inhibitory checkpoint receptors, e.g., in chronic inflammatory states, can also induce certain immune cells to differentiate toward their immunosuppressive phenotype. This can be observed in myeloid derived suppressor cells (MDSC), tissue regulatory T cells (Treg), and M2 macrophages. Conversely, these immunosuppressive cells stimulate in senescent cells the expression of many ligand proteins for inhibitory checkpoint receptors. Paradoxically, senescent cells not only promote the pro-inflammatory state but they maintain it at a low-grade level by expressing ligands for inhibitory immune checkpoint receptors. Thus, the cooperation between senescent cells and immunosuppressive cells enhances the senescence state of immune cells, i.e., immune senescence/exhaustion, and cellular senescence within tissues via bystander effects.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland.
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7
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Cui X, Song Y, Han J, Yuan Z. The multifaceted role of SMAD4 in immune cell function. Biochem Biophys Rep 2025; 41:101902. [PMID: 39802394 PMCID: PMC11721226 DOI: 10.1016/j.bbrep.2024.101902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.
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Affiliation(s)
- Xinmu Cui
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Yu Song
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Jianfeng Han
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
- Cellular Biomedicine Group Inc, Shanghai, 201203, China
| | - Zhaoxin Yuan
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
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8
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Mannion JM, Rahimi RA. Tissue-Resident Th2 Cells in Type 2 Immunity and Allergic Diseases. Immunol Rev 2025; 330:e70006. [PMID: 39981858 PMCID: PMC11897987 DOI: 10.1111/imr.70006] [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: 08/23/2024] [Accepted: 02/06/2025] [Indexed: 02/22/2025]
Abstract
Type 2 immunity represents a unique immune module that provides host protection against macro-parasites and noxious agents such as venoms and toxins. In contrast, maladaptive type 2 immune responses cause allergic diseases. While multiple cell types play important roles in type 2 immunity, recent studies in humans and murine models of chronic allergic diseases have shown that a distinct population of tissue-resident, CD4+ T helper type 2 (Th2) cells play a critical role in chronic allergic inflammation. The rules regulating Th2 cell differentiation have remained less well defined than other T cell subsets, but recent studies have shed new light into the specific mechanisms controlling Th2 cell biology in vivo. Here, we review our current understanding of the checkpoints regulating the development and function of tissue-resident Th2 cells with a focus on chronic allergic diseases. We discuss evidence for a barrier tissue checkpoint in initial Th2 cell priming, including the role of neuropeptides, damage-associated molecular patterns, and dendritic cell macro-clusters. Furthermore, we review the evidence for a second barrier tissue checkpoint that instructs the development of multi-cytokine producing, tissue-resident Th2 cells that orchestrate allergic inflammation. Lastly, we discuss potential approaches to therapeutically target tissue-resident Th2 cells in chronic allergic diseases.
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Affiliation(s)
- Jenny M Mannion
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Rod A Rahimi
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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9
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Gabrielli F, Bernasconi E, Toscano A, Avossa A, Cavicchioli A, Andreone P, Gitto S. Side Effects of Immunosuppressant Drugs After Liver Transplant. Pharmaceuticals (Basel) 2025; 18:342. [PMID: 40143120 PMCID: PMC11946649 DOI: 10.3390/ph18030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Liver transplantation (LT) is the standard of care for both end-stage liver failure and hepatocellular carcinoma (HCC). Side effects of the main used immunosuppressive drugs have a noteworthy impact on the long-term outcome of LT recipients. Consequently, to achieve a balance between optimal immunosuppression and minimal side effects is a cornerstone of the post-LT period. Today, there are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring, and immunosuppression regimens vary from center to center and from country to country. Currently, there are many drugs with different efficacy and safety profiles. Using different agents permits a decrease in the dosage and minimizes the toxicities. A small subset of recipients achieves immunotolerance with the chance to stop immunosuppressive therapy. This article focuses on the side effects of immunosuppressive drugs, which significantly impact long-term outcomes for LT recipients. The primary aim is to highlight the balance between achieving effective immunosuppression and minimizing adverse effects, emphasizing the role of personalized therapeutic strategies. Moreover, this review evaluates the mechanisms of action and specific complications associated with immunosuppressive agents. Finally, special attention is given to strategies for reducing immunosuppressive burdens, improving patient quality of life, and identifying immunotolerant individuals.
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Affiliation(s)
- Filippo Gabrielli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Elisa Bernasconi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Toscano
- Division of Internal Medicine, University Hospital of Policlinico G. Martino, 98124 Messina, Italy
| | - Alessandra Avossa
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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10
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Layton E, Goldsworthy S, Yang E, Ong WY, Sutherland TE, Bancroft AJ, Thompson S, Au VB, Griffiths-Jones S, Grencis RK, Fairhurst AM, Roberts IS. An optimised faecal microRNA sequencing pipeline reveals fibrosis in Trichuris muris infection. Nat Commun 2025; 16:1589. [PMID: 39939598 PMCID: PMC11822213 DOI: 10.1038/s41467-025-56698-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: 07/10/2024] [Accepted: 01/24/2025] [Indexed: 02/14/2025] Open
Abstract
The intestine is a site of diverse functions including digestion, nutrient absorption, immune surveillance, and microbial symbiosis. Intestinal microRNAs (miRNAs) are detectable in faeces and regulate barrier integrity, host-microbe interactions and the immune response, potentially offering valuable non-invasive tools to study intestinal health. However, current experimental methods are suboptimal and heterogeneity in study design limits the utility of faecal miRNA data. Here, we develop an optimised protocol for faecal miRNA detection and report a reproducible murine faecal miRNA profile in healthy mice. We use this pipeline to study faecal miRNAs during infection with the gastrointestinal helminth, Trichuris muris, revealing roles for miRNAs in fibrosis and wound healing. Intestinal fibrosis was confirmed in vivo using Hyperion® imaging mass cytometry, demonstrating the efficacy of this approach. Further applications of this optimised pipeline to study host-microbe interactions and intestinal disease will enable the generation of hypotheses and therapeutic strategies in diverse contexts.
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Affiliation(s)
- Emma Layton
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Sian Goldsworthy
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - EnJun Yang
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Wei Yee Ong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
- Microbiology and Immunology Department, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tara E Sutherland
- Institute of Medical Sciences, School of Medicine, Medical Sciences and Dentistry, University of Aberdeen, Aberdeen, UK
| | - Allison J Bancroft
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Seona Thompson
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Veonice Bijin Au
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Sam Griffiths-Jones
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Richard K Grencis
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
- The Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
| | - Anna-Marie Fairhurst
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore.
| | - Ian S Roberts
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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11
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Lu Y, Shan X, Huang J, Zhou H, Zhu Y, Wang S, Luo Z, Liu X, Guo X, Shi Y, Hu Y, Liu H, Zhang J, Huang P, Luo L, You J. Reductive Adjuvant Nanosystem for Alleviated Atopic Dermatitis Syndromes. ACS NANO 2025; 19:4195-4212. [PMID: 39846120 DOI: 10.1021/acsnano.4c08767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Atopic dermatitis (AD) is a recurrent and chronic inflammatory skin condition characterized by a high lifetime prevalence and significant impairment of patients' quality of life, primarily due to intense itching and discomfort. However, current pharmacological interventions provide only moderate efficacy and are frequently accompanied by adverse side effects. The immune-pathogenesis of AD involves dysregulation of the Th2 immune response and exacerbation of inflammation related to excessive reactive oxygen species (ROS). Therefore, to address these issues, in this study, we targeted the upstream pathogenesis by designing a pro-Th1 adjuvant nanoemulsion loaded with poly(I:C) and encapsulated with the ROS-scavenger vitamin E, termed PV-NE. PV-NE effectively rebalanced the Th1/Th2 immune response and reduced ROS levels both in vivo and ex vivo, leading to the restoration of immune balance in AD-affected skin and alleviation of symptoms such as lichenification and erythematous patches. In conclusion, our development of the reductive adjuvant nanosystem PV-NE demonstrates its biocompatibility and efficacy in combating AD progression without the use of immunosuppressant glucocorticoids. This has the potential to significantly impact the design and enhancement of pharmacotherapy in future clinical research aimed at curing AD.
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Affiliation(s)
- Yichao Lu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
- Zhejiang Provincial Clinical Research Center for Head & Neck Cancer, Hangzhou 310014, China
- Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou 310014, China
| | - Xinyu Shan
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Jiaxin Huang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Huanli Zhou
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Ying Zhu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Sijie Wang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Zhenyu Luo
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Xu Liu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Xuemeng Guo
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Yingying Shi
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Yilong Hu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Huihui Liu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Junlei Zhang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
- Zhejiang Provincial Clinical Research Center for Head & Neck Cancer, Hangzhou 310014, China
- Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou 310014, China
| | - Lihua Luo
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
- Zhejiang-California International NanoSystems Institute, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
| | - Jian You
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
- Zhejiang-California International NanoSystems Institute, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China
- Jinhua Institute of Zhejiang University, 498 Yiwu Street, Jinhua, Zhejiang 321299, P. R. China
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Sebastião AI, Simões G, Oliveira F, Mateus D, Falcão A, Carrascal MA, Gomes C, Neves B, Cruz MT. Dendritic cells in triple-negative breast cancer: From pathophysiology to therapeutic applications. Cancer Treat Rev 2025; 133:102884. [PMID: 39837068 DOI: 10.1016/j.ctrv.2025.102884] [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: 09/21/2024] [Revised: 11/28/2024] [Accepted: 01/11/2025] [Indexed: 01/23/2025]
Abstract
Breast cancer is the second most commonly diagnosed cancer in women and the fifth leading cause of cancer-related deaths worldwide. It is a highly heterogeneous disease, consisting of multiple subtypes that vary significantly in clinical characteristics and survival outcomes. Triple-negative breast cancer (TNBC) is a particularly aggressive and challenging subtype of breast cancer. Several immunotherapeutic approaches have been tested in patients with TNBC to improve disease outcomes, including the administration of dendritic cell (DC)-based vaccines. DCs are a heterogeneous cell population that play a crucial role in bridging the innate and adaptive immune systems. Therefore, DCs have been increasingly used in cancer vaccines due to their ability to prime and boost antigen specific T-cell immune responses. This review aims to provide a comprehensive overview of TNBC, including potential targets and pharmacological strategies, as well as an overview of DCs and their relevance in TNBC. In addition, we review ongoing clinical trials and shed light on the evolving landscape of DC-based immunotherapy for TNBC.
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Affiliation(s)
- Ana Isabel Sebastião
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, 3004-504, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Gonçalo Simões
- Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, 3004-504, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal; Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Filomena Oliveira
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Daniela Mateus
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, 3004-504, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal; BioMark@UC/CEB-LABBELS, Department of Chemical Engineering, Faculty of Sciences and Technology, University of Coimbra, 3030-790 Coimbra, Portugal
| | - Amílcar Falcão
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, 3000-548 Coimbra, Portugal
| | | | - Célia Gomes
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research - iCBR, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Bruno Neves
- Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal; Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Maria Teresa Cruz
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), Coimbra, 3004-504, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal.
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13
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Zhang H, Cao F, Zhou Y, Wu B, Li C. Peripheral Immune Cells Contribute to the Pathogenesis of Alzheimer's Disease. Mol Neurobiol 2025; 62:264-270. [PMID: 38842674 DOI: 10.1007/s12035-024-04266-6] [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: 12/05/2023] [Accepted: 05/26/2024] [Indexed: 06/07/2024]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder with progressive memory and cognitive loss. Neuroinflammation is a central mechanism involved in the progression of AD. With the disruption of the blood-brain barrier (BBB), peripheral immune cells and inflammatory molecules enter into AD brain. However, the exact relationship between peripheral immune cells and AD remains unknown due to various challenges. This study aimed to investigate the potential causal association between peripheral immune cells and AD by using a two-sample Mendelian randomization (TSMR) analysis. We conducted a TSMR to decipher the causal relationship between AD and 731 types of peripheral immune cell parameters from the TBNK, regulatory T cell (Treg), myeloid cell, monocyte, maturation stages of T cell, dendritic cell (DC), and B cell panels. Various analytical methods were employed, including inverse variance weighting (IVW), MR Egger, and weighted median methods. The Cochran's Q statistic, MR-Egger intercept, and MR-PRESSO tests were used to verify the heterogeneity and horizontal pleiotropy of the results. To further verify our results, we also conducted a replication analysis. The analysis identified CD33 on CD14 + monocyte (OR = 1.03; 95% CI, 1.01-1.04; p = 1.14E-04; adjust-p = 0.042) had an increased risk association for AD, which was verified by the replication study. CD33 on CD33dim HLA DR + CD11b- cell (OR = 1.02; 95% CI, 1.01-1.04; p = 2.87E-04; adjust-p = 0.035) had an increased risk association for AD, while secreting CD4 regulatory T cell %CD4 regulatory T cell (OR = 0.97; 95% CI, 0.96-0.99; p = 1.90E-04; adjust-p = 0.046) and CD25 on switched memory B cell (OR = 0.95; 95% CI, 0.92-0.98; p = 2.87E-04; adjust-p = 0.042) were discovered to be related to a lower risk of AD. However, the causal effect of these three immune cells on AD was insufficiently validated in the replication analysis. The MR analysis suggests a potential causal relationship between peripheral immune cells and the risk of AD. Further extensive research is needed on the specific role of peripheral immune cells in AD.
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Affiliation(s)
- Houwen Zhang
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fangzheng Cao
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yu Zhou
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Bin Wu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chunrong Li
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China.
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14
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Kania AK, Kokkinou E, Pearce E, Pearce E. Metabolic adaptations of ILC2 and Th2 cells in type 2 immunity. Curr Opin Immunol 2024; 91:102503. [PMID: 39520759 DOI: 10.1016/j.coi.2024.102503] [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: 07/19/2024] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
Type 2 immune responses play a crucial role in host defense against parasitic infections but can also promote the development of allergies and asthma. This response is orchestrated primarily by group 2 innate lymphoid cells (ILC2) and helper type 2 (Th2) cells, both of which undergo substantial metabolic reprogramming as they transition from resting to activated states. Understanding these metabolic adaptations not only provides insights into the fundamental biology of ILC2 and Th2 cells but also opens up potential therapeutic avenues for the identification of novel metabolic targets that can extend the current treatment regimens for diseases in which type 2 immune responses play pivotal roles. By integrating recent findings, this review underscores the significance of cellular metabolism in orchestrating immune functions and highlights future directions for research in this evolving field.
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Affiliation(s)
- Anna K Kania
- Bloomberg Kimmel Institute of Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Efthymia Kokkinou
- Bloomberg Kimmel Institute of Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Erika Pearce
- Bloomberg Kimmel Institute of Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Edward Pearce
- Bloomberg Kimmel Institute of Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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15
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Fan X, Qu PY, Luan KF, Sun CY, Ren HP, Sun XH, Lan J. A cleaved adhesin DNA vaccine targeting dendritic cell against Porphyromonas gingivalis-induced periodontal disease. Mol Oral Microbiol 2024; 39:433-445. [PMID: 38696249 DOI: 10.1111/omi.12465] [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: 12/28/2023] [Revised: 02/28/2024] [Accepted: 04/09/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Arg-gingipain A (RgpA) is the primary virulence factor of Porphyromonas gingivalis and contains hemagglutinin adhesin (HA), which helps bacteria adhere to cells and proteins. Hemagglutinin's functional domains include cleaved adhesin (CA), which acts as a hemagglutination and hemoglobin-binding actor. Here, we confirmed that the HA and CA genes are immunogenic, and using adjuvant chemokine to target dendritic cells (DCs) enhanced protective autoimmunity against P. gingivalis-induced periodontal disease. METHODS C57 mice were immunized prophylactically with pVAX1-CA, pVAX1-HA, pVAX1, and phosphate-buffered saline (PBS) through intramuscular injection every 2 weeks for a total of three administrations before P. gingivalis-induced periodontitis. The DCs were analyzed using flow cytometry and ribonucleic acid sequencing (RNA-seq) transcriptomic assays following transfection with CA lentivirus. The efficacy of the co-delivered molecular adjuvant CA DNA vaccine was evaluated in vivo using flow cytometry, immunofluorescence techniques, and micro-computed tomography. RESULTS After the immunization, both the pVAX1-CA and pVAX1-HA groups exhibited significantly elevated P. gingivalis-specific IgG and IgG1, as well as a reduction in bone loss around periodontitis-affected teeth, compared to the pVAX1 and PBS groups (p < 0.05). The expression of CA promoted the secretion of HLA, CD86, CD83, and DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) in DCs. Furthermore, the RNA-seq analysis revealed a significant increase in the chemokine (C-C motif) ligand 19 (p < 0.05). A notable elevation in the quantities of DCs co-labeled with CD11c and major histocompatibility complex class II, along with an increase in interferon-gamma (IFN-γ) cells, was observed in the inguinal lymph nodes of mice subjected to CCL19-CA immunization. This outcome effectively illustrated the preservation of peri-implant bone mass in rats afflicted with P. gingivalis-induced peri-implantitis (p < 0.05). CONCLUSIONS The co-administration of a CCL19-conjugated CA DNA vaccine holds promise as an innovative and targeted immunization strategy against P. gingivalis-induced periodontitis and peri-implantitis.
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Affiliation(s)
- Xin Fan
- Department of Stomatology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Peng-Yu Qu
- Department of Stomatology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Ke-Feng Luan
- Department of Stomatology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Chen-Yu Sun
- Department of Stomatology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Hui-Ping Ren
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Xue-Hui Sun
- Department of Stomatology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Jing Lan
- School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
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16
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Leyva-Castillo JM, Das M, Strakosha M, McGurk A, Artru E, Kam C, Alasharee M, Wesemann DR, Tomura M, Karasuyama H, Brombacher F, Geha RS. IL-4 acts on skin-derived dendritic cells to promote the T H2 response to cutaneous sensitization and the development of allergic skin inflammation. J Allergy Clin Immunol 2024; 154:1462-1471.e3. [PMID: 38996877 PMCID: PMC11625010 DOI: 10.1016/j.jaci.2024.06.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 06/06/2024] [Accepted: 06/24/2024] [Indexed: 07/14/2024]
Abstract
BACKGROUND Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells. OBJECTIVE We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. METHODS DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4+ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. RESULTS Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4-/- mice and CD11c-CreIl4rflox/- mice, which lack IL-4Rα expression in DCs (DCΔ/Δll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DCΔ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. CONCLUSIONS Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.
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Affiliation(s)
| | - Mrinmoy Das
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass
| | - Maria Strakosha
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass
| | - Alex McGurk
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass
| | - Emilie Artru
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass
| | - Christy Kam
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass
| | - Mohammed Alasharee
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass
| | - Duane R Wesemann
- Division of Allergy and Clinical Immunology, Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Broad Institute, Cambridge, Mass; Ragon Institute, Cambridge, Mass
| | - Michio Tomura
- Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Hajime Karasuyama
- Inflammation, Infection and Immunity Laboratory, Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Frank Brombacher
- International Center for Genetic Engineering and Biotechnology & University of Cape Town & South Africa Medical Research Council, Cape Town, South Africa
| | - Raif S Geha
- Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass.
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17
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Wang K, Cunha E Rocha K, Qin H, Zeng Z, Ying W. Host metabolic inflammation fueled by bacterial DNA. Trends Endocrinol Metab 2024:S1043-2760(24)00294-7. [PMID: 39609222 DOI: 10.1016/j.tem.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 10/29/2024] [Accepted: 11/06/2024] [Indexed: 11/30/2024]
Abstract
Metabolic diseases, characterized by chronic low-grade inflammation, exhibit a compromised gut barrier allowing the translocation of bacteria-derived products to bloodstream and distant metabolic organs. Bacterial DNA can be detected in metabolic tissues during the onset of these diseases, highlighting its role in the development of metabolic diseases. Extracellular vesicles (EVs) are involved in the delivery of bacterial DNA to the local tissues, and its sensing by the host triggers local and system inflammation. Understanding bacterial DNA translocation and its induced inflammation is crucial in deciphering metabolic disease pathways. Here, we delve into the mechanisms dictating the interaction between host physiology and bacterial DNA, focusing on its origin and delivery, host immune responses against it, and its roles in metabolic disorders.
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Affiliation(s)
- Ke Wang
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Karina Cunha E Rocha
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Houji Qin
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Zixuan Zeng
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Wei Ying
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
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18
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Verstegen NJM, Jorritsma T, ten Brinke A, Barberis M, van Ham SM. TCR-CD3 signal strength regulates plastic coexpression of IL-4 and IFN-γ in Tfh-like cells. Front Immunol 2024; 15:1481243. [PMID: 39582865 PMCID: PMC11581847 DOI: 10.3389/fimmu.2024.1481243] [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: 08/15/2024] [Accepted: 10/14/2024] [Indexed: 11/26/2024] Open
Abstract
The development of T follicular helper (Tfh) cells is an ongoing process resulting in the formation of various Tfh subsets. Despite advancements, the precise impact of T cell receptor (TCR) stimulation on this process remains incompletely understood. This study explores how TCR-CD3 signaling strength influences naive CD4+ T cell differentiation into Tfh-like cells and the concurrent expression of interleukin-21 (IL-21), interleukin-4 (IL-4), and interferon-gamma (IFN-γ). Strong TCR-CD3 stimulation induces proliferation and increased IL-21 expression in Tfh-like cells, which exhibit a characteristic phenotype expressing CXCR5 and PD1. The coexpression of IL-4 and IFN-γ in IL-21-producing Tfh-like cells is controlled by the strength TCR-CD3 stimulation; low stimulation favors IL-4, while strong stimulation enhances IFN-γ secretion. Exogenous addition of the effector cytokines IL-21 and IL-4 further modulate cytokine coexpression. These findings highlight the intricate regulatory mechanisms governing cytokine production and plasticity in Tfh-like cells, providing insights into B cell response modulation. In vivo, antigen availability may regulate Tfh cell plasticity, impacting subsequent B cell differentiation, emphasizing the need for further exploration through animal models or antigen-specific Tfh cell analyses in human lymph node biopsies.
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Affiliation(s)
- Niels J. M. Verstegen
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
| | - Tineke Jorritsma
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Anja ten Brinke
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Matteo Barberis
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
- Molecular Systems Biology, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
- Centre for Mathematical and Computational Biology (CMCB), University of Surrey, Guildford, United Kingdom
| | - S. Marieke van Ham
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
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Teng F, Ju X, Gao Z, Xu J, Li Y, Wang Y, Zou B, Yu J. Perioperative immunotherapy for patients with EGFR mutant non-small cell lung cancer: Unexpected potential benefits. Biochim Biophys Acta Rev Cancer 2024; 1879:189194. [PMID: 39413856 DOI: 10.1016/j.bbcan.2024.189194] [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: 05/30/2024] [Revised: 09/01/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024]
Abstract
Given that immunotherapy has resulted in a significant overall survival (OS) benefit in advanced-stage disease, it is of notable interest to determine the effectiveness of these agents in early-stage non-small cell lung cancer (NSCLC). The potential exists for the immunotherapeutic approach in early-stage NSCLC to mirror the paradigm seen in advanced NSCLC, wherein survival enhancements have notably benefited the majority of patients. However, their performance in early-stage epidermal growth factor receptor (EGFR) mutant NSCLC is controversial. In the limited studies that included patients with EGFR mutation status, we found unexpected, good survival benefits of perioperative immune checkpoint inhibitors (ICIs) in resectable EGFR-positive NSCLC, which is controversial with those in advanced EGFR-mutant NSCLC. It is possible because of the shift toward immunosuppression that the immune environment undergoes during tumor progression. In the early disease stages, the anti-tumor immune response can be activated with fewer hindrances. In the context of EGFR mutant tumors, intratumor genetic heterogeneity can generate treatment-sensitive and -resistant subclones. The subclonality of the resistant subclone is pivotal in therapy response, with tyrosine kinase inhibitors (TKIs) selectively controlling EGFR-mutant cell proliferation and "competitive release" potentially explaining lower pathological responses in adjuvant TKIs trials. This review delves into emerging data on perioperative treatment modalities for early-stage EGFR mutant NSCLC, exploring unique mechanisms and predictive biomarkers to guide perioperative management strategies.
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Affiliation(s)
- Feifei Teng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Xiao Ju
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhenhua Gao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Junhao Xu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yikun Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yungang Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Bingwen Zou
- Department of Radiation Oncology, West China Hospital of Sichuan University, Sichuan, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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20
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Brombacher EC, Patente TA, van der Ham AJ, Moll TJ, Otto F, Verheijen FW, Zaal EA, de Ru AH, Tjokrodirijo RT, Berkers CR, van Veelen PA, Guigas B, Everts B. AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism. J Cell Biol 2024; 223:e202401024. [PMID: 39115541 PMCID: PMC11310580 DOI: 10.1083/jcb.202401024] [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: 01/05/2024] [Revised: 05/30/2024] [Accepted: 07/10/2024] [Indexed: 09/13/2024] Open
Abstract
Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.
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Affiliation(s)
- Eline C. Brombacher
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Thiago A. Patente
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Alwin J. van der Ham
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Tijmen J.A. Moll
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Frank Otto
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Fenne W.M. Verheijen
- Department Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands
| | - Esther A. Zaal
- Department Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands
| | - Arnoud H. de Ru
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | | | - Celia R. Berkers
- Department Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands
| | - Peter A. van Veelen
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Bart Everts
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
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21
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Tan KBC, Alexander HD, Linden J, Murray EK, Gibson DS. Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro. Exp Mol Pathol 2024; 139:104924. [PMID: 39208564 DOI: 10.1016/j.yexmp.2024.104924] [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: 01/09/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
AIMS Phytocannabinoids and terpenes from Cannabis sativa have demonstrated limited anti-inflammatory and analgesic effects in several inflammatory conditions. In the current study, we test the hypothesis that phytocannabinoids exert immunomodulatory effects in vitro by decreasing inflammatory cytokine expression and activation. KEY METHODS CD3/CD28 and lipopolysaccharide activated peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 6) were treated with phytocannabinoid compounds and terpenes in vitro. Flow cytometry was used to determine regulatory T cell (Treg) and T helper 17 (Th17) cell responses to treatments. Cell pellets were harvested for qRT-PCR gene expression analysis of cytokines, cell activation markers, and inflammation-related receptors. Cell culture supernatants were analysed by ELISA to quantify IL-6, TNF-α and IL-10 secretion. MAIN FINDINGS In an initial screen of 20 μM cannabinoids and terpenes which were coded to blind investigators, cannabigerol (GL4a), caryophyllene oxide (GL5a) and gamma-terpinene (GL6a) significantly reduced cytotoxicity and gene expression levels of IL6, IL10, TNF, TRPV1, CNR1, HTR1A, FOXP3, RORC and NFKΒ1. Tetrahydrocannabinol (GL7a) suppression of T cell activation was associated with downregulation of RORC and NFKΒ1 gene expression and reduced IL-6 (p < 0.0001) and IL10 (p < 0.01) secretion. Cannabidiol (GL1b) significantly suppressed activation of Tregs (p < 0.05) and Th17 cells (p < 0.05) in a follow-on in vitro dose-response study. IL-6 (p < 0.01) and IL-10 (p < 0.01) secretion was significantly reduced with 50 μM cannabidiol. SIGNIFICANCE The study provides the first evidence that cannabidiol and tetrahydrocannabinol suppress extracellular expression of both anti- and pro-inflammatory cytokines in an in vitro PBMC model of inflammation.
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Affiliation(s)
- Kyle B C Tan
- Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Londonderry BT47 6SB, United Kingdom
| | - H Denis Alexander
- Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Londonderry BT47 6SB, United Kingdom
| | - James Linden
- GreenLight Pharmaceuticals Ltd, Unit 2, Block E, Nutgrove Office Park, Dublin 14, Ireland
| | - Elaine K Murray
- Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Londonderry BT47 6SB, United Kingdom
| | - David S Gibson
- Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Londonderry BT47 6SB, United Kingdom.
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22
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You H, Shin U, Kwon DH, Hwang J, Lee GY, Han SN. The effects of in vitro vitamin D treatment on glycolytic reprogramming of bone marrow-derived dendritic cells from Ldlr knock-out mouse. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167436. [PMID: 39067537 DOI: 10.1016/j.bbadis.2024.167436] [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: 01/29/2024] [Revised: 07/14/2024] [Accepted: 07/18/2024] [Indexed: 07/30/2024]
Abstract
Dendritic cells (DCs) undergo glycolytic reprogramming, a metabolic conversion process essential for their activation. Vitamin D has been reported to affect the function of DCs, but studies in metabolic diseases are insufficient. This study investigates the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on glycolytic reprogramming of bone marrow-derived dendritic cells (BMDCs) from control, obese, and atherosclerosis mice. Six-week-old male C57BL/6J mice were fed a control diet (CON) or a Western diet (WD), and B6.129S7-Ldlrtm1Her/J mice were fed a Western diet (LDLR-/-) for 16 weeks. BMDCs were cultured in a medium containing 1,25(OH)2D3 (10 nM) for 7 days and stimulated with lipopolysaccharide (LPS, 50 ng/mL) for 24 h. In mature BMDCs, 1,25(OH)2D3 treatment decreased basal and compensatory glycolytic proton efflux rates (glycoPER), the expression of surface markers related to immune function of DCs (MHC class II, CD80, and CD86), and IL-12p70 production. In addition, mTORC1 activation and nitric oxide (NO) production were suppressed by 1,25(OH)2D3 treatment in mature BMDCs. The effect of 1,25(OH)2D3 treatment on IL-12p70 production and mTORC1 activity in the LDLR-/- group was greater than in the CON group. These findings suggest that vitamin D can affect the metabolic environment of BMDCs by regulating glycolytic reprogramming as well as by inducing tolerogenic phenotypes of DCs.
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Affiliation(s)
- Hyeyoung You
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea
| | - Ungue Shin
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea
| | - Deok Hoon Kwon
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea
| | - Jungwon Hwang
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea
| | - Ga Young Lee
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea
| | - Sung Nim Han
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea; Research Institute of Human Ecology, College of Human Ecology, Seoul National University, Seoul, Republic of Korea.
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23
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Khan K, Burki S, Alsaiari AA, Alhuthali HM, Alharthi NS, Jalal K. A therapeutic epitopes-based vaccine engineering against Salmonella enterica XDR strains for typhoid fever: a Pan-vaccinomics approach. J Biomol Struct Dyn 2024; 42:8559-8573. [PMID: 37578072 DOI: 10.1080/07391102.2023.2246587] [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: 12/20/2022] [Accepted: 08/05/2023] [Indexed: 08/15/2023]
Abstract
A prevalent food-borne pathogen, Salmonella enterica serotypes Typhi, is responsible for gastrointestinal and systemic infections globally. Salmonella vaccines are the most effective, however, producing a broad-spectrum vaccine remains challenging due to Salmonella's many serotypes. Efforts are urgently required to develop a novel vaccine candidate that can tackle all S. Typhi strains because of their high resistance to multiple kinds of antibiotics (particularly the XDR H58 strain). In this work, we used a computational pangenome-based vaccine design technique on all available (n = 119) S. Typhi reference genomes and identified one TonB-dependent siderophore receptor (WP_001034967.1) as highly conserved and prospective vaccine candidates from the predicted core genome (n = 3,351). The applied pan-proteomics and Immunoinformatic approaches help in the identification of four epitopes that may trigger adequate host body immune responses. Furthermore, the proposed vaccine ensemble demonstrates a stable binding conformation with the examined immunological receptor (HLAs and TRL2/4) and has large interaction energy determined via molecular docking and molecular dynamics simulation techniques. Eventually, an expression vector for the Escherichia. coli K12 strain was constructed from the vaccine sequence. Additional analysis revealed that the vaccine may help to elicit strong immune responses for typhoid infections, however, experimental analysis is required to verify the vaccine's effectiveness based on these results. Moreover, the applied computer-assisted vaccine design may considerably decrease vaccine development costs and speed up the process. The study's findings are intriguing, but they must be evaluated in the experimental labs to confirm the developed vaccine's biological efficiency against XDR S. Typhi.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Kanwal Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Samiullah Burki
- Department of Pharmacology, Institute of Pharmaceutical Sciences, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Ahad Amer Alsaiari
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Nahed S Alharthi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Khurshid Jalal
- HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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24
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Ren H, Zhu A, Yang W, Jia Y, Cheng H, Wu Y, Tang Z, Ye W, Sun M, Xie Y, Yu M, Chen Y. 2D Differential Metallic Immunopotentiators Drive High Diversity and Capability of Antigen-specific Immunity Against Tumor. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405729. [PMID: 39225346 PMCID: PMC11516112 DOI: 10.1002/advs.202405729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/27/2024] [Indexed: 09/04/2024]
Abstract
The therapeutic efficacy of vaccines for treating cancers in clinics remains limited. Here, a rationally designed cancer vaccine by placing immunogenically differential and clinically approved aluminum (Al) or manganese (Mn) in a 2D nanosheet (NS) architecture together with antigens is reported. Structurally optimal NS with a high molar ratio of Mn to Al (MANS-H) features distinctive immune modulation, markedly promoting the influx of heterogeneous innate immune cells at the injection site. Stimulation of multiple subsets of dendritic cells (DCs) significantly increases the levels, subtypes, and functionalities of antigen-specific T cells. MANS-H demonstrates even greater effectiveness in the production of antigen-specific antibodies than the commercial adjuvant (Alhydrogel) by priming T helper (Th)2 cells rather than T follicular helper (Tfh) cells. Beyond humoral immunity, MANS-H evokes high frequencies of antigen-specific Th1 and CD8+ cell immunity, which are comparable with Quil-A that is widely used in veterinary vaccines. Immunized mice with MANS-H adjuvanted vaccines exert strong potency in tumor regression by promoting effector T cells infiltrating at tumor and overcoming tumor resistance in multiple highly aggressive tumor models. The engineered immunogen with an intriguing NS architecture and safe immunopotentiators offers the next clinical advance in cancer immunotherapy.
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Affiliation(s)
- Hongze Ren
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
- School of medicineShanghai UniversityShanghai200444China
| | - Anqi Zhu
- Department of Medical UltrasoundShanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghai200070China
| | - Wei Yang
- Department of UrologyXinhua HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200092China
| | - Yiwen Jia
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
| | - Hui Cheng
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
| | - Ye Wu
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
- School of medicineShanghai UniversityShanghai200444China
| | - Zhengqi Tang
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
| | - Weifan Ye
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
| | - Mayu Sun
- Laboratory CenterShanghai Municipal Hospital of Traditional Chinese MedicineShanghai University of Traditional Chinese MedicineShanghai201203China
| | - Yujie Xie
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
- School of medicineShanghai UniversityShanghai200444China
| | - Meihua Yu
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
| | - Yu Chen
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai200444China
- School of medicineShanghai UniversityShanghai200444China
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25
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Lensch V, Gabba A, Hincapie R, Bhagchandani SH, Basak A, Alam MM, Noble J, Irvine DJ, Shalek AK, Johnson JA, Finn MG, Kiessling LL. Carbohydrate-Lectin Interactions Reprogram Dendritic Cells to Promote Type 1 Anti-Tumor Immunity. ACS NANO 2024; 18:26770-26783. [PMID: 39283240 PMCID: PMC11646345 DOI: 10.1021/acsnano.4c07360] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) is thought to shape immunity by directing T cell function. Controlling downstream responses, however, remains a major challenge. A critical goal in advancing vaccine development involves the identification of receptors that drive type 1 cellular immunity. The immune system monitors cells for aberrant glycosylation (a sign of a foreign entity), but potent activation occurs when a second signal, such as single-stranded RNA or lipopolysaccharide, is present to activate TLR signaling. To exploit dual signaling, we engineered a glycan-costumed virus-like particle (VLP) vaccine that displays a DC-SIGN-selective aryl mannose ligand and encapsulates TLR7 agonists. These VLPs deliver programmable peptide antigens to induce robust DC activation and type 1 cellular immunity. In contrast, VLPs lacking this critical DC-SIGN ligand promoted DC-mediated humoral immunity, offering limited tumor control. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, significantly inhibiting tumor growth in a murine melanoma model. The tailored VLPs also afforded protection against the reintroduction of tumor cells. Thus, DC lectin-driven immune reprogramming, combined with the modular programmability of VLP platforms, provides a promising framework for directing cellular immunity to advance cancer immunotherapies and vaccines.
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Affiliation(s)
- Valerie Lensch
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Adele Gabba
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Robert Hincapie
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Sachin H Bhagchandani
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Ankit Basak
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Mohammad Murshid Alam
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Jeffery Noble
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Darrell J Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, United States
| | - Alex K Shalek
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Jeremiah A Johnson
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - M G Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Laura L Kiessling
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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26
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Tehrani HG, Rezaei M, Mehrabian F, Naghshineh E, Moghoofei M. Viral Infection in Endometritis: Is There an Important Role or Not? Am J Reprod Immunol 2024; 92:e13930. [PMID: 39302213 DOI: 10.1111/aji.13930] [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: 08/06/2024] [Accepted: 08/30/2024] [Indexed: 09/22/2024] Open
Abstract
Chronic endometritis (CE) is a frequent pathological condition that is defined as localized inflammation in the endometrium. Some adverse fertility consequences such as recurrent miscarriage and failure of implantation are associated with chronic endometritis. On the one hand, inflammation plays an important role in the pathogenesis of endometritis, and on the other hand, the role of viral infections in inducing inflammation can make this review strongly attractive and practical. We set out to provide an overview of viral infections as a potential etiology of CE pathophysiology through the alteration of an endometrial microenvironment and its association with infertility. To the best of our knowledge, this is the first review to demonstrate the role of viral infection in chronic endometritis, and whether or not infection ultimately plays a role..
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Affiliation(s)
- Hatav Ghasemi Tehrani
- Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Rezaei
- Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ferdous Mehrabian
- Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elham Naghshineh
- Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Moghoofei
- Infectious Diseases Research Center, Health Research Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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27
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Yuan Y. Imbalance of dendritic cell function in pulmonary fibrosis. Cytokine 2024; 181:156687. [PMID: 38963940 DOI: 10.1016/j.cyto.2024.156687] [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: 03/23/2024] [Revised: 05/08/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
Pulmonary fibrosis (PF) is a chronic, irreversible interstitial lung disease. The pathogenesis of PF remains unclear, and there are currently no effective treatments or drugs that can completely cure PF. The primary cause of PF is an imbalance of inflammatory response and inappropriate repair following lung injury. Dendritic cells (DCs), as one of the immune cells in the body, play an important role in regulating immune response, immune tolerance, and promoting tissue repair following lung injury. However, the role of DCs in the PF process is ambiguous or even contradictory in the existing literature. On the one hand, DCs can secrete transforming growth factor β(TGF-β), stimulate Th17 cell differentiation, stimulate fibroblast proliferation, and promote the generation of inflammatory factors interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α), thereby promoting PF. On the other hand, DCs suppress PF through mechanisms including the secretion of IL-10 to inhibit effector T cell activity in the lungs and promote the function of regulatory T cells (Tregs), as well as by expressing matrix metalloproteinases (MMPs) which facilitate the degradation of the extracellular matrix (ECM). This article will infer possible reasons for the different roles of DCs in PF and analyze possible reasons for the functional imbalance of DCs in pulmonary fibrosis from the complexity and changes of the pulmonary microenvironment, autophagy defects of DCs, and changes in the pulmonary physical environment.
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Affiliation(s)
- Yuan Yuan
- Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China.
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28
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Cheon J, Kim B, Lee J, Shin J, Kim TH. Functions and Clinical Applications of Extracellular Vesicles in T H2 Cell-Mediated Airway Inflammatory Diseases: A Review. Int J Mol Sci 2024; 25:9455. [PMID: 39273399 PMCID: PMC11394744 DOI: 10.3390/ijms25179455] [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: 07/29/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Type 2 airway inflammation (T2AI), driven by type 2 innate lymphoid and CD4+ T helper 2 cells, leads to various diseases and conditions, such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma. Emerging evidence suggests the involvement of extracellular vesicles (EVs) in these diseases. In this review, we describe the immunological T2AI pathogenic mechanisms, outline EV characteristics, and highlight their applications in the diagnosis and treatment of T2AI. An extensive literature search was conducted using appropriate strategies to identify relevant articles from various online databases. EVs in various biological samples showed disease-specific characteristics for chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma, with some demonstrating therapeutic effects against these conditions. However, most studies have been limited to in vitro and animal models, highlighting the need for further clinical research on the diagnostic and therapeutic applications of EVs.
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Affiliation(s)
- Jaehwan Cheon
- Department of Biomedical Science, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Byoungjae Kim
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Neuroscience Research Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Juhyun Lee
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Mucosal Immunology Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Jaemin Shin
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Mucosal Immunology Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Tae Hoon Kim
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Mucosal Immunology Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
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29
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Vardam-Kaur T, Banuelos A, Gabaldon-Parish M, Macedo BG, Salgado CL, Wanhainen KM, Zhou MH, van Dijk S, Santiago-Carvalho I, Beniwal AS, Leff CL, Peng C, Tran NL, Jameson SC, Borges da Silva H. The ATP-exporting channel Pannexin 1 promotes CD8 + T cell effector and memory responses. iScience 2024; 27:110290. [PMID: 39045105 PMCID: PMC11263643 DOI: 10.1016/j.isci.2024.110290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/17/2024] [Accepted: 06/14/2024] [Indexed: 07/25/2024] Open
Abstract
Sensing of extracellular ATP (eATP) controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin 1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses in vivo, however, has not been previously addressed. Here, we report that T-cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ T cell responses. Panx1 favors initial effector CD8+ T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ T cells through distinct purinergic receptors and different metabolic and signaling pathways.
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Affiliation(s)
- Trupti Vardam-Kaur
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | - Alma Banuelos
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | | | - Bruna Gois Macedo
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | | | | | - Maggie Hanqi Zhou
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | - Sarah van Dijk
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | | | - Angad S. Beniwal
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | - Chloe L. Leff
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | - Changwei Peng
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Nhan L. Tran
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
| | - Stephen C. Jameson
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Henrique Borges da Silva
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85255, USA
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Fang Q, Wu W, Xiao Z, Zeng D, Liang R, Wang J, Yuan J, Su W, Xu X, Zheng Y, Lai T, Sun J, Fu Q, Zheng SG. Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models. iScience 2024; 27:109818. [PMID: 38766356 PMCID: PMC11099335 DOI: 10.1016/j.isci.2024.109818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/25/2024] [Accepted: 04/24/2024] [Indexed: 05/22/2024] Open
Abstract
Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.
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Affiliation(s)
- Qiannan Fang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
- Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Wenbin Wu
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zexiu Xiao
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Donglan Zeng
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rongzhen Liang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
| | - Julie Wang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Jia Yuan
- Division of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yue Zheng
- Department of Dermatology Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tianwen Lai
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jianbo Sun
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Qingling Fu
- Otorhinolaryngology Department, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Song Guo Zheng
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
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Park MK, Park HK, Yu HS. The Recombinant Profilin from Free-Living Amoebae Induced Allergic Immune Responses via TLR2. J Inflamm Res 2024; 17:2915-2925. [PMID: 38764493 PMCID: PMC11100517 DOI: 10.2147/jir.s450866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/25/2024] [Indexed: 05/21/2024] Open
Abstract
Background Repeated exposure to recombinant profilin from Acanthamoeba (rAc-PF) induces allergic airway responses in vitro and in vivo. Based on the role of toll-like receptors (TLRs) in allergic airway diseases, TLRs play a central role in innate immune responses and the adaptive immune system and regulate responses against antigens through antigen-specific receptors. In this study, we attempted to determine the molecular mechanisms underlying rAc-PF-induced allergic inflammatory responses. Methods We determined the correlation between rAc-PF and TLRs and analyzed changes in allergic immune responses after blocking multiple TLR signaling under rAc-PF treatment conditions in vitro. We also compared allergic inflammatory responses in TLR2 knockout (KO) and wild-type (WT) mice. To investigate the effect of TLR2 on antigen prototyping and T cell activation in the inflammatory response induced by rAc-PF, we assessed maturation of BMDCs and polarization of naïve T cells by rAc-PF stimulation. Additionally, we compared changes in inflammation-related gene expression by rAc-PF treatment in primary lung epithelial cells isolated from TLR2 KO and WT mice. Results The rAc-PF treatment was increased the expression level of TLR2 and 9 in vitro. But, there were not significantly differ the others TLRs expression by rAc-PF treated group. And then, the mRNA expression levels of inflammation-related genes were reduced in the TLR2 or TLR9 antagonist-treated groups compared to those in the rAc-PF alone, were no difference the treated with the other TLRs (TLR4, 6, and 7/8) antagonist. The difference was higher in the TLR2 antagonist group. Additionally, the levels of airway inflammatory disease indicators were lower in the TLR2 KO group than in the WT group after rAc-PF treatment. Furthermore, the expression of bone marrow-derived dendritic cell (BMDC) surface molecular markers following rAc-PF stimulation was lower in TLR2 KO mice than in WT mice, and TLR2 KO in BMDCs resulted in a remarkable decline in Th2/17-related cytokine production and Th2/17 subset differentiation. In addition, the expression levels of rAc-PF-induced inflammatory genes were reduced inTLR2 KO primary lung cells compared to those in normal primary lung cells. Conclusion These results suggest that the rAc-PF-induced airway inflammatory response is regulated by TLR2 signaling.
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Affiliation(s)
- Mi Kyung Park
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Hye-Kyung Park
- Department of Internal Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Hak Sun Yu
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
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Vardam-Kaur T, Banuelos A, Gabaldon-Parish M, Macedo BG, Salgado CL, Wanhainen KM, Zhou MH, van Dijk S, Santiago-Carvalho I, Beniwal AS, Leff CL, Peng C, Tran NL, Jameson SC, da Silva HB. The ATP-exporting channel Pannexin-1 promotes CD8 + T cell effector and memory responses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.04.19.537580. [PMID: 37131831 PMCID: PMC10153284 DOI: 10.1101/2023.04.19.537580] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Sensing of extracellular ATP (eATP) controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses in vivo, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ T cell responses. Panx1 favors initial effector CD8+ T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ T cells through distinct purinergic receptors and different metabolic and signaling pathways.
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Affiliation(s)
- Trupti Vardam-Kaur
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
- Current address: Omeros Corporation, Seattle, Washington, United States
| | - Alma Banuelos
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
| | - Maria Gabaldon-Parish
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
- Current address: University of New Mexico, Albuquerque, New Mexico, United States
| | - Bruna Gois Macedo
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
| | | | | | - Maggie Hanqi Zhou
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
| | - Sarah van Dijk
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
- Current address: Biomedical Sciences Graduate Program, University of California, San Diego, California, United States
| | | | - Angad S. Beniwal
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
| | - Chloe L. Leff
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
| | - Changwei Peng
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota, United States
- Current address: Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, Massachusetts, United States
| | - Nhan L. Tran
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
| | - Stephen C. Jameson
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota, United States
| | - Henrique Borges da Silva
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona, United States
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Almeida L, van Roey R, Patente TA, Otto F, Veldhuizen T, Ghorasaini M, van Diepen A, Schramm G, Liu J, Idborg H, Korotkova M, Jakobsson PJ, Giera M, Hokke CH, Everts B. High-mannose glycans from Schistosoma mansoni eggs are important for priming of Th2 responses via Dectin-2 and prostaglandin E2. Front Immunol 2024; 15:1372927. [PMID: 38742105 PMCID: PMC11089121 DOI: 10.3389/fimmu.2024.1372927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 04/12/2024] [Indexed: 05/16/2024] Open
Abstract
The parasitic helminth Schistosoma mansoni is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that S. mansoni soluble egg antigens (SEA) promote the synthesis of Prostaglandin E2 (PGE2) by DCs through ERK-dependent signaling via Dectin-1 and Dectin-2 that subsequently induces OX40L expression, licensing them for Th2 priming, yet the ligands present in SEA involved in driving this response and whether specific targeting of PGE2 synthesis by DCs could affect Th2 polarization are unknown. We here show that the ability of SEA to bind Dectin-2 and drive ERK phosphorylation, PGE2 synthesis, OX40L expression, and Th2 polarization is impaired upon cleavage of high-mannose glycans by Endoglycosidase H treatment. This identifies high-mannose glycans present on glycoproteins in SEA as important drivers of this signaling axis. Moreover, we find that OX40L expression and Th2 induction are abrogated when microsomal prostaglandin E synthase-1 (mPGES) is selectively inhibited, but not when a general COX-1/2 inhibitor is used. This shows that the de novo synthesis of PGE2 is vital for the Th2 priming function of SEA-stimulated DCs as well as points to the potential existence of other COX-dependent lipid mediators that antagonize PGE2-driven Th2 polarization. Lastly, specific PGE2 inhibition following immunization with S. mansoni eggs dampened the egg-specific Th cell response. In summary, our findings provide new insights in the molecular mechanisms underpinning Th2 induction by S. mansoni and identify druggable targets for potential control of helminth driven-Th2 responses.
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Affiliation(s)
- Luís Almeida
- Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands
| | - Ruthger van Roey
- Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands
| | | | - Frank Otto
- Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands
| | - Tom Veldhuizen
- Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands
| | - Mohan Ghorasaini
- Centre for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, Netherlands
| | - Angela van Diepen
- Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands
| | - Gabriele Schramm
- Experimental Pneumology, Research Centre Borstel, Borstel, Germany
| | - Jianyang Liu
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Helena Idborg
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Marina Korotkova
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Per-Johan Jakobsson
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Martin Giera
- Centre for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, Netherlands
| | | | - Bart Everts
- Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands
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Rošić Despalatović B, Babić M, Bratanić A, Tonkić A, Ardalić Ž, Vilović K. The Impact of Phenotype of Inflammatory Bowel Diseases, Inflammation Activity and Therapy on Mucosal Mature Cd83 + Dendritic Cell. J Clin Med 2024; 13:2070. [PMID: 38610835 PMCID: PMC11012704 DOI: 10.3390/jcm13072070] [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: 01/31/2024] [Revised: 03/08/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Background: Crohn's disease (CD) and ulcerative colitis (UC) are well-defined phenotypes of chronic inflammatory bowel diseases (IBDs). A mechanism of inflammation in these diseases is partially controlled by the intestinal dendritic cell (DC). In this study, we observed a mature CD83+ DC in colonic bioptic samples, and its correlation with disease phenotype and activity. Methods: The study included 219 subjects: 100 with UC, 44 with CD and 75 healthy subjects. Colonic biopsy specimens were incubated with the primary antibody Anti-CD83. Intraepithelial CD83+ DCs were counted per 100 enterocytes. The presence of CD83+ DC was analysed according to the type of IBD, histopathologic inflammation activity and treatment outcome. Results: The presence of mature CD83+ DCs (0, ≥1) differed according to disease types of IBD (p = 0.001), histologic inflammation activity (p = 0.049) and applied therapy (p = 0.001). The odds for CD83+ DC presence were 5.2 times higher in the CD group than in the control/UC group. The odds for CD83+ DC presence were 2.6 times higher in subjects without inflammation or chronic inflammation than with acute inflammation. They were also 3.7 times higher in subjects without therapy. The cut-off value 0.5 CD83+ DC (Rock analysis area = 0.699; SE 0.046; p < 0.001; 95% CI: 0.609-0.788) had been assessed as a differentiation marker between UC and CD. Conclusion: Presence of CD83+ DC could be used as a possible parameter in distinction between UC and CD, as well as a predictor of inflammation activity and treatment outcome.
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Affiliation(s)
| | - Marija Babić
- Medical School, University of Split, 21000 Split, Croatia;
| | - Andre Bratanić
- Department of Gastroenterology and Hepatology, University Hospital Split, 21000 Split, Croatia; (A.T.); (Ž.A.)
| | - Ante Tonkić
- Department of Gastroenterology and Hepatology, University Hospital Split, 21000 Split, Croatia; (A.T.); (Ž.A.)
| | - Žarko Ardalić
- Department of Gastroenterology and Hepatology, University Hospital Split, 21000 Split, Croatia; (A.T.); (Ž.A.)
| | - Katarina Vilović
- Department of Pathology, University Hospital Split, 21000 Split, Croatia;
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Li H, Bradbury JA, Edin ML, Gruzdev A, Li H, Graves JP, DeGraff LM, Lih FB, Feng C, Wolf ER, Bortner CD, London SJ, Sparks MA, Coffman TM, Zeldin DC. TXA2 attenuates allergic lung inflammation through regulation of Th2, Th9, and Treg differentiation. J Clin Invest 2024; 134:e165689. [PMID: 38483511 PMCID: PMC11060738 DOI: 10.1172/jci165689] [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: 01/03/2023] [Accepted: 03/12/2024] [Indexed: 05/02/2024] Open
Abstract
In lung, thromboxane A2 (TXA2) activates the TP receptor to induce proinflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and TXA2 synthase inhibitors have been tested as potential asthma therapeutics in humans. Th9 cells play key roles in asthma and regulate the lung immune response to allergens. Herein, we found that TXA2 reduces Th9 cell differentiation during allergic lung inflammation. Th9 cells were decreased approximately 2-fold and airway hyperresponsiveness was attenuated in lungs of allergic mice treated with TXA2. Naive CD4+ T cell differentiation to Th9 cells and IL-9 production were inhibited dose-dependently by TXA2 in vitro. TP receptor-deficient mice had an approximately 2-fold increase in numbers of Th9 cells in lungs in vivo after OVA exposure compared with wild-type mice. Naive CD4+ T cells from TP-deficient mice exhibited increased Th9 cell differentiation and IL-9 production in vitro compared with CD4+ T cells from wild-type mice. TXA2 also suppressed Th2 and enhanced Treg differentiation both in vitro and in vivo. Thus, in contrast to its acute, proinflammatory effects, TXA2 also has longer-lasting immunosuppressive effects that attenuate the Th9 differentiation that drives asthma progression. These findings may explain the paradoxical failure of anti-thromboxane therapies in the treatment of asthma.
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Affiliation(s)
- Hong Li
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - J. Alyce Bradbury
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Matthew L. Edin
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Artiom Gruzdev
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Huiling Li
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Joan P. Graves
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Laura M. DeGraff
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Fred B. Lih
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Chiguang Feng
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Erin R. Wolf
- Department of Nephrology, Duke University Medical Center, Durham, North Carolina, USA
| | - Carl D. Bortner
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Stephanie J. London
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
| | - Matthew A. Sparks
- Department of Nephrology, Duke University Medical Center, Durham, North Carolina, USA
| | - Thomas M. Coffman
- Department of Nephrology, Duke University Medical Center, Durham, North Carolina, USA
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - Darryl C. Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, North Carolina, USA
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Guo Y, Chen J, Huang Y, Ke S, Xie F, Li D, Li B, Lu H. Increased infiltration of CD4 + IL-17A + FOXP3 + T cells in Helicobacter pylori-induced gastritis. Eur J Immunol 2024; 54:e2350662. [PMID: 38366919 DOI: 10.1002/eji.202350662] [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: 07/11/2023] [Revised: 12/24/2023] [Accepted: 01/09/2024] [Indexed: 02/19/2024]
Abstract
Helicobacter pylori is one of the main predisposing factors for gastric cancer, causing chronic inflammation and proper glands atrophy in the gastric mucosa. Although H. pylori-induced inflammation is a key inducer of precancerous lesions in the gastric mucosa, it remains unclear which precise immune cell subsets are responsible for the progression of H. pylori-induced gastritis. Here, we observed an abundance of CD4+ IL-17A+ FOXP3+ T cells exhibiting a Th17-like phenotype within the microenvironment of H. pylori-induced gastritis. Mechanistically, H. pylori upregulated the expression of IL-6 in Dendritic cells and macrophages, by activating NF-κB signaling through the virulence factor CagA and thus, induced IL-17A expression in FOXP3+ T cells. Moreover, CD4+ IL-17A+ FOXP3+ T cells were positively associated with advanced precancerous lesions. Therefore, these findings offer essential insights into how FOXP3+ T cells sense inflammatory signals from the environment, such as IL-6, during H. pylori infections, thereby guiding the effector immune response and aggravating the gastritis.
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Affiliation(s)
- Yixian Guo
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jinnan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu Huang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shouyu Ke
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Feng Xie
- Department of Immunology and Microbiology, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Li
- Department of Immunology and Microbiology, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Department of Immunology and Microbiology, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Lu
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Feng L, Han N, Han YB, Shang MW, Liang TW, Liu ZH, Li SK, Zhai JX, Yin J. Structural analysis of a soluble polysaccharide GSPA-0.3 from the root of Panax ginseng C. A. Meyer and its adjuvant activity with mechanism investigation. Carbohydr Polym 2024; 326:121591. [PMID: 38142068 DOI: 10.1016/j.carbpol.2023.121591] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/09/2023] [Accepted: 11/13/2023] [Indexed: 12/25/2023]
Abstract
A novel polysaccharide (GSPA-0.3) was isolated and purified from the root of cultivated Panax ginseng C. A. Meyer, and its structure, adjuvant activities, and mechanisms for inducing the maturation of mouse dendritic 2.4 cells (DC2.4) were extensively studied. Fraction GSPA-0.3, mainly composed by the galacturonic acid, galactose, arabinose, glucose, rhamnose, mannose, and xylose, had a molecular weight of 62,722 Da. The main chain of GSPA-0.3 was composed of →3)-α-L-Rhap-(1→, →4)-α-D-GalpA-(1→, and →3, 4)-α-D-GalpA-(1→. Branched chains comprised α-L-Araf-(1→3, 5)-α-L-Araf-(1→5)-α-L-Araf-(1→, α-D-Glcp-(1→6)-α-D-Glcp-(1→6)-α-D-Glcp-(1→, β-D-Galp-(1→4)-β-D-Galp-(1→4)-β-D-Galp-(1→, and α-D-GalpA-(1→ units connected to the C3 position of →3, 4)-α-D-GalpA-(1→. In vivo, GSPA-0.3 was found to stimulate the production of IgG, IgG1, and IgG2a; increase the splenocyte proliferation index; and promote the expression of GATA-3, T-bet, IFN-γ, and IL-4 in H1N1 vaccine-immunized mice. Moreover, GSPA-0.3 significantly increased the levels of neutralizing antibodies in the mice, and its adjuvant activity was found to be superior to aluminum adjuvant (Alum adjuvant). Mechanistic investigations showed that GSPA-0.3 activated the TLR4-dependent pathway by upregulating the expressions of TLR4, MyD88, TRAF-6, and NF-κB proteins and gens. The results presented herein suggested that GSPA-0.3 could significantly promote the efficacy of the H1N1 vaccine by modulating Th1/Th2 response via the TLR4-MyD88-NF-κB signaling pathway.
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Affiliation(s)
- Lei Feng
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Na Han
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Yu-Bo Han
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Meng-Wen Shang
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Teng-Wei Liang
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Zhi-Hui Liu
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Si-Kai Li
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China
| | - Jian-Xiu Zhai
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China.
| | - Jun Yin
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, Shenyang 110016, China.
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Mourot-Bousquenaud M, Langonné I, Buchheit M, Muller S, Coiscaud A, Mathiot J, Jacquenet S, Battais F. Identification of the allergenic sensitizing potential of bisphenol A substitutes used in the industry. Contact Dermatitis 2024; 90:169-181. [PMID: 37927141 DOI: 10.1111/cod.14452] [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: 09/12/2023] [Revised: 10/11/2023] [Accepted: 10/19/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Bisphenol (BP-)A is a chemical used in Europe to produce polycarbonate plastics and epoxy resin or as colour developer in thermal paper. Due to its toxicity, BPA presence was restricted by European regulations. Therefore, substitute chemicals are replacing BPA. OBJECTIVE To assess the allergenic sensitizing potential of 27 substitutes to BPA used in the industry. METHODS The expression of two costimulatory molecules and six cytokines were analysed by flow cytometry in mouse bone marrow-derived dendritic cells (BMDCs) exposed to the chemicals. RESULTS All substances except one induced overexpression of at least one receptor and were thus identified as having allergenic sensitizing potential. Based on the BMDC model, they were classified as extreme (1 out of 27), strong (20 out of 27) and moderate (5 out of 27) sensitizers. BPA was classified as a moderate sensitizer and BPF was the only substitute classified as a non-sensitizer. The more potent substitutes induced more than 2-fold secretion of CCL3, CCL4 and/or CCL5 by dendritic cells. CONCLUSION Most of the BPA substitutes tested in this study have an allergenic sensitizing potential; 24 of them being more potent than BPA itself. Only BPE, BPF and 2,4-BPS appeared to be weaker sensitizers than BPA.
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Affiliation(s)
- Mélanie Mourot-Bousquenaud
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Isabelle Langonné
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Maurane Buchheit
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Samuel Muller
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Amélie Coiscaud
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Julianne Mathiot
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Sandrine Jacquenet
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
| | - Fabrice Battais
- Toxicology and Biomonitoring Division, French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Vandoeuvre les Nancy, France
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Khazaei S, Varela-Calviño R, Rad-Malekshahi M, Quattrini F, Jokar S, Rezaei N, Balalaie S, Haririan I, Csaba N, Garcia-Fuentes M. Self-assembled peptide/polymer hybrid nanoplatform for cancer immunostimulating therapies. Drug Deliv Transl Res 2024; 14:455-473. [PMID: 37721693 PMCID: PMC10761384 DOI: 10.1007/s13346-023-01410-y] [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] [Accepted: 08/04/2023] [Indexed: 09/19/2023]
Abstract
Integrating peptide epitopes in self-assembling materials is a successful strategy to obtain nanovaccines with high antigen density and improved efficacy. In this study, self-assembling peptides containing MAGE-A3/PADRE epitopes were designed to generate functional therapeutic nanovaccines. To achieve higher stability, peptide/polymer hybrid nanoparticles were formulated by controlled self-assembly of the engineered peptides. The nanoparticles showed good biocompatibility to both human red blood- and dendritic cells. Incubation of the nanoparticles with immature dendritic cells triggered immune effects that ultimately activated CD8 + cells. The antigen-specific and IgG antibody responses of healthy C57BL/6 mice vaccinated with the nanoparticles were analyzed. The in vivo results indicate a specific response to the nanovaccines, mainly mediated through a cellular pathway. This research indicates that the immunogenicity of peptide epitope vaccines can be effectively enhanced by developing self-assembled peptide-polymer hybrid nanostructures.
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Affiliation(s)
- Saeedeh Khazaei
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, CiMUS Research Center and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ruben Varela-Calviño
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Mazda Rad-Malekshahi
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Federico Quattrini
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, CiMUS Research Center and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Safura Jokar
- Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Balalaie
- Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, Iran
| | - Ismaeil Haririan
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Noemi Csaba
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, CiMUS Research Center and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Marcos Garcia-Fuentes
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, CiMUS Research Center and Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain.
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Lensch V, Gabba A, Hincapie R, Bhagchandani SH, Basak A, Alam MM, Irvine DJ, Shalek AK, Johnson JA, Finn MG, Kiessling LL. Glycan-costumed virus-like particles promote type 1 anti-tumor immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.18.575711. [PMID: 38293025 PMCID: PMC10827186 DOI: 10.1101/2024.01.18.575711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) shapes immunity by directing T cell function. Strategies to activate specific DC signaling pathways via targeted receptor engagement are crucial to unlocking type 1 cellular immunity. Here, we engineered a glycan-costumed virus-like particle (VLP) vaccine that delivers programmable peptide antigens to induce tumor-specific cellular immunity in vivo. VLPs encapsulating TLR7 agonists and decorated with a selective mannose-derived ligand for the lectin DC-SIGN induced robust DC activation and type 1 cellular immunity, whereas VLPs lacking this key DC-SIGN ligand failed to promote DC-mediated immunity. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, inhibiting tumor growth in a murine melanoma model. Thus, VLPs employing lectin-driven immune reprogramming provide a framework for advancing cancer immunotherapies.
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Affiliation(s)
- Valerie Lensch
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Adele Gabba
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Robert Hincapie
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA
| | - Sachin H. Bhagchandani
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ankit Basak
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | | | - Darrell J. Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Alex K. Shalek
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Jeremiah A. Johnson
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - M. G. Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA
| | - Laura L. Kiessling
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
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Elemam NM, Mekky RY, Rashid G, Braoudaki M, Youness RA. Pharmacogenomic and epigenomic approaches to untangle the enigma of IL-10 blockade in oncology. Expert Rev Mol Med 2024; 26:e1. [PMID: 38186186 PMCID: PMC10941350 DOI: 10.1017/erm.2023.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/29/2023] [Accepted: 11/10/2023] [Indexed: 01/09/2024]
Abstract
The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.
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Affiliation(s)
- Noha M. Elemam
- Research Instiute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Radwa Y. Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo 12622, Egypt
| | - Gowhar Rashid
- Amity Medical School, Amity University, Gurugram (Manesar) 122413, Haryana, India
| | - Maria Braoudaki
- Department of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Rana A. Youness
- Biology and Biochemistry Department, Faculty of Biotechnology, German International University, Cairo 11835, Egypt
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Freen-van Heeren JJ. Posttranscriptional Events Orchestrate Immune Homeostasis of CD8 + T Cells. Methods Mol Biol 2024; 2782:65-80. [PMID: 38622392 DOI: 10.1007/978-1-0716-3754-8_4] [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: 04/17/2024]
Abstract
Maintaining immune homeostasis is instrumental for host health. Immune cells, such as T cells, are instrumental for the eradication of pathogenic bacteria, fungi and viruses. Furthermore, T cells also play a major role in the fight against cancer. Through the formation of immunological memory, a pool of antigen-experienced T cells remains in the body to rapidly protect the host upon reinfection or retransformation. In order to perform their protective function, T cells produce cytolytic molecules, such as granzymes and perforin, and cytokines such as interferon γ and tumor necrosis factor α. Recently, it has become evident that posttranscriptional regulatory events dictate the kinetics and magnitude of cytokine production by murine and human CD8+ T cells. Here, the recent literature regarding the role posttranscriptional regulation plays in maintaining immune homeostasis of antigen-experienced CD8+ T cells is reviewed.
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Melo MGND, Reino IBDSM, Vaitkevicius-Antão V, Silva JMD, Júnior JNDS, Andrade AFD, Bezerra RP, Marques DDAV, Silva SDFFD, Araújo PSRD, Lorena VMBD, Morais RCSD, Paiva-Cavalcanti MD. Chlorella vulgaris extract and Imiquimod as new therapeutic targets for leishmaniasis: An immunological approach. Immunobiology 2024; 229:152779. [PMID: 38118344 DOI: 10.1016/j.imbio.2023.152779] [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: 05/24/2023] [Revised: 11/20/2023] [Accepted: 12/10/2023] [Indexed: 12/22/2023]
Abstract
The therapeutic regimen for the treatment of American Tegumentary Leishmaniasis (ATL) is targeted at the death of the parasite; therefore, it is essential to develop a treatment that can act on the parasite, combined with the modulation of the inflammatory profile. Thus, the aim of this study was to make an in vitro evaluation of the therapeutic potential of Chlorella vulgaris extract (CV) and Imiquimod for ATL. Selectivity indices (SI) were determined by inhibitory concentration assays (IC50) in L. braziliensis cells and cytotoxic concentrations (CC50) were measured in human cells using the MTT method, based on the CV microalgae extract (IC50 concentrations of 15.63 to 500 µg/mL; CC50 concentrations of 62.5-1000 µg/mL) in comparison with the reference drugs and Imiquimod. The immune response was evaluated in healthy human cells by gene expression (RT-qPCR) and cytokine production (Flow Cytometry). The CV extract (SI = 6.89) indicated promising results by showing higher SI than meglumine antimoniate (SI = 3.44) (reference drug). In all analyses, CV presented a protective profile by stimulating the production of Th1 profile cytokines to a larger extent than the reference drugs. Imiquimod showed a high expression for Tbx21, GATA3, RORc and Foxp3 genes, with increased production only of the TNF cytokine. Therefore, the data highlight the natural extract and Imiquimod as strong therapeutic or adjuvant candidates against ATL, owing to modulation of immune response profiles, low toxicity in human cells and toxic action on the parasite.
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Affiliation(s)
| | | | - Victor Vaitkevicius-Antão
- Department of Microbiology, Aggeu Magalhães Institute, Fiocruz Pernambuco Recife, Pernambuco, Brazil
| | - Jady Moreira da Silva
- Department of Microbiology, Aggeu Magalhães Institute, Fiocruz Pernambuco Recife, Pernambuco, Brazil; Federal University of Pernambuco, UFPE Recife, Pernambuco, Brazil
| | - José Noé da Silva Júnior
- Research Support Center, Federal Rural University of Pernambuco, UFRPE Recife, Pernambuco, Brazil
| | | | - Raquel Pedrosa Bezerra
- Research Support Center, Federal Rural University of Pernambuco, UFRPE Recife, Pernambuco, Brazil
| | | | | | - Paulo Sérgio Ramos de Araújo
- Federal University of Pernambuco, UFPE Recife, Pernambuco, Brazil; Departament of Parasitology, Aggeu Magalhães Institute, Fiocruz Pernambuco Recife, Pernambuco, Brazil
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Zhang H, Yang L, Wang T, Li Z. NK cell-based tumor immunotherapy. Bioact Mater 2024; 31:63-86. [PMID: 37601277 PMCID: PMC10432724 DOI: 10.1016/j.bioactmat.2023.08.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/16/2023] [Accepted: 08/01/2023] [Indexed: 08/22/2023] Open
Abstract
Natural killer (NK) cells display a unique inherent ability to identify and eliminate virus-infected cells and tumor cells. They are particularly powerful for elimination of hematological cancers, and have attracted considerable interests for therapy of solid tumors. However, the treatment of solid tumors with NK cells are less effective, which can be attributed to the very complicated immunosuppressive microenvironment that may lead to the inactivation, insufficient expansion, short life, and the poor tumor infiltration of NK cells. Fortunately, the development of advanced nanotechnology has provided potential solutions to these issues, and could improve the immunotherapy efficacy of NK cells. In this review, we summarize the activation and inhibition mechanisms of NK cells in solid tumors, and the recent advances in NK cell-based tumor immunotherapy boosted by diverse nanomaterials. We also propose the challenges and opportunities for the clinical application of NK cell-based tumor immunotherapy.
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Affiliation(s)
- Hao Zhang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Li Yang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Tingting Wang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Zhen Li
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
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Saini S, Anand A, Singh A, Mahapatra B, Sirohi S, Singh S, Singh RK. Swarna Bhasma Induces Antigen-Presenting Abilities of Macrophages and Helps Antigen Experienced CD4 + T Cells to Acquire Th1 Phenotypes Against Leishmania donovani Antigens. Biol Trace Elem Res 2024; 202:210-220. [PMID: 37088826 PMCID: PMC10123016 DOI: 10.1007/s12011-023-03659-3] [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: 02/12/2023] [Accepted: 04/03/2023] [Indexed: 04/25/2023]
Abstract
In leishmaniasis, the protective immunity is largely mediated by proinflammatory cytokine producing abilities of T cells and an efficient parasite killing by phagocytic cells. Notwithstanding a substantial progress that has been made during last decades, the mechanisms or factors involved in establishing protective immunity against Leishmania are not identified. In ancient Indian literature, metallic "bhasma," particularly that of "swarna" or gold (fine gold particles), is indicated as one of the most prominent metal-based therapeutic medicine, which is known to impart protective and curative properties in various health issues. In this work, we elucidated the potential of swarna bhasma (SB) on the effector properties of phagocytes and antigen-activated CD4+ T cells in augmenting the immunogenicity of L. donovani antigens. The characterization of SB revealing its shape, size, composition, and measurement of cytotoxicity established the physiochemical potential for its utilization as an immunomodulator. The activation of macrophages with SB enhanced their capacity to produce nitric oxide and proinflammatory cytokines, which eventually resulted in reduced uptake of parasites and their proliferation in infected cells. Further, in Leishmania-infected animals, SB administration reduced the generation of IL-10, an anti-inflammatory cytokine, and enhanced pro-inflammatory cytokine generation by antigen activated CD4+ T cells with increased frequency of double (IFNγ+/TNFα+) and triple (IFNγ+TNFα+IL-2+) positive cells and abrogated disease pathogeneses at the early days of infection. Our results also suggested that cow-ghee (A2) emulsified preparation of SB, either alone or with yashtimadhu, a known natural immune modulator which enhances the SB's potential in enhancing the immunogenicity of parasitic antigens. These findings suggested a definite potential of SB in enhancing the effector functions of phagocytes and CD4+ T cells against L. donovani antigens. Therefore, more studies are needed to elucidate the mechanistic details of SB and its potential in enhancing vaccine-induced immunity.
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Affiliation(s)
- Shashi Saini
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Anshul Anand
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Abhishek Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Baishakhi Mahapatra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Shruti Sirohi
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Samer Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Science, Banaras Hindu University, Varanasi, 221 005, India
| | - Rakesh K Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India.
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Zhen W, Luo T, Wang Z, Jiang X, Yuan E, Weichselbaum RR, Lin W. Mechanoregulatory Cholesterol Oxidase-Functionalized Nanoscale Metal-Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2305440. [PMID: 37635106 PMCID: PMC10840730 DOI: 10.1002/smll.202305440] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/27/2023] [Indexed: 08/29/2023]
Abstract
Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.
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Affiliation(s)
- Wenyao Zhen
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
- Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA
| | - Taokun Luo
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Zitong Wang
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Xiaomin Jiang
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
- Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA
| | - Eric Yuan
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA
| | - Wenbin Lin
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
- Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA
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Li J, Ma S, Pei H, Jiang J, Zou Q, Lv Z. Review of T cell proliferation regulatory factors in treatment and prognostic prediction for solid tumors. Heliyon 2023; 9:e21329. [PMID: 37954355 PMCID: PMC10637962 DOI: 10.1016/j.heliyon.2023.e21329] [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: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/19/2023] [Indexed: 11/14/2023] Open
Abstract
T cell proliferation regulators (Tcprs), which are positive regulators that promote T cell function, have made great contributions to the development of therapies to improve T cell function. CAR (chimeric antigen receptor) -T cell therapy, a type of adoptive cell transfer therapy that targets tumor cells and enhances immune lethality, has led to significant progress in the treatment of hematologic tumors. However, the applications of CAR-T in solid tumor treatment remain limited. Therefore, in this review, we focus on the development of Tcprs for solid tumor therapy and prognostic prediction. We summarize potential strategies for targeting different Tcprs to enhance T cell proliferation and activation and inhibition of cancer progression, thereby improving the antitumor activity and persistence of CAR-T. In summary, we propose means of enhancing CAR-T cells by expressing different Tcprs, which may lead to the development of a new generation of cell therapies.
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Affiliation(s)
- Jiayu Li
- Student Innovation Competition Team, College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
- College of Life Science, Sichuan University, Chengdu 610065, China
| | - Shuhan Ma
- Student Innovation Competition Team, College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
| | - Hongdi Pei
- Student Innovation Competition Team, College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
| | - Jici Jiang
- Student Innovation Competition Team, College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
| | - Quan Zou
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu 610054, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou 324000, China
| | - Zhibin Lv
- Student Innovation Competition Team, College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
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Singh R, Anand A, Mahapatra B, Saini S, Singh A, Singh S, Kumar V, Das P, Singh S, Singh RK. Adjuvantation of whole-killed Leishmania vaccine with anti-CD200 and anti-CD300a antibodies potentiates its efficacy and provides protection against wild-type parasites. Mol Immunol 2023; 163:136-146. [PMID: 37778149 DOI: 10.1016/j.molimm.2023.09.014] [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: 06/05/2023] [Revised: 08/17/2023] [Accepted: 09/17/2023] [Indexed: 10/03/2023]
Abstract
One of the major reasons behind the limited success of vaccine candidates against all forms of leishmaniasis is the inability of parasitic antigens to induce robust cell-mediated immunity and immunological memory. Here we find, for the first time, that the adjuvantation of whole-killed Leishmania vaccine (Leishvacc) with anti-CD200 and anti-CD300a antibodies enhances CD4+ T cells mediated immunity in vaccinated mice and provides protection against wild-type parasites. The antibody adjuvantation, either alone or with a TLR4 agonist monophosphoryl A (MPL-A), induced the production of pro-inflammatory cytokines viz., IFN-γ, TNF-α, and IL-2 by antigen experienced CD4+ T cells, and also enhanced their rate of conversion into their memory phenotypes against Leishvacc antigens. The antibody adjuvanted vaccine also promoted the generation of IgG2a-mediated protective humoral immunity in vaccinated mice. Further, the mice vaccinated with antibodies adjuvanted vaccine showed strong resilience against metacyclic forms of L. donovani parasites as we observed reduced clinical features such as splenomegaly, hepatomegaly, granulomatous tissues in the liver, and parasitic load in their spleen. The findings of this study demonstrate that the anti-CD200 and anti-CD300a antibodies have potential to increase the protective efficacy of the whole-killed Leishmania vaccine, and opens up a new gateway to diversify the roles of immune checkpoints in vaccine development against leishmaniasis.
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Affiliation(s)
- Rajan Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Anshul Anand
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Baishakhi Mahapatra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Shashi Saini
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Abhishek Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Samer Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Science, Banaras Hindu University, Varanasi 221005, India
| | - Vinod Kumar
- Department of Molecular Biology, Rajendra Memorial Research Institute, Patna 800007, Bihar, India
| | - Pradeep Das
- ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, WB, India
| | - Sangram Singh
- Department of Biochemistry, Faculty of Science, Dr. RMLA University, Ayodhya 224001, India
| | - Rakesh K Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
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Güzel N, Rink L, Fischer HJ. Zinc Modulates Glutamine Metabolism in T Cells. Mol Nutr Food Res 2023; 67:e2300155. [PMID: 37658486 DOI: 10.1002/mnfr.202300155] [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: 03/17/2023] [Revised: 07/27/2023] [Indexed: 09/03/2023]
Abstract
SCOPE Zinc and glutamine are well known to be essential for the function and polarization of immune cells. TH 17 cells are more frequently induced during zinc deficiency and cover their energy requirement mainly through glutaminolysis. A dysregulation of TH 17 cells can contribute to the development of autoimmune diseases. Both inhibition of glutaminolysis and zinc supplementation suppress experimental autoimmune encephalomyelitis in mice. Therefore, the aim of this study is to investigate whether zinc modulates glutaminolysis in T cells. METHODS AND RESULTS CD3/CD28 stimulation and mixed lymphocytes culture are used as in vitro models for T cell activation. Then, the glutaminolysis is investigated on mRNA, protein, and functional level. Zinc deficiency and glutaminase (GLS) inhibition decrease immune responses in vitro. Furthermore, extracellular zinc and glutamine levels both modulate glutaminolysis by changing the expression of glutamine transporters and key enzymes. Intriguingly, zinc directly interferes with the activity of GLS both in a cell free system and in the cytosol. CONCLUSION Besides T cell subset differentiation, zinc also impacts on the cellular metabolism by inhibiting glutaminolysis. This suggests that zinc deficiency can contribute to the development of autoimmune diseases whereas zinc supplementation can support their therapy.
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Affiliation(s)
- Nergis Güzel
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Lothar Rink
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Henrike Josephine Fischer
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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50
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Santalla Méndez R, Rodgers Furones A, Classens R, Fedorova K, Haverdil M, Canela Capdevila M, van Duffelen A, Spruijt CG, Vermeulen M, Ter Beest M, van Spriel AB, Querol Cano L. Galectin-9 interacts with Vamp-3 to regulate cytokine secretion in dendritic cells. Cell Mol Life Sci 2023; 80:306. [PMID: 37755527 PMCID: PMC10533640 DOI: 10.1007/s00018-023-04954-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/20/2023] [Accepted: 09/06/2023] [Indexed: 09/28/2023]
Abstract
Intracellular vesicle transport is essential for cellular homeostasis and is partially mediated by SNARE proteins. Endosomal trafficking to the plasma membrane ensures cytokine secretion in dendritic cells (DCs) and the initiation of immune responses. Despite its critical importance, the specific molecular components that regulate DC cytokine secretion are poorly characterised. Galectin-9, a ß-galactoside-binding protein, has emerged as a novel cellular modulator although its exact intracellular roles in regulating (immune) cell homeostasis and vesicle transport are virtually unknown. We investigated galectin-9 function in primary human DCs and report that galectin-9 is essential for intracellular cytokine trafficking to the cell surface. Galectin-9-depleted DCs accumulate cytokine-containing vesicles in the Golgi complex that eventually undergo lysosomal degradation. We observed galectin-9 to molecularly interact with Vamp-3 using immunoprecipitation-mass-spectrometry and identified galectin-9 was required for rerouting Vamp-3-containing endosomes upon DC activation as the underlying mechanism. Overall, this study identifies galectin-9 as a necessary mechanistic component for intracellular trafficking. This may impact our general understanding of vesicle transport and sheds new light into the multiple roles galectins play in governing cell function.
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Affiliation(s)
- Rui Santalla Méndez
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
- Department of Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Andrea Rodgers Furones
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - René Classens
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Kristina Fedorova
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Manon Haverdil
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Marta Canela Capdevila
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Anne van Duffelen
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Cornelia G Spruijt
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, 6525 GA, Nijmegen, The Netherlands
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, 6525 GA, Nijmegen, The Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Martin Ter Beest
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Annemiek B van Spriel
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
| | - Laia Querol Cano
- Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands.
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