|
1
|
Ou J, Li Z, Yao D, Lu C, Zeng X. Multimodal Function of Mesenchymal Stem Cells in Psoriasis Treatment. Biomolecules 2025; 15:737. [PMID: 40427630 PMCID: PMC12109568 DOI: 10.3390/biom15050737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 05/05/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Psoriasis is a chronic inflammatory disease mediated by the innate and adaptive immune systems, and its pathogenesis involves multiple aspects, including abnormal interleukin (IL)-23-Th17 axis, dysfunction of Tregs and other immune cells, and a complex relationship between keratinocytes and the vascular endothelium. Dysfunction of mesenchymal stem cells in psoriatic skin may also be the main reason for the dysregulated inflammatory response. Mesenchymal stem cells, a type of adult stem cells with multidifferentiation potential, are involved in the regulation of multiple links and targets in the pathogenesis of psoriasis. Thus, a detailed exploration of these mechanisms may lead to the development of new therapeutic strategies for the treatment of psoriasis. In this paper, the role of mesenchymal stem cells in skin homeostasis, the pathogenesis of psoriasis, and the multimodal function of using mesenchymal stem cells in the treatment of psoriasis are reviewed.
Collapse
Affiliation(s)
- Jiaxin Ou
- The Second Clinical School of Guangzhou University of Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine/Guangdong Provincial Hospital of Chinese Medicine/Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510120, China; (J.O.); (Z.L.); (D.Y.)
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research and Guangdong Provincial Key Laboratory of Clinical Research on Chinese Medicine Syndrome, Guangzhou 510120, China
- National Institute of Stem Cell Clinical Research, Guangdong Hospital of Chinese Medicine, Guangzhou 510120, China
- Lab of Stem Cell Biology and Innovative Research of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine/Guangdong Academy of Chinese Medicine, Guangzhou 510120, China
| | - Ziqing Li
- The Second Clinical School of Guangzhou University of Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine/Guangdong Provincial Hospital of Chinese Medicine/Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510120, China; (J.O.); (Z.L.); (D.Y.)
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research and Guangdong Provincial Key Laboratory of Clinical Research on Chinese Medicine Syndrome, Guangzhou 510120, China
| | - Danni Yao
- The Second Clinical School of Guangzhou University of Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine/Guangdong Provincial Hospital of Chinese Medicine/Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510120, China; (J.O.); (Z.L.); (D.Y.)
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research and Guangdong Provincial Key Laboratory of Clinical Research on Chinese Medicine Syndrome, Guangzhou 510120, China
| | - Chuanjian Lu
- The Second Clinical School of Guangzhou University of Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine/Guangdong Provincial Hospital of Chinese Medicine/Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510120, China; (J.O.); (Z.L.); (D.Y.)
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research and Guangdong Provincial Key Laboratory of Clinical Research on Chinese Medicine Syndrome, Guangzhou 510120, China
- National Institute of Stem Cell Clinical Research, Guangdong Hospital of Chinese Medicine, Guangzhou 510120, China
| | - Xiang Zeng
- The Second Clinical School of Guangzhou University of Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine/Guangdong Provincial Hospital of Chinese Medicine/Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510120, China; (J.O.); (Z.L.); (D.Y.)
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, China
- National Institute of Stem Cell Clinical Research, Guangdong Hospital of Chinese Medicine, Guangzhou 510120, China
- Lab of Stem Cell Biology and Innovative Research of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine/Guangdong Academy of Chinese Medicine, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou 510120, China
| |
Collapse
|
|
2
|
Khan FU, Khongorzul P, Gris D, Amrani A. Role of USP7 in the regulation of tolerogenic dendritic cell function in type 1 diabetes. Cell Mol Biol Lett 2025; 30:47. [PMID: 40247205 PMCID: PMC12004606 DOI: 10.1186/s11658-025-00727-5] [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: 12/18/2024] [Accepted: 04/03/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Tolerogenic dendritic cells (toDCs) are critical for maintaining immune homeostasis and preventing autoimmune disease development, such as type 1 diabetes (T1D). We have previously shown that DCs of non-obese diabetic (NOD) mice expressing active Stat5b (Stat5b-CA.DCs) acquire toDCs signature and protect against diabetes. However, the mechanisms involved in reprogramming DCs to adopt tolerogenic or immunogenic signatures are not fully known. This study investigates for the first time the role of USP7 in DC-mediated immune regulation in T1D using a transgenic NOD mouse model expressing an active form of Stat5b (NOD.Stat5b-CA). METHODS Splenic DCs were purified from diabetes-prone NOD mice and diabetes-resistant NOD.Stat5b-CA transgenic mice and their tolerogenic and immunogenic phenotypes were analyzed by FACS. Their pro-and anti-inflammatory cytokine patterns, IRF4, IRF8, de-ubiquitin ligase USP7, and methyltransferase Ezh2 expression were assessed by FACS and Western blot. Moreover, the impact of USP7 inhibition in DCs on Th1/Th2/Th17 and Treg and diabetes onset was assessed using an in vivo DC-based transfer model. RESULTS In this study, we found that splenic Stat5b-CA.DCs expressed high levels of USP7, Ezh2, and PD-L-1/2 and contained a higher proportion of tolerogenic conventional DC2 (cDC2) subsets than immunogenic cDC1 compared to NOD mice DCs. We also found that the USP7 blockade increased Stat5b-CA.DCs maturation and proinflammatory cytokines production while decreasing anti-inflammatory cytokines and PD-L1 and PD-L2 expressions. Mechanistically, USP7 blockade in Stat5-CA.DCs promoted cDC1 over cDC2 subsets by increasing IRF8 expression in an Ezh2-dependent manner and decreasing IRF4 expression independently of Ezh2. USP7 blockade also increased Stat5b-CA.DC capacity to promote Th17 and to restrain Th2 and Treg cells. Importantly, the capacity of Stat5b-CA.DCs to protect NOD mice from diabetes were lost when treated with USP7 inhibitor. CONCLUSIONS Our findings underscore the role of the USP7/Ezh2 axis in maintaining tolerogenic DC functions that are required to tailor adaptive immune response and diabetes protection in NOD mice.
Collapse
Affiliation(s)
- Farhan Ullah Khan
- Department of Pediatrics, Immunology Division, Université de Sherbrooke Faculté de Médecine et des Sciences de la Santé, 3001, 12 th Avenue North, Sherbrooke, QC, J1H 5 N4, Canada
| | - Puregmaa Khongorzul
- Department of Pediatrics, Immunology Division, Université de Sherbrooke Faculté de Médecine et des Sciences de la Santé, 3001, 12 th Avenue North, Sherbrooke, QC, J1H 5 N4, Canada
| | - Denis Gris
- Department of Phamacology-Physiology, Université de Sherbrooke Faculté de Médecine et des Sciences de la Santé, 3001, 12 th Avenue North, Sherbrooke, QC, J1H 5 N4, Canada
| | - Abdelaziz Amrani
- Department of Pediatrics, Immunology Division, Université de Sherbrooke Faculté de Médecine et des Sciences de la Santé, 3001, 12 th Avenue North, Sherbrooke, QC, J1H 5 N4, Canada.
| |
Collapse
|
|
3
|
Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [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: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
Collapse
Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
4
|
Zhang X, Chen Y, Sun G, Fei Y, Zhu H, Liu Y, Dan J, Li C, Cao X, Liu J. Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling. Nat Metab 2024; 6:2118-2137. [PMID: 39425002 DOI: 10.1038/s42255-024-01149-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 09/24/2024] [Indexed: 10/21/2024]
Abstract
Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA-MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.
Collapse
Affiliation(s)
- Xiaomin Zhang
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yali Chen
- Department of Immunology, Institute of Basic Medical Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Geng Sun
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yankang Fei
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Ha Zhu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yanfang Liu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Junyan Dan
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Chunzhen Li
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Xuetao Cao
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
- Department of Immunology, Institute of Basic Medical Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, China
| | - Juan Liu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China.
| |
Collapse
|
|
5
|
Chen Q, Shao B, Xu YN, Li X, Ren SH, Wang HD, Zhang JY, Sun CL, Liu T, Xiao YY, Zhao PY, Yang GM, Liu X, Wang H. IGF2 contributes to the immunomodulatory effects of exosomes from endometrial regenerative cells on experimental colitis. Int Immunopharmacol 2024; 140:112825. [PMID: 39079347 DOI: 10.1016/j.intimp.2024.112825] [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: 05/13/2024] [Revised: 07/19/2024] [Accepted: 07/25/2024] [Indexed: 09/01/2024]
Abstract
BACKGROUND Exosomes derived from endometrial regenerative cells (ERC-Exos) can inherit the immunomodulatory function from ERCs, however, whether ERC-Exos exhibit such effect on inflammatory bowel diseases with mucosal immune dysregulation has not been explored. Insulin-like growth factor-Ⅱ (IGF2) is considered to possess the potential to induce an anti-inflammatory phenotype in immune cells. In this study, the contribution of IGF2 in mediating the protective efficacy of ERC-Exos on colitis was investigated. METHODS Lentiviral transfection was employed to obtain IGF2-specific knockout ERC-Exos (IGF2-/--ERC-Exos). Experimental colitis mice induced by dextran sulfate sodium (DSS) were divided into the phosphate-buffered saline (untreated), ERC-Exos-treated and IGF2-/--ERC-Exos-treated groups. Colonic histopathological analysis and intestinal barrier function were explored. The infiltration of CD4+ T cells and dendritic cells (DCs) were analyzed by immunofluorescence staining and flow cytometry. The maturation and function of bone marrow-derived dendritic cells (BMDCs) in different exosome administrations were evaluated by flow cytometry, ELISA and the coculture system, respectively. RESULTS Compared with the untreated group, ERC-Exos treatment significantly attenuated DSS-induced weight loss, bloody stools, shortened colon length, pathological damage, as well as repaired the weakened intestinal mucosal barrier, including promoting the goblet cells retention, restoring the intestinal barrier integrity and enhancing the expression of tight junction proteins, while the protective effect of exosomes was impaired with the knockout of IGF2 in ERC-Exos. Additionally, IGF2-expressing ERC-Exos decreased the proportions of Th1 and Th17, increased the proportions of Treg, as well as attenuated DC infiltration and maturation in mesenteric lymph nodes and lamina propria of the colitis mice. ERC-Exos were also observed to be phagocytosed by BMDCs and IGF2 is responsible for the modulating effect of ERC-Exos on BMDCs in vitro. CONCLUSIONS Exosomes derived from ERCs can exert a therapeutic effect on experimental colitis with remarkable alleviation of the intestinal barrier damage and the abnormal mucosal immune responses. We emphasized that IGF2 plays a critical role for ERC-Exos mediated immunomodulatory function and protection against colitis.
Collapse
Affiliation(s)
- Qiang Chen
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Yi-Ni Xu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Shao-Hua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Jing-Yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Cheng-Lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Yi-Yi Xiao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Peng-Yu Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Guang-Mei Yang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Xu Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin, China.
| |
Collapse
|
|
6
|
Lu J, Li Y, Gao X, Chen S, Jin Z, Guo X, Xie W, Guo Z, Wei Y, Zhao L. DC-derived whole cell cytokine nano-regulator for remodelling extracellular matrix and synergizing tumor immunotherapy. RSC Med Chem 2024:d4md00496e. [PMID: 39345717 PMCID: PMC11428036 DOI: 10.1039/d4md00496e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/29/2024] [Indexed: 10/01/2024] Open
Abstract
A smart dendritic cell (DC)-derived whole cell cytokine (DWC) nano-regulator of TCPs was developed for tumor cytokine-immunotherapy. The DWCs were purified from activated DC-cultured media and applied as a nano-dosage form. It was found that TCPs could remodel extracellular matrices via the elimination of fibronectin and type I collagen (Col-I) in tumor tissues, as well as the inhibition of α-SMA expression in cancer associated fibroblasts (CAFs). Furthermore, after local TCP treatment, significant tumor inhibition could be achieved combined with radiotherapy.
Collapse
Affiliation(s)
- Jingsong Lu
- Department of Chemistry, Tsinghua University Beijing 100084 China
| | - Ying Li
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| | - Xiaohan Gao
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| | - Sumei Chen
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| | - Zeping Jin
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| | - Xiaoxiao Guo
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| | - Wensheng Xie
- College of Life Science and Technology, Beijing University of Chemical Technology Beijing 100029 China
| | - Zhenhu Guo
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| | - Yen Wei
- Department of Chemistry, Tsinghua University Beijing 100084 China
| | - Lingyun Zhao
- School of Materials Science and Engineering, Tsinghua University Beijing 100084 China
| |
Collapse
|
|
7
|
Rojas M, Acosta-Ampudia Y, Heuer LS, Zang W, M Monsalve D, Ramírez-Santana C, Anaya JM, M Ridgway W, A Ansari A, Gershwin ME. Antigen-specific T cells and autoimmunity. J Autoimmun 2024; 148:103303. [PMID: 39141985 DOI: 10.1016/j.jaut.2024.103303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024]
Abstract
Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the "two-hit" hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.
Collapse
Affiliation(s)
- Manuel Rojas
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA; Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
| | - Yeny Acosta-Ampudia
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Luke S Heuer
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Weici Zang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Diana M Monsalve
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Carolina Ramírez-Santana
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | | | - William M Ridgway
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Aftab A Ansari
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA.
| |
Collapse
|
|
8
|
Barrett KA, Kassama FJ, Surks W, Mulholland AJ, Moulton KD, Dube DH. Helicobacter pylori glycan biosynthesis modulates host immune cell recognition and response. Front Cell Infect Microbiol 2024; 14:1377077. [PMID: 38572314 PMCID: PMC10987845 DOI: 10.3389/fcimb.2024.1377077] [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: 01/26/2024] [Accepted: 03/11/2024] [Indexed: 04/05/2024] Open
Abstract
Introduction The pathogenic bacterium Helicobacter pylori has evolved glycan-mediated mechanisms to evade host immune defenses. This study tests the hypothesis that genetic disruption of H. pylori glycan biosynthesis alters immune recognition and response by human gastric epithelial cells and monocyte-derived dendritic cells. Methods To test this hypothesis, human cell lines were challenged with wildtype H. pylori alongside an array of H. pylori glycosylation mutants. The relative levels of immune response were measured via immature dendritic cell maturation and cytokine secretion. Results Our findings indicate that disruption of lipopolysaccharide biosynthesis diminishes gastric cytokine production, without disrupting dendritic cell recognition and activation. In contrast, variable immune responses were observed in protein glycosylation mutants which prompted us to test the hypothesis that phase variation plays a role in regulating bacterial cell surface glycosylation and subsequent immune recognition. Lewis antigen presentation does not correlate with extent of immune response, while the extent of lipopolysaccharide O-antigen elaboration does. Discussion The outcomes of this study demonstrate that H. pylori glycans modulate the host immune response. This work provides a foundation to pursue immune-based tailoring of bacterial glycans towards modulating immunogenicity of microbial pathogens.
Collapse
Affiliation(s)
| | | | | | | | | | - Danielle H. Dube
- Department of Chemistry & Biochemistry, Bowdoin College, Brunswick, ME, United States
| |
Collapse
|
|
9
|
Karimi F, Nejati B, Rahimi F, Alivirdiloo V, Alipourfard I, Aghighi A, Raji-Amirhasani A, Eslami M, Babaeizad A, Ghazi F, Firouzi Amandi A, Dadashpour M. A State-of-the-Art Review on the Recent Advances of Mesenchymal Stem Cell Therapeutic Application in Systematic Lupus Erythematosus. Immunol Invest 2024; 53:160-184. [PMID: 38031988 DOI: 10.1080/08820139.2023.2289066] [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: 12/01/2023]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology that has widespread clinical and immunological manifestations. Despite the increase in knowledge about the pathogenesis process and the increase in treatment options, however, the treatments fail in half of the cases. Therefore, there is still a need for research on new therapies. Mesenchymal stem cells (MSCs) are powerful regulators of the immune system and can reduce the symptoms of systemic lupus erythematosus. This study aimed to review the mechanisms of immune system modulation by MSCs and the role of these cells in the treatment of SLE. MSCs suppress T lymphocytes through various mechanisms, including the production of transforming growth factor-beta (TGF-B), prostaglandin E2 (PGE2), nitric oxide (NO), and indolamine 2 and 3-oxygenase (IDO). In addition, MSCs inhibit the production of their autoantibodies by inhibiting the differentiation of lymphocytes. The production of autoantibodies against nuclear antigens is an important feature of SLE. On the other hand, MSCs inhibit antigen delivery by antigen-presenting cells (APCs) to T lymphocytes. Studies in animal models have shown the effectiveness of these cells in treating SLE. However, few studies have been performed on the effectiveness of this treatment in humans. It can be expected that new treatment strategies for SLE will be introduced in the future, given the promising results of MSCs application.
Collapse
Affiliation(s)
- Farshid Karimi
- Department of Optometry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Babak Nejati
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Rahimi
- Division of Clinical Laboratory, Zahra Mardani Azar Children Training Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Alivirdiloo
- Medical Doctor Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Science, Warsaw, Poland
| | - Ali Aghighi
- Department of Clinical Biochemistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Alireza Raji-Amirhasani
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Babaeizad
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Farhood Ghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Dadashpour
- Department of Medical Biotechnology, Semnan University of Medical Sciences, Semnan, Iran
| |
Collapse
|
|
10
|
Alipour S, Kazemi T, Sadeghi MR, Heris JA, Masoumi J, Naseri B, Baghbani E, Sohrabi S, Baradaran B. Glyburide-treated human monocyte-derived dendritic cells loaded with insulin represent tolerogenic features with anti-inflammatory responses and modulate autologous T cell responses in vitro. Int Immunopharmacol 2024; 126:111230. [PMID: 37979448 DOI: 10.1016/j.intimp.2023.111230] [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: 10/05/2023] [Revised: 11/10/2023] [Accepted: 11/11/2023] [Indexed: 11/20/2023]
Abstract
Tolerogenic dendritic cells (TolDCs) are attractive therapeutic options for autoimmune disorders because they suppress autologous T-cell responses. Dendritic cells (DCs) are equipped with pattern recognition receptors (PRR), including nucleotide-binding and oligomerization domain-like receptors (NLRs) such as NLRP3. Abnormal NLRP3 activation has been reported to be correlated with the occurrence of autoimmune disorders. Accordingly, we hypothesized that glyburide treatment of DCs by blocking the ATP-sensitive K+ (kATP) channels generates TolDCs by inhibiting NLRP3. Insulin was even loaded on a group of glyburide-treated mature DCs (mDCs) to investigate the antigen (Ag) loading effects on glyburide-treated mDCs' phenotypical and functional features. Consequently, T lymphocytes' mediated responses ensuing co-culture of them with control mDCs, insulin loaded and unloaded glyburide treated mDCs were evaluated to determine generated TolDCs' capacity in inhibition of T cell responses that are inducer of destruction in insulin-producing pancreatic beta cells in Type 1 Diabetes Mellitus (T1DM). Our findings indicated that glyburide generates desirable TolDCs with decreased surface expression of maturation and Ag presentation related markers and diminished level of inflammatory but increased level of anti-inflammatory cytokines, which even insulin loading demonstrated more anti-inflammatory functions. In addition, co-cultured T cells showed regulatory or T helper 2 phenotype instead of T helper 1 features. Our findings suggested that insulin-loaded and unloaded glyburide-treated DCs are promising therapeutic approaches for autoimmune patients, specifically DCs loaded with insulin for T1DM patients. However, further research is required before this technique can be applied in clinical practice.
Collapse
Affiliation(s)
- Shiva Alipour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Sadeghi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Sohrabi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
11
|
Wang J, Dong D, Zhao W, Wang J. Intravital microscopy visualizes innate immune crosstalk and function in tissue microenvironment. Eur J Immunol 2024; 54:e2350458. [PMID: 37830252 DOI: 10.1002/eji.202350458] [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: 03/01/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/14/2023]
Abstract
Significant advances have been made in the field of intravital microscopy (IVM) on myeloid cells due to the growing number of validated fluorescent probes and reporter mice. IVM provides a visualization platform to directly observe cell behavior and deepen our understanding of cellular dynamics, heterogeneity, plasticity, and cell-cell communication in native tissue environments. This review outlines the current studies on the dynamic interaction and function of innate immune cells with a focus on those that are studied with IVM and covers the advances in data analysis with emerging artificial intelligence-based algorithms. Finally, the prospects of IVM on innate immune cells are discussed.
Collapse
Affiliation(s)
- Jin Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dong Dong
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenying Zhao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
12
|
Zhang J, Chen L, Xu Q, Zou Y, Sun F, Zhou Q, Luo X, Li Y, Chen C, Zhang S, Xiong F, Yang P, Liu S, Wang CY. Ubc9 regulates the expression of MHC II in dendritic cells to enhance DSS-induced colitis by mediating RBPJ SUMOylation. Cell Death Dis 2023; 14:737. [PMID: 37957143 PMCID: PMC10643556 DOI: 10.1038/s41419-023-06266-1] [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: 05/14/2023] [Revised: 10/24/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023]
Abstract
SUMOylation is an evolutionary conserved regulatory mechanism, in which Ubc9 is the only E2 conjugating enzyme. Previous studies demonstrated that SUMOylation is involved in multiple biological processes, but its role in dendritic cells (DCs) remains to be fully addressed. Herein in this report, we found that DCs deficient in Ubc9 protected mice from dextran sulfate sodium (DSS)-induced colitis, as evidenced by the ameliorated weight loss, colon length, and disrupted colon structure. Mechanistically, Ubc9 mediated SUMOylation of RBPJ, by which it stabilized RBPJ from ubiquitin-mediated degradation to enhance its transcriptional activity, while Ciita, a critical transcription factor, is a direct target downstream of RBPJ, which forms an enhanceosome complex to transcribe the expression of MHC II genes. Therefore, loss of Ubc9 abolished RBPJ SUMOylation, which was coupled with reduced Ciita transcription, thereby attenuating the expression of MHC class II genes. As a consequence of defective MHC II expression, Ubc9-/- DCs were featured by the impaired capability to process antigen and to prime effector CD4+ T cells, thereby protecting mice from DSS-induced colitis. Together, our results shed novel insight into the understanding of SUMOylation in the regulation of DC functions in pathological conditions.
Collapse
Affiliation(s)
- Jing Zhang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Longmin Chen
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Rheumatology and Immunology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianqian Xu
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Zou
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Sun
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Zhou
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Luo
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Li
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cai Chen
- Department of Endocrinology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shu Zhang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Xiong
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiwei Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China.
| | - Cong-Yi Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China.
| |
Collapse
|
|
13
|
Zhang Q, Luo Y, Zheng Q, Zhao H, Wei X, Li X. Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy. Heliyon 2023; 9:e17551. [PMID: 37449121 PMCID: PMC10336503 DOI: 10.1016/j.heliyon.2023.e17551] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 06/14/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023] Open
Abstract
Autoimmune hepatitis (AIH) results from an autoimmune-mediated chronic inflammatory response against liver cells. Defective self-tolerance and dysfunctional dendritic cells (DCs) play a regulatory role in AIH. Itaconate has recently attracted attention in the field of immunometabolism because of its crucial role as an anti-inflammatory metabolite that negatively regulates the inflammatory response. However, the underlying mechanism of itaconate mediation of DCs in AIH remains unclear. In this study, we found that itaconate acts as an anti-inflammatory factor in the liver. Endogenous itaconate levels were significantly increased in mice with S100-induced AIH model and correlated with upregulation of the immune-responsive gene 1 expression. However, the anti-inflammatory response from endogenously itaconate may not represent the effects exogenously-produced itaconate. We investigated the anti-inflammatory response from exogenous itaconate in S100-induced AIH, and our results showed that itaconate treatment attenuated liver histopathological damage, hepatocyte apoptosis, aminotransferase elevation, and IL-6 production in the S100-induced AIH model. In addition, Itaconate decreased glycolysis to suppress the maturation of DCs in the liver and spleen of AIH models, thereby directly regulating differentiation of Th17 and Tregs in vivo. The percentage of Th17 cells among the CD4+ population were decreased and Tregs were increased (P < 0.05). Furthermore, Itaconate-induced bone marrow-derived monocytes suppressed CD4+cells proliferation. In vitro and in vivo, we found that itaconate suppressed autophagy via activating the PI3K/AKT/mTOR signalling pathway in bone marrow-derived DCs and liver tissues. We further investigated the function of Itaconate on DC-specific mTOR-deficient mice. mTOR-deficient DCs augmented inflammatory reactions in mTORDC-/- AIH mice and induced autophagy. MHY1485 (an agonist of mTOR) and itaconate significantly alleviated the inflammatory reaction and autophagy signalling. In conclusion, itaconate ameliorate liver inflammation in S100-induced AIH mice by regulating the PI3K/AKT/mTOR pathway to decrease DCs autophagy and maturation. These results provide insight useful for treating AIH.
Collapse
Affiliation(s)
- Qiyu Zhang
- The First School of Clinical Medicine, Lanzhou University, 730000 Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, 730000 Lanzhou, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China
| | - Yang Luo
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, 730000 Lanzhou, China
| | - Qiuxia Zheng
- The First School of Clinical Medicine, Lanzhou University, 730000 Lanzhou, China
| | - Haixia Zhao
- The First School of Clinical Medicine, Lanzhou University, 730000 Lanzhou, China
| | - Xiaofeng Wei
- The First School of Clinical Medicine, Lanzhou University, 730000 Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, 730000 Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, 730000 Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, 730000 Lanzhou, China
| |
Collapse
|
|
14
|
Zhang X, Liu J, Cheng Y, Chen K, Chen Y, Zhu H, Li Z, Liu S, Cao X. Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation. J Autoimmun 2023; 138:103048. [PMID: 37216870 DOI: 10.1016/j.jaut.2023.103048] [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: 12/05/2022] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 05/24/2023]
Abstract
Metabolic reprogramming plays a pivotal role in the differentiation and function of immune cells including dendritic cells (DCs). Regulatory DCs can be generated in regional tissue niches like splenic stroma and act as an important part of stromal control of immune response for the maintenance of immune tolerance. However, the metabolic alterations during splenic stroma-driven regulatory DCs differentiation and the metabolic enzyme involved in regulatory DCs function remain poorly understood. By combining metabolomic, transcriptomic, and functional investigations of mature DCs (maDCs) and diffDCs (regulatory DCs differentiated from activated mature DCs through coculturing with splenic stroma), here we identified succinate-CoA ligase subunit beta Suclg2 as a key metabolic enzyme that reprograms the proinflammatory status of mature DCs into a tolerogenic phenotype via preventing NF-κB signaling activation. diffDCs downregulate succinic acid levels and increase the Suclg2 expression along with their differentiation from mature DCs. Suclg2-interference impaired the tolerogenic function of diffDCs in inducing T cell apoptosis and enhanced activation of NF-κB signaling and expression of inflammatory genes CD40, Ccl5, and Il12b in diffDCs. Furthermore, we identified Lactb as a new positive regulator of NF-κB signaling in diffDCs whose succinylation at the lysine 288 residue was inhibited by Suclg2. Our study reveals that the metabolic enzyme Suclg2 is required to maintain the immunoregulatory function of diffDCs, adding mechanistic insights into the metabolic regulation of DC-based immunity and tolerance.
Collapse
Affiliation(s)
- Xiaomin Zhang
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Juan Liu
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
| | - Yujie Cheng
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Kun Chen
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Yali Chen
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Ha Zhu
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Zhiqing Li
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Shuxun Liu
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Xuetao Cao
- National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, 200433, China; Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China; Frontier Research Center for Cell Response, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
| |
Collapse
|
|
15
|
Shan XQ, Luo YY, Chang J, Song JJ, Hao N, Zhao L. Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke. World J Stem Cells 2023; 15:52-70. [PMID: 37007453 PMCID: PMC10052343 DOI: 10.4252/wjsc.v15.i3.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/19/2023] [Accepted: 02/27/2023] [Indexed: 03/23/2023] Open
Abstract
Ischemic stroke (IS) is the most prevalent form of brain disease, characterized by high morbidity, disability, and mortality. However, there is still a lack of ideal prevention and treatment measures in clinical practice. Notably, the transplantation therapy of mesenchymal stem cells (MSCs) has been a hot research topic in stroke. Nevertheless, there are risks associated with this cell therapy, including tumor formation, coagulation dysfunction, and vascular occlusion. Also, a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes (MSC-Exos). And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy, and it may be the most promising new strategy for treating stroke as stem cell replacement therapy. Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS. Intriguingly, MSC-Exos mediates the inflammatory immune response following IS by modulating the central nervous system, the peripheral immune system, and immunomodulatory molecules, thereby promoting neurofunctional recovery after stroke. Thus, this paper reviews the role, potential mechanisms, and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.
Collapse
Affiliation(s)
- Xiao-Qian Shan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Yong-Yin Luo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Jun Chang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Jing-Jing Song
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Nan Hao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| |
Collapse
|
|
16
|
Simulated Microgravity Disrupts Nuclear Factor κB Signaling and Impairs Murine Dendritic Cell Phenotype and Function. Int J Mol Sci 2023; 24:ijms24021720. [PMID: 36675236 PMCID: PMC9865583 DOI: 10.3390/ijms24021720] [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: 12/07/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
During spaceflights, astronauts face different forms of stress (e.g., socio-environmental and gravity stresses) that impact physiological functions and particularly the immune system. In this context, little is known about the effect of such stress on dendritic cells (DCs). First, we showed that hypergravity, but not chronic ultra-mild stress, a socio-environmental stress, induced a less mature phenotype characterized by a decreased expression of MHCII and co-stimulatory molecules. Next, using the random positioning machine (RPM), we studied the direct effects of simulated microgravity on either splenic DCs or Flt-3L-differentiated bone marrow dendritic cells (BMDCs). Simulated microgravity was found to reduce the BM-conventional DC (cDC) and splenic cDC activation/maturation phenotype. Consistent with this, BMDCs displayed a decreased production of pro-inflammatory cytokines when exposed to microgravity compared to the normogravity condition. The induction of a more immature phenotype in microgravity than in control DCs correlated with an alteration of the NFκB signaling pathway. Since the DC phenotype is closely linked to their function, we studied the effects of microgravity on DCs and found that microgravity impaired their ability to induce naïve CD4 T cell survival, proliferation, and polarization. Thus, a deregulation of DC function is likely to induce immune deregulation, which could explain the reduced efficiency of astronauts' immune response.
Collapse
|
|
17
|
Hu Y, Liu C, Han W, Wang P. A theoretical framework of immune cell phenotypic classification and discovery. Front Immunol 2023; 14:1128423. [PMID: 36936975 PMCID: PMC10018129 DOI: 10.3389/fimmu.2023.1128423] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Immune cells are highly heterogeneous and show diverse phenotypes, but the underlying mechanism remains to be elucidated. In this study, we proposed a theoretical framework for immune cell phenotypic classification based on gene plasticity, which herein refers to expressional change or variability in response to conditions. The system contains two core points. One is that the functional subsets of immune cells can be further divided into subdivisions based on their highly plastic genes, and the other is that loss of phenotype accompanies gain of phenotype during phenotypic conversion. The first point suggests phenotypic stratification or layerability according to gene plasticity, while the second point reveals expressional compatibility and mutual exclusion during the change in gene plasticity states. Abundant transcriptome data analysis in this study from both microarray and RNA sequencing in human CD4 and CD8 single-positive T cells, B cells, natural killer cells and monocytes supports the logical rationality and generality, as well as expansibility, across immune cells. A collection of thousands of known immunophenotypes reported in the literature further supports that highly plastic genes play an important role in maintaining immune cell phenotypes and reveals that the current classification model is compatible with the traditionally defined functional subsets. The system provides a new perspective to understand the characteristics of dynamic, diversified immune cell phenotypes and intrinsic regulation in the immune system. Moreover, the current substantial results based on plasticitomics analysis of bulk and single-cell sequencing data provide a useful resource for big-data-driven experimental studies and knowledge discoveries.
Collapse
Affiliation(s)
- Yuzhe Hu
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
| | - Chen Liu
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Wenling Han
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
| | - Pingzhang Wang
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University Center for Human Disease Genomics, Beijing, China
- *Correspondence: Pingzhang Wang,
| |
Collapse
|
|
18
|
Dendritic cells in systemic lupus erythematosus: From pathogenesis to therapeutic applications. J Autoimmun 2022; 132:102856. [DOI: 10.1016/j.jaut.2022.102856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022]
|
|
19
|
Frutos-Rincón L, Gómez-Sánchez JA, Íñigo-Portugués A, Acosta MC, Gallar J. An Experimental Model of Neuro-Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells. Int J Mol Sci 2022; 23:ijms23062997. [PMID: 35328417 PMCID: PMC8951464 DOI: 10.3390/ijms23062997] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 12/04/2022] Open
Abstract
The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye.
Collapse
Affiliation(s)
- Laura Frutos-Rincón
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - José Antonio Gómez-Sánchez
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- Correspondence: ; Tel.: +34-965-91-9594
| | - Almudena Íñigo-Portugués
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
| | - M. Carmen Acosta
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - Juana Gallar
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
- Instituto de Investigación Biomédica y Sanitaria de Alicante, 03010 Alicante, Spain
| |
Collapse
|
|
20
|
Kysielova H, Yampolska K, Dubrava T, Lutsenko O, Bondarovych M, Babenko N, Gaevska Y, Ostankov M, Goltsev A. Improvement of bone marrow mononuclear cells cryopreservation methods to increase the efficiency of dendritic cell production. Cryobiology 2022; 106:122-130. [PMID: 35245536 DOI: 10.1016/j.cryobiol.2022.02.004] [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: 08/27/2021] [Revised: 02/09/2022] [Accepted: 02/20/2022] [Indexed: 11/27/2022]
Abstract
Cryopreservation is now considered an integral part of the biotechnological process, exploiting different types of cells and tissues in clinical practice. Among them, dendritic cells (DCs) deserve special attention, notably the immature tolerogenic cells (tolDCs), which provide natural tolerance in humans and animals. High cryolability of tolDCs has necessitated the search for the methods that would provide cryopreservation of their precursors; those more resistant to negative effects of cryopreservation factors, in particular, bone marrow or peripheral blood mononuclear cells (MNCs). Based on this, the aim of our research was to optimize the cryopreservation conditions for mice bone marrow MNCs with further assessment of their ability to form tolDCs ex vivo. A cryopreservation mode for bone marrow MNCs has been developed which provides structural and functional completeness of tolDCs obtained from them ex vivo. The ability of DCs derived from cryopreserved MNCs by the developed mode to induce T-regulatory (FOXP3+) cells in vitro when co-cultured with CD4+-lymphocytes was shown.Tolerogenic properties of the DCs derived from cryopreserved MNCs are implemented by increasing the content of hsp70 heat shock proteins and the expression rate of glucocorticoid-induced leucine zipper (GILZ). DCs with increased tolerogenic activities, obtained by the developed cryopreservation regimen, can be used in treatment of autoimmune diseases. In this research we not only evaluated the qualitative characteristics and tolerogenic activity of DCs produced in vitro from cryopreserved MNCs, but also outlined the prospects of accumulating their reserves in low-temperature banks for clinical use.
Collapse
Affiliation(s)
- H Kysielova
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine.
| | - K Yampolska
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - T Dubrava
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - O Lutsenko
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - M Bondarovych
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - N Babenko
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - Yu Gaevska
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - M Ostankov
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| | - A Goltsev
- Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23, Pereyaslavska str., Kharkiv, 61016, Ukraine
| |
Collapse
|
|
21
|
Ji Z, Xu J, Li M, Wang H, Xu B, Yang Y, Hu Y. The Mechanisms of Immune-chemotherapy with Nanocomplex Codelivery of pTRP-2 and Adjuvant of Paclitaxel against Melanoma. Drug Dev Ind Pharm 2022; 47:1744-1752. [PMID: 35193436 DOI: 10.1080/03639045.2022.2045306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Melanoma accounts for the highest proportion of all skin cancer deaths. Immune-chemotherapy has transformed anti-melanoma therapy and is a preferred first-line combination strategy for melanoma. We previously prepared dendritic cells (DCs) targeting the nanocomplex paclitaxel (PTX)-encapsulated sulfobutylether-β-cyclodextrin (SBE)/mannosylated N,N,N-trimethyl chitosan (mTMC)/DNA (PTX/SBE-DNA/Man-TMC) for the co-delivery of pTRP-2 DNA and adjuvant PTX. The nanocomplex PTX/SBE-DNA/Man-TMC promoted DC maturation and antigen presentation and spur potent anti-melanoma immunity. However, the mechanism by which PTX/SBE-DNA/Man-TMC regulates the biological functions of DCs and T lymphocytes is unknown. Therefore, we explored the underlying signaling pathways and mixed leukocyte reactions, resulting in enhanced T cell-mediated anti-tumor immunity. Interleukin-12 secretion from nanocomplex-pulsed mouse bone marrow-derived dendritic cells was inhibited by treatment with Toll-like receptor 4 (TLR-4), nuclear factor kappa-B (NF-κB), and a specific blocker of p38 mitogen-activated protein kinase (MAPK). The results revealed that TLR-4, NF-κB, and MAPK signaling pathways were essential anti-tumor immune responses regulation factors. Furthermore, mixed leukocytes pulsed with PTX/SBE-DNA/Man-TMC induced tumor cell apoptosis and arrested the cell cycle in G0/G1, significantly promoting the synergy. Thus, we concluded that the mechanism driving the PTX/SBE-DNA/Man-TMC immune-chemotherapy synergistic effect was multifactorial.
Collapse
Affiliation(s)
- Zhonghua Ji
- Pharmacy, Zhejiang pharmaceutical college, Ningbo, Zhejiang, People's republic of China
| | - Jiaojiao Xu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's republic of China
| | - Min Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's republic of China
| | - Hui Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's republic of China
| | - Beihua Xu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's republic of China
| | - Yunxu Yang
- Pharmacy, Zhejiang pharmaceutical college, Ningbo, Zhejiang, People's republic of China
| | - Ying Hu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's republic of China.,Pharmacy, Zhejiang pharmaceutical college, Ningbo, Zhejiang, People's republic of China
| |
Collapse
|
|
22
|
Li M, Hu J, Mao H, Li D, Jiang Z, Sun Z, Yu T, Hu C, Xu X. Grass Carp ( Ctenopharyngodon idella) KAT8 Inhibits IFN 1 Response Through Acetylating IRF3/IRF7. Front Immunol 2022; 12:808159. [PMID: 35046960 PMCID: PMC8761793 DOI: 10.3389/fimmu.2021.808159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/09/2021] [Indexed: 12/30/2022] Open
Abstract
Post-translational modifications (PTMs), such as phosphorylation and ubiquitination, etc., have been reported to modulate the activities of IRF3 and IRF7. In this study, we found an acetyltransferase KAT8 in grass carp (CiKAT8, MW286472) that acetylated IRF3/IRF7 and then resulted in inhibition of IFN 1 response. CiKAT8 expression was up-regulated in the cells under poly I:C, B-DNA or Z-DNA stimulation as well as GCRV(strain 873) or SVCV infection. The acetyltransferase domain (MYST domain) of KAT8 promoted the acetylation of IRF3 and IRF7 through the direct interaction with them. So, the domain is essential for KAT8 function. Expectedly, KAT8 without MYST domain (KAT8-△264-487) was granularly aggregated in the nucleus and failed to down-regulate IFN 1 expression. Subcellular localization analysis showed that KAT8 protein was evenly distributed in the nucleus. In addition, we found that KAT8 inhibited the recruitment of IRF3 and IRF7 to ISRE response element. Taken together, our findings revealed that grass carp KAT8 blocked the activities of IRF3 and IRF7 by acetylating them, resulting in a low affinity interaction of ISRE response element with IRF3 and IRF7, and then inhibiting nucleic acids-induced innate immune response.
Collapse
Affiliation(s)
- Meifeng Li
- School of Life Science, Nanchang University, Nanchang, China
| | - Jihuan Hu
- School of Life Science, Nanchang University, Nanchang, China
| | - Huiling Mao
- School of Life Science, Nanchang University, Nanchang, China
| | - Dongming Li
- Fuzhou Medical College, Nanchang University, Fuzhou, China
| | - Zeyin Jiang
- School of Life Science, Nanchang University, Nanchang, China
| | - Zhichao Sun
- School of Life Science, Nanchang University, Nanchang, China
| | - Tingting Yu
- School of Life Science, Nanchang University, Nanchang, China
| | - Chengyu Hu
- School of Life Science, Nanchang University, Nanchang, China
| | - Xiaowen Xu
- School of Life Science, Nanchang University, Nanchang, China.,State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| |
Collapse
|
|
23
|
Dendritic cell migration in inflammation and immunity. Cell Mol Immunol 2021; 18:2461-2471. [PMID: 34302064 PMCID: PMC8298985 DOI: 10.1038/s41423-021-00726-4] [Citation(s) in RCA: 262] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/09/2021] [Indexed: 02/08/2023] Open
Abstract
Dendritic cells (DCs) are the key link between innate immunity and adaptive immunity and play crucial roles in both the promotion of immune defense and the maintenance of immune tolerance. The trafficking of distinct DC subsets across lymphoid and nonlymphoid tissues is essential for DC-dependent activation and regulation of inflammation and immunity. DC chemotaxis and migration are triggered by interactions between chemokines and their receptors and regulated by multiple intracellular mechanisms, such as protein modification, epigenetic reprogramming, metabolic remodeling, and cytoskeletal rearrangement, in a tissue-specific manner. Dysregulation of DC migration may lead to abnormal positioning or activation of DCs, resulting in an imbalance of immune responses and even immune pathologies, including autoimmune responses, infectious diseases, allergic diseases and tumors. New strategies targeting the migration of distinct DC subsets are being explored for the treatment of inflammatory and infectious diseases and the development of novel DC-based vaccines. In this review, we will discuss the migratory routes and immunological consequences of distinct DC subsets, the molecular basis and regulatory mechanisms of migratory signaling in DCs, and the association of DC migration with the pathogenesis of autoimmune and infectious diseases.
Collapse
|
|
24
|
Biologia Futura: Emerging antigen-specific therapies for autoimmune diseases. Biol Futur 2021; 72:15-24. [PMID: 34554499 DOI: 10.1007/s42977-021-00074-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/16/2021] [Indexed: 02/05/2023]
Abstract
Autoimmune diseases are caused by breaking the central and/or peripheral tolerance against self, leading to uncontrolled immune response to autoantigens. The incidences of autoimmune diseases have increased significantly worldwide over the last decades; nearly 5% of the world's population is affected. The current treatments aim to reduce pain and inflammation to prevent organ damage and have a general immunosuppressive effect, but they cannot cure the disease. There is a huge unmet need for autoantigen-specific therapy, without affecting the immune response against pathogens. This goal can be achieved by targeting autoantigen-specific T or B cells and by restoring self-tolerance by inducing tolerogenic antigen-presenting cells (APC) and the development of regulatory T (Treg) cells, for example, by using autoantigenic peptides bound to nanoparticles. Transferring in vitro manipulated autologous tolerogenic APC or autologous autoantigen-specific Treg cells to patients is the promising approach to develop cellular therapeutics. Most recently, chimeric autoantibody receptor T cells have been designed to specifically deplete autoreactive B cells. Limitations of these novel autoantigen-specific therapies will also be discussed.
Collapse
|
|
25
|
Ríos-Ríos WDJ, Sosa-Luis SA, Torres-Aguilar H. Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes. World J Diabetes 2021; 12:603-615. [PMID: 33995848 PMCID: PMC8107985 DOI: 10.4239/wjd.v12.i5.603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/26/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.
Collapse
Affiliation(s)
- William de Jesús Ríos-Ríos
- Department of Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico
| | - Sorely Adelina Sosa-Luis
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico
| | - Honorio Torres-Aguilar
- Department of Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico
| |
Collapse
|
|
26
|
Rahimi K, Hassanzadeh K, Khanbabaei H, Haftcheshmeh SM, Ahmadi A, Izadpanah E, Mohammadi A, Sahebkar A. Curcumin: A Dietary Phytochemical for Targeting the Phenotype and Function of Dendritic Cells. Curr Med Chem 2021; 28:1549-1564. [PMID: 32410550 DOI: 10.2174/0929867327666200515101228] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 04/05/2020] [Accepted: 04/19/2020] [Indexed: 11/22/2022]
Abstract
Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context, DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hence, dysregulated DCs are the most attractive pharmacological target for the development of new therapies aiming at reducing their immunogenicity and at enhancing their tolerogenicity. Curcumin is the polyphenolic phytochemical component of the spice turmeric with a wide range of pharmacological activities. It acts in several ways as a modulator of DCs and converts them into tolerogenic DCs. Tolerogenic DCs possess anti-inflammatory and immunomodulatory activities that regulate the immune responses in health and disease. Curcumin by blocking maturation markers, cytokines and chemokines expression, and disrupting the antigen-presenting machinery of DCs render them non- or hypo-responsive to immunostimulants. It also reduces the expression of co-stimulatory and adhesion molecules on DCs and prevents them from both migration and antigen presentation but enhances their endocytosis capacity. Hence, curcumin causes DCs-inducing regulatory T cells and dampens CD4+ T helper 1 (Th1), Th2, and Th17 polarization. Inhibition of transcription factors such as NF-κB, AP-1, MAPKs (p38, JNK, ERK) and other intracellular signaling molecules such as JAK/STAT/SOCS provide a plausible explanation for most of these observations. In this review, we summarize the potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses.
Collapse
Affiliation(s)
- Kaveh Rahimi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Kambiz Hassanzadeh
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed M Haftcheshmeh
- Department of Medical Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91766-99199, Iran
| | - Abbas Ahmadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Esmael Izadpanah
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Asadollah Mohammadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | |
Collapse
|
|
27
|
Dysregulation of the gut-brain-skin axis and key overlapping inflammatory and immune mechanisms of psoriasis and depression. Biomed Pharmacother 2021; 137:111065. [PMID: 33540138 DOI: 10.1016/j.biopha.2020.111065] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/14/2020] [Accepted: 11/20/2020] [Indexed: 12/21/2022] Open
Abstract
The occurrence, progression and recurrence of psoriasis are thought to be related to mood and psychological disorders such as depression. Psoriasis can lead to depression, and depression, in turn, exacerbates psoriasis. No specific mechanism can explain the association between psoriasis and depression. The gut-brain-skin axis has been used to explain correlations among the gut microbiota, emotional states and systemic and skin inflammation, and this axis may be associated with overlapping mechanisms between psoriasis and depression. Therefore, in the context of the gut-brain-skin axis, we systematically summarized and comparatively analysed the inflammatory and immune mechanisms of psoriasis and depression and illustrated the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and the gut microbiota. This review provides a theoretical basis and new targets for the treatment of psoriasis and depression.
Collapse
|
|
28
|
Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins. BioDrugs 2021; 35:125-146. [PMID: 33523413 PMCID: PMC7848667 DOI: 10.1007/s40259-020-00465-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2020] [Indexed: 12/12/2022]
Abstract
The subcutaneous route of administration has provided convenient and non-inferior delivery of therapeutic proteins compared to intravenous infusion, but there is potential for enhanced immunogenicity toward subcutaneously administered proteins in a subset of patients. Unwanted anti-drug antibody response toward proteins or monoclonal antibodies upon repeated administration is shown to impact the pharmacokinetics and efficacy of multiple biologics. Unique immunogenicity challenges of the subcutaneous route have been realized through various preclinical and clinical examples, although subcutaneous delivery has often demonstrated comparable immunogenicity to intravenous administration. Beyond route of administration as a treatment-related factor of immunogenicity, certain product-related risk factors are particularly relevant to subcutaneously administered proteins. This review attempts to provide an overview of the mechanism of immune response toward proteins administered subcutaneously (subcutaneous proteins) and comments on product-related risk factors related to protein structure and stability, dosage form, and aggregation. A two-wave mechanism of antigen presentation in the immune response toward subcutaneous proteins is described, and interaction with dynamic antigen-presenting cells possessing high antigen processing efficiency and migratory activity may drive immunogenicity. Mitigation strategies for immunogenicity are discussed, including those in general use clinically and those currently in development. Mechanistic insights along with consideration of risk factors involved inspire theoretical strategies to provide antigen-specific, long-lasting effects for maintaining the safety and efficacy of therapeutic proteins.
Collapse
|
|
29
|
Mohmmad‐Rezaei M, Arefnezhad R, Ahmadi R, Abdollahpour‐Alitappeh M, Mirzaei Y, Arjmand M, Ferns GA, Bashash D, Bagheri N. An overview of the innate and adaptive immune system in atherosclerosis. IUBMB Life 2021; 73:64-91. [DOI: 10.1002/iub.2425] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022]
Abstract
AbstractCardiovascular disease is the leading cause of death globally. Coronary artery disease (CAD) is a chronic inflammatory disease usually caused by atherosclerosis, in which the coronary arteries become narrowed by atheromatous plaque. Plaques in atherosclerosis are formed through the accumulation of lipids and various immune cells. Both adaptive and innate immune systems are involved in the pathogenesis of atherosclerosis and facilitate plaque formation and disease progression. Almost all immune system cells, including neutrophils, B cells, T cells monocytes, macrophages, foam cells, and dendritic cells (DCs), play a vital role in atherosclerotic plaque. Atherogenesis, the normal function of the endothelium, is initially disrupted and, then, cells of the immune system are recruited to the endothelium following increased expression of cell adhesion molecules. Accumulation of immune cells and lipids leads to the formation of a necrotic nucleus. As the disease progresses, smooth muscle cells form fibrous layers, whose rupture results in exposing the necrotic nucleus and thrombosis. Accordingly, the present review was conducted to determine the role of different cells in innate and adaptive immune systems in inhibition and progression of atherosclerosis.
Collapse
Affiliation(s)
- Mina Mohmmad‐Rezaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute Shahrekord University of Medical Sciences Shahrekord Iran
| | - Reza Arefnezhad
- Halal Research Center of IRI, FDA Tehran Iran
- Department of Anatomy, School of Medicine Shiraz University of Medical Sciences Shiraz Iran
| | - Reza Ahmadi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute Shahrekord University of Medical Sciences Shahrekord Iran
| | | | - Yousef Mirzaei
- Department of Biogeosciences, Scientific Research Center Soran University Soran Iraq
| | - Mohammad‐Hassan Arjmand
- Cellular and Molecular Research Center, Basic Health Sciences Institute Shahrekord University of Medical Sciences Shahrekord Iran
- Cancer Research Center Shahrekord University of Medical Sciences Shahrekord Iran
| | - Gordon A. Ferns
- Brighton & Sussex Medical School, Division of Medical Education Sussex United Kingdom
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute Shahrekord University of Medical Sciences Shahrekord Iran
| |
Collapse
|
|
30
|
Wohn C, Le Guen V, Voluzan O, Fiore F, Henri S, Malissen B. Absence of MHC class II on cDC1 dendritic cells triggers fatal autoimmunity to a cross-presented self-antigen. Sci Immunol 2020; 5:5/45/eaba1896. [PMID: 32169954 DOI: 10.1126/sciimmunol.aba1896] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/18/2020] [Indexed: 12/19/2022]
Abstract
Conventional dendritic cells expressing the XCR1 chemokine receptor (cDC1s) excel at cross-presentation. Here, we developed and used a mouse model in which a Cre recombinase is expressed under the control of the Xcr1 gene while preserving XCR1 expression. We used it to generate mice with conditional deletion of MHC class II (MHCII) molecules on cDC1s. By preventing cDC1s to receive suppressive regulatory T cell inputs via MHCII-restricted interactions, the objective of the present study was to gauge whether MHCII-deficient cDC1s lose their capacity of tolerizing autoreactive CD8+ T cells. Whereas MHCII+ cDC1 readily cross-tolerized strongly autoreactive CD8+ T cells specific for a keratinocyte-derived self-antigen, MHCII-deficient cDC1s converted them into potent effectors capable of triggering a fast-onset lethal autoimmunity associated with severe skin histopathological manifestations. Preventing egress of such pathogenic self-reactive CD8+ T cell effectors from the cutaneous draining lymph nodes abrogated the autoimmune condition. Therefore, our results revealed that the cross-tolerizing capacity of cDC1s is not a property fully acquired at the time they undergo homeostatic maturation but needs to be enforced via MHCII-restricted, suppressive interactions with regulatory T cells.
Collapse
Affiliation(s)
- Christian Wohn
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France
| | - Valentin Le Guen
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France
| | - Odessa Voluzan
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France
| | - Frédéric Fiore
- Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France
| | - Sandrine Henri
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France.
| | - Bernard Malissen
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France. .,Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France
| |
Collapse
|
|
31
|
Tokuyama M, Mabuchi T. New Treatment Addressing the Pathogenesis of Psoriasis. Int J Mol Sci 2020; 21:ijms21207488. [PMID: 33050592 PMCID: PMC7589905 DOI: 10.3390/ijms21207488] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/06/2020] [Accepted: 10/08/2020] [Indexed: 12/14/2022] Open
Abstract
Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.
Collapse
|
|
32
|
Shahir M, Mahmoud Hashemi S, Asadirad A, Varahram M, Kazempour‐Dizaji M, Folkerts G, Garssen J, Adcock I, Mortaz E. Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol 2020; 235:7043-7055. [PMID: 32043593 PMCID: PMC7496360 DOI: 10.1002/jcp.29601] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022]
Abstract
Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T-cell activation via direct cell-cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T-cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC-derived exosomes on the induction of mouse tolDCs, murine adipose-derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick-TC kits. BM-derived DCs (BMDCs) were prepared and cocultured with MSCs-derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1μg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester-labeled BALB/C-derived splenocytes p. Interleukin-6 (IL-6), IL-10, and transforming growth factor-β (TGF-β) release were measured by enzyme-linked immunosorbent assay. MSC-derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC-derived exosomes decrease IL-6 release but augment IL-10 and TGF-β release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC-derived exosomes. CMSC-derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC-induced immune responses.
Collapse
Affiliation(s)
- Mehri Shahir
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Ali Asadirad
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Mohammad Varahram
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran
| | - Mehdi Kazempour‐Dizaji
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran
| | - Gert Folkerts
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
- Immunology Platform for Specialized NutritionDanone Nutricia ResearchUtrechtThe Netherlands
| | - Ian Adcock
- Experimental Studies and Cell and Molecular Biology, Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research UnitRoyal Brompton HospitalLondonUK
- Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research InstituteUniversity of NewcastleNewcastleNew South WalesAustralia
| | - Esmaeil Mortaz
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
| |
Collapse
|
|
33
|
Passerini L, Gregori S. Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases. Front Immunol 2020; 11:2194. [PMID: 33133064 PMCID: PMC7550404 DOI: 10.3389/fimmu.2020.02194] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/11/2020] [Indexed: 12/22/2022] Open
Abstract
The development of novel approaches to control unwanted immune responses represents an ambitious goal in the management of a number of clinical conditions, including autoimmunity, autoinflammatory diseases, allergies and replacement therapies, in which the T cell response to self or non-harmful antigens threatens the physiological function of tissues and organs. Current treatments for these conditions rely on the use of non-specific immunosuppressive agents and supportive therapies, which may efficiently dampen inflammation and compensate for organ dysfunction, but they require lifelong treatments not devoid of side effects. These limitations induced researchers to undertake the development of definitive and specific solutions to these disorders: the underlying principle of the novel approaches relies on the idea that empowering the tolerogenic arm of the immune system would restore the immune homeostasis and control the disease. Researchers effort resulted in the development of cell-free strategies, including gene vaccination, protein-based approaches and nanoparticles, and an increasing number of clinical trials tested the ability of adoptive transfer of regulatory cells, including T and myeloid cells. Here we will provide an overview of the most promising approaches currently under development, and we will discuss their potential advantages and limitations. The field is teaching us that the success of these strategies depends primarily on our ability to dampen antigen-specific responses without impairing protective immunity, and to manipulate directly or indirectly the immunomodulatory properties of antigen presenting cells, the ultimate in vivo mediators of tolerance.
Collapse
Affiliation(s)
- Laura Passerini
- Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Gregori
- Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
34
|
Mannie MD, DeOca KB, Bastian AG, Moorman CD. Tolerogenic vaccines: Targeting the antigenic and cytokine niches of FOXP3 + regulatory T cells. Cell Immunol 2020; 355:104173. [PMID: 32712270 PMCID: PMC7444458 DOI: 10.1016/j.cellimm.2020.104173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
FOXP3+ regulatory T cells (Tregs) constitute a critical barrier that enforces tolerance to both the self-peptidome and the extended-self peptidome to ensure tissue-specific resistance to autoimmune, allergic, and other inflammatory disorders. Here, we review intuitive models regarding how T cell antigen receptor (TCR) specificity and antigen recognition efficiency shape the Treg and conventional T cell (Tcon) repertoires to adaptively regulate T cell maintenance, tissue-residency, phenotypic stability, and immune function in peripheral tissues. Three zones of TCR recognition efficiency are considered, including Tcon recognition of specific low-efficiency self MHC-ligands, Treg recognition of intermediate-efficiency agonistic self MHC-ligands, and Tcon recognition of cross-reactive high-efficiency agonistic foreign MHC-ligands. These respective zones of TCR recognition efficiency are key to understanding how tissue-resident immune networks integrate the antigenic complexity of local environments to provide adaptive decisions setting the balance of suppressive and immunogenic responses. Importantly, deficiencies in the Treg repertoire appear to be an important cause of chronic inflammatory disease. Deficiencies may include global deficiencies in Treg numbers or function, subtle 'holes in the Treg repertoire' in tissue-resident Treg populations, or simply Treg insufficiencies that are unable to counter an overwhelming molecular mimicry stimulus. Tolerogenic vaccination and Treg-based immunotherapy are two therapeutic modalities meant to restore dominance of Treg networks to reverse chronic inflammatory disease. Studies of these therapeutic modalities in a preclinical setting have provided insight into the Treg niche, including the concept that intermediate-efficiency TCR signaling, high IFN-β concentrations, and low IL-2 concentrations favor Treg responses and active dominant mechanisms of immune tolerance. Overall, the purpose here is to assimilate new and established concepts regarding how cognate TCR specificity of the Treg repertoire and the contingent cytokine networks provide a foundation for understanding Treg suppressive strategy.
Collapse
Affiliation(s)
- Mark D Mannie
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States.
| | - Kayla B DeOca
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Alexander G Bastian
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Cody D Moorman
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| |
Collapse
|
|
35
|
Soltani S, Mahmoudi M, Farhadi E. Dendritic Cells Currently under the Spotlight; Classification and Subset Based upon New Markers. Immunol Invest 2020; 50:646-661. [PMID: 32597286 DOI: 10.1080/08820139.2020.1783289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dendritic cells (DCs) are considered as a subset of mononuclear phagocytes that composed of multiple subsets with distinct phenotypic features. DCs play crucial roles in the initiation and modulation of immune responses to both allo- and auto-antigens during pathogenic settings, encompassing infectious diseases, cancer, autoimmunity, transplantation, as well as vaccination. DCs play a role in preventing autoimmunity via inducing tolerance to self-antigens. This review focus on the most common subsets of DCs in human. Owing to the low frequencies of DC cells in blood and tissues and also the lack of specific DC markers, studies of DCs have been greatly hindered. Human DCs arise by a dedicated pathway of lympho-myeloid hematopoiesis and give rise into specialized subtypes under the influence of transcription factors that are specific for each linage. In humans, the classification of DCs has been generally separated into the blood and cutaneous subsets, mainly because these parts are more comfortable to examine in humans.
Collapse
Affiliation(s)
- Samaneh Soltani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Farhadi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
36
|
Machhi J, Kevadiya BD, Muhammad IK, Herskovitz J, Olson KE, Mosley RL, Gendelman HE. Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders. Mol Neurodegener 2020; 15:32. [PMID: 32503641 PMCID: PMC7275301 DOI: 10.1186/s13024-020-00375-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities.
Collapse
Affiliation(s)
- Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - Bhavesh D. Kevadiya
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, 94304 USA
| | - Ijaz Khan Muhammad
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Pharmacy, University of Swabi, Anbar Swabi, 23561 Pakistan
| | - Jonathan Herskovitz
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - Katherine E. Olson
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - R. Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| | - Howard E. Gendelman
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5880 USA
| |
Collapse
|
|
37
|
Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis. Brain Sci 2020; 10:brainsci10060333. [PMID: 32486045 PMCID: PMC7348736 DOI: 10.3390/brainsci10060333] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and is considered to be the leading non-traumatic cause of neurological disability in young adults. Current treatments for MS comprise long-term immunosuppressant drugs and disease-modifying therapies (DMTs) designed to alter its progress with the enhanced risk of severe side effects. The Holy Grail for the treatment of MS is to specifically suppress the disease while at the same time allow the immune system to be functionally active against infectious diseases and malignancy. This could be achieved via the development of immunotherapies designed to specifically suppress immune responses to self-antigens (e.g., myelin antigens). The present study attempts to highlight the various antigen-specific immunotherapies developed so far for the treatment of multiple sclerosis (e.g., vaccination with myelin-derived peptides/proteins, plasmid DNA encoding myelin epitopes, tolerogenic dendritic cells pulsed with encephalitogenic epitopes of myelin proteins, attenuated autologous T cells specific for myelin antigens, T cell receptor peptides, carriers loaded/conjugated with myelin immunodominant peptides, etc), focusing on the outcome of their recent preclinical and clinical evaluation, and to shed light on the mechanisms involved in the immunopathogenesis and treatment of multiple sclerosis.
Collapse
|
|
38
|
Manouchehri N, Hussain RZ, Cravens PD, Doelger R, Greenberg BM, Okuda DT, Forsthuber TG, Eagar TN, Stüve O. Limitations of cell-lineage-specific non-dynamic gene recombination in CD11c.Cre +ITGA4 fl/fl mice. J Neuroimmunol 2020; 344:577245. [PMID: 32335319 DOI: 10.1016/j.jneuroim.2020.577245] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND The Cre-lox system is a non-dynamic method of gene modification and characterization. Promoters thought to be relatively cell-specific are utilized for generation of cell-lineage-specific gene modifications. METHODS CD11c.Cre+ITGA4fl/fl mice were generated to abolish the expression of ITGA (α4-integrin) in CD11c+ cells. Ex vivo flow cytometry studies were used to assess the expression of cellular surface markers in different lymphoid compartments and leukocytes subsets after Cre-mediated recombination. RESULTS A significant reduction of α4-integrin expression among CD11c+- cells was achieved in CD11c.Cre+ITGA4fl/fl mice in primary and secondary lymphoid tissues. A similar reduction in the expression of α4-integrin was also observed in CD11c- cells. CONCLUSION Cre-lox-mediated cell lineage-specific gene deletion is limited by the transient expression of recombination regulating sequences in hematopoietic cell lines. These methodological issues indicate the need to consider when to employ non-dynamic DNA recombination models in animal models of CNS autoimmunity. An experimental algorithm to address the biological complexities of non-dynamic gene recombination is provided.
Collapse
Affiliation(s)
- Navid Manouchehri
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Rehana Z Hussain
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Petra D Cravens
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Richard Doelger
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Benjamin M Greenberg
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Darin T Okuda
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Thomas G Forsthuber
- Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA
| | - Todd N Eagar
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, USA
| | - Olaf Stüve
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA; Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX, USA.
| |
Collapse
|
|
39
|
I-a lowCD11b high DC Regulates the Immune Response in the Eyes of Experimental Autoimmune Uveitis. Mediators Inflamm 2020; 2020:6947482. [PMID: 32256194 PMCID: PMC7085850 DOI: 10.1155/2020/6947482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 12/30/2019] [Indexed: 12/23/2022] Open
Abstract
Regulatory dendritic cells (DCreg) have been reported to be a negative regulator in the immune response. These cells are widely distributed in the liver, spleen, and lung. However, the status and function of DCreg in the eyes and disease are still not very clear. Herein, we found that the number of I-alowCD11bhigh DC increased in the eye and spleen at the recovery stage of experimental autoimmune uveitis (EAU), which is a mouse model for autoimmune uveitis. These cells expressed lower levels of CD80, CD86, and CD54 than the mature DCs and expressed interleukin 10 (IL-10), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor beta (TGF-β) as well. Moreover, these DCreg can regulate the development of EAU by promoting CD4+CD25+Foxp3+ regulatory T cells. The increased interferon-gamma (IFN-γ) in the aqueous humor of EAU participates in inducing DCreg to alleviate the symptom of EAU. Furthermore, DCreg was found to exist in the eyes of normal mice. Aqueous humor, containing a certain concentration of IL-10, TGF-β, prostaglandin E2 (PGE2), IDO, and nitric oxide (NO), induced the tolerance of DCreg in normal eyes. It can be concluded that DCreg exists in the eyes and plays a protective role in inflamed eyes. These DCreg induced by IFN-γ might be used as a strategy to develop therapy for EAU management.
Collapse
|
|
40
|
Nazimek K, Bryniarski K. Approaches to inducing antigen-specific immune tolerance in allergy and autoimmunity: Focus on antigen-presenting cells and extracellular vesicles. Scand J Immunol 2020; 91:e12881. [PMID: 32243636 DOI: 10.1111/sji.12881] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 12/11/2022]
Abstract
Increasing prevalence of allergic and autoimmune diseases urges clinicians and researchers to search for new and efficient treatments. Strategies that activate antigen-specific immune tolerance and simultaneously maintain immune reactivity to all other antigens deserve special attention. Accordingly, antigen-presenting cells (APCs) seem to be the best suited for orchestrating these mechanisms by directing T cell immune responses towards a tolerant subtype. Recent advances in understanding cell-to-cell communication via extracellular vesicles (EVs) make the latter promising candidates for reprogramming APCs towards a tolerant phenotype, and for mediating tolerogenic APC function. Thus, comprehensive studies have been undertaken to describe the interactions of APCs and EVs naturally occurring during immune tolerance induction, as well as to develop EV-based manoeuvres enabling the induction of immune tolerance in an antigen-specific manner. In this review, we summarize the findings of relevant studies, with a special emphasis on future perspectives on their translation to clinical practice.
Collapse
Affiliation(s)
- Katarzyna Nazimek
- Jagiellonian University Medical College, Department of Immunology, Krakow, Poland
| | - Krzysztof Bryniarski
- Jagiellonian University Medical College, Department of Immunology, Krakow, Poland
| |
Collapse
|
|
41
|
Chen S, Liu L, Zhang W, Sun L, Wang F, Zhao Y, Liu S, Zhao L, Xu Y. Suppressed dendritic cell functions by cystatin C lead to compromised immunity in vivo. Cell Immunol 2020; 349:104049. [PMID: 32057353 DOI: 10.1016/j.cellimm.2020.104049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/19/2020] [Accepted: 01/26/2020] [Indexed: 12/30/2022]
Abstract
Pathogenic microorganisms utilize multiple approaches to break down host immunity in favor of their invasion, of which, cystatin C is one of the soluble factors secreted by parasites reported to affect host immunity in vivo. The cellular targets and mechanisms of action in vivo of cystatin C, however, are far from clear. As professional antigen-presenting cells, dendritic cells (DCs) are first immune cells that contact foreign pathogenic agents or their products to initiate immune responses. We previously reported that cystatin C can regulate the functions of DCs in terms of suppressed CD4+ T cell activation but enhanced Th1/Th17 differentiation via different mechanisms. Here, we further verified these regulatory effects of cystatin C on DCs in vivo. We found that the suppressive role of DC-mediated CD4+ T cell proliferation by cystatin C was partly cell-contact independent and extended to CD8+ T cells in vivo. Although cystatin C-overexpressing DCs trafficked equally as their mock-transduced counterparts, their adoptive transfer suppressed CD8+ T cell immunity and resulted in compromised tumor rejection in both vaccination and treatment regimes. Compared with their role in promoting Th17 differentiation in vivo, cystatin C-transduced DCs had far greater ability to induce T regulatory cells (Tregs), leading to collectively a higher Treg/Th17 ratio in an adoptively transferred disease model, and thus relieved Th17-dependent autoimmunity. Collectively, these data demonstrated strong in vivo evidences for immune regulatory roles of cystatin C in DCs and provided theoretical basis for the application of cystatin C-transduced cell therapy in the treatment or remission of certain autoimmune diseases. (246).
Collapse
Affiliation(s)
- Shun Chen
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Lei Liu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Wenjie Zhang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Li Sun
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Fengge Wang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Yanfang Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Shan Liu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Lin Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China
| | - Yuekang Xu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu 241000, China.
| |
Collapse
|
|
42
|
Wang A, Bai Y. Dendritic cells: The driver of psoriasis. J Dermatol 2019; 47:104-113. [PMID: 31833093 DOI: 10.1111/1346-8138.15184] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 11/17/2019] [Indexed: 12/20/2022]
Abstract
Psoriasis is a chronic skin inflammatory disorder, the immune mechanism of which has been profoundly elucidated in the past few years. The dominance of the interleukin (IL)-23/IL-17 axis is a significant breakthrough in the understanding of the pathogenesis of psoriasis, and treatment targeting IL-23 and IL-17 has successfully benefited patients with the disease. The skin contains a complex network of dendritic cells (DC) mainly composed of epidermal Langerhans cells, bone marrow-derived dermal conventional DC, plasmacytoid DC and inflammatory DC. As the prominent cellular source of α-interferon, tumor necrosis factor-α, IL-12 and IL-23, DC play a pivotal role in psoriasis. Thus, targeting pathogenic DC subsets is a valid strategy for alleviating and preventing psoriasis and other DC-derived diseases. In this review, we survey the known role of DC in this disease.
Collapse
Affiliation(s)
- Ao Wang
- Clinical Institute of China-Japan Friendship Hospital, Graduate School of Peking Union Medical College, Beijing, China.,Department of Dermatology and Venerology, China-Japan Friendship Hospital, Beijing, China
| | - YanPing Bai
- Clinical Institute of China-Japan Friendship Hospital, Graduate School of Peking Union Medical College, Beijing, China.,Department of Dermatology and Venerology, China-Japan Friendship Hospital, Beijing, China
| |
Collapse
|
|
43
|
Wang H, Wang G, Liang Y, Du X, Boor PJ, Sun J, Khan MF. Redox regulation of hepatic NLRP3 inflammasome activation and immune dysregulation in trichloroethene-mediated autoimmunity. Free Radic Biol Med 2019; 143:223-231. [PMID: 31419475 PMCID: PMC6848782 DOI: 10.1016/j.freeradbiomed.2019.08.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/09/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022]
Abstract
Trichloroethene (TCE) exposure is associated with the development of various autoimmune diseases (ADs), including autoimmune hepatitis (AIH) and systemic lupus erythematosus (SLE), potentially through the generation of excessive reactive oxygen and nitrogen species (RONS; oxidative stress). However, the mechanisms by which oxidative stress contributes to these TCE-mediated ADs are not fully understood, and are the focus of current investigation. Female MRL+/+ mice were treated with TCE along with or without antioxidant N-acetylcysteine (NAC) for 6 weeks (TCE, 10 mmol/kg, i. p., every 4th day; NAC, 250 mg/kg/day via drinking water). TCE-treated mice had elevated antinuclear antibodies (ANA) and 4-hydroxynonenal (HNE)-specific circulating immune complexes, suggesting the association of TCE-induced oxidative stress with autoimmune response. In addition, TCE exposure led to prominent lobular inflammation with sinusoid dilation, increased sinusoidal cellularity and increased staining for proliferating cell nuclear antigen (PCNA), confirming inflammatory and hepatocellular cell proliferation. Importantly, TCE exposure resulted in the activation of hepatic inflammasome (NLRP3 and caspase-1) and up-regulation of pro-inflammatory cytokine IL-1β, and these changes were attenuated by NAC supplementation. TCE treatment also led to dysregulation of hepatic immune response as evident from markedly increased hepatic lymphocyte infiltration (especially B cells) and imbalance between Tregs (decreased) and Th17 cells (increased). Interestingly, TCE-mediated dysregulation of various hepatic and splenic immune cells was also effectively attenuated by NAC. Taken together, our findings provide evidence for TCE-mediated inflammasome activation, infiltration of various immune cells, and skewed balance of Treg and Th17 cells in the liver. The attenuation of TCE-mediated hepatic inflammasome activation and immune responses by NAC further supports a critical role of oxidative stress in TCE-mediated inflammation and autoimmunity. These novel findings could help in designing therapeutic strategies for such ADs.
Collapse
Affiliation(s)
- Hui Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Gangduo Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Xiaotang Du
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Paul J Boor
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Jiaren Sun
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - M Firoze Khan
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
| |
Collapse
|
|
44
|
Herrero-Fernandez B, Gomez-Bris R, Somovilla-Crespo B, Gonzalez-Granado JM. Immunobiology of Atherosclerosis: A Complex Net of Interactions. Int J Mol Sci 2019; 20:E5293. [PMID: 31653058 PMCID: PMC6862594 DOI: 10.3390/ijms20215293] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis.
Collapse
Affiliation(s)
- Beatriz Herrero-Fernandez
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
- Departamento de Fisiología. Facultad de Medicina. Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
| | - Raquel Gomez-Bris
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
| | | | - Jose Maria Gonzalez-Granado
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
- Departamento de Fisiología. Facultad de Medicina. Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain.
| |
Collapse
|
|
45
|
Toghi M, Bitarafan S, Kasmaei HD, Ghafouri-Fard S. Bifidobacteria: A probable missing puzzle piece in the pathogenesis of multiple sclerosis. Mult Scler Relat Disord 2019; 36:101378. [PMID: 31487552 DOI: 10.1016/j.msard.2019.101378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 06/29/2019] [Accepted: 08/27/2019] [Indexed: 12/27/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune disorder in which the immunopathogenesis is not fully understood. In the recent years, the role of gut microbiome in the pathogenesis of this disorder has been highlighted. Bifidobacteria as a component of gut microbiome might also be involved in MS pathogenesis. Being emerged in early days after birth, bifidobacteria have a prominent role in immune system maturation and function. Some factors like mode of delivery, breast feeding, mother's blood group and her secretory state and also environmental factors could influence its level in the early infancy, which may remain throughout lifetime. In this review, we discussed possible immunopathogenic link between the bifidobacteria and MS.
Collapse
Affiliation(s)
- Mehdi Toghi
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Bitarafan
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hosein Delavar Kasmaei
- Department of Neurology, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
46
|
Cao T, Shao S, Fang H, Li B, Wang G. Role of Regulatory Immune Cells and Molecules in Autoimmune Bullous Dermatoses. Front Immunol 2019; 10:1746. [PMID: 31428090 PMCID: PMC6688483 DOI: 10.3389/fimmu.2019.01746] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 07/10/2019] [Indexed: 12/12/2022] Open
Abstract
Autoimmune bullous dermatoses (AIBD) include a series of typical organ-specific autoimmune diseases characterized by extensive mucocutaneous blisters. It is generally accepted to be caused by pathological autoantibodies that directly target specific adhesion components of the skin or the adjacent mucous membranes. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Recent studies have indicated that the dysfunction of regulatory T cells, regulatory B cells, and complement regulatory proteins that play essential roles in maintaining a healthy immune environment is also closely related to immune disorders in AIBD. It is important to summarize these studies, elucidate the changes in these regulatory immune cells and molecules for the pathogenesis of AIBD, and reveal the mechanisms by which they lose their ability to regulate immune disorders. In this review, we highlight the role of regulatory immune cells and molecules in the pathogenesis of pemphigus vulgaris and bullous pemphigoid, the two most representative forms of AIBD, and indicate issues that should be addressed in future investigations.
Collapse
Affiliation(s)
- Tianyu Cao
- Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Shuai Shao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Hui Fang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Bing Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
47
|
Myeloid Dendritic Cells Are Enriched in Lymph Node Tissue of Early Rheumatoid Arthritis Patients but not in At Risk Individuals. Cells 2019; 8:cells8070756. [PMID: 31330824 PMCID: PMC6679555 DOI: 10.3390/cells8070756] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/12/2019] [Accepted: 07/18/2019] [Indexed: 12/26/2022] Open
Abstract
Lymph nodes (LNs) are highly organized structures where specific immune responses are initiated by dendritic cells (DCs). We investigated the frequency and distribution of human myeloid (mDCs) and plasmacytoid (pDCs) in LNs and blood during the earliest phases of rheumatoid arthritis (RA). We included 22 RA-risk individuals positive for IgM rheumatoid factor and/or anti-citrullinated protein antibodies, 16 biological-naïve RA patients and 8 healthy controls (HCs). DC subsets (CD1c+ mDCs and CD304+ pDCs) in LN tissue and paired peripheral blood were analyzed using flow cytometry and confocal microscopy. In blood of RA patients a significant decreased frequency of pDCs was found, with a similar trend for mDCs. In contrast, mDC frequencies were higher in RA compared with HCs and RA-risk individuals, especially in LN. Frequency of mDCs seemed higher in LNs compared to paired blood samples in all donors, while pDCs were higher in LNs only in RA patients. As expected, both mDCs and pDCs localized mainly in T-cell areas of LN tissue. In conclusion, compared with RA-risk individuals, mDCs and pDCs were enriched in the LN tissue of early-RA patients, while their frequency in RA-risk individuals was comparable to HCs. This may suggest that other antigen-presenting cells are responsible for initial breaks of tolerance, while mDCs and pDCs are involved in sustaining inflammation.
Collapse
|
|
48
|
Mölzer C, Shankar SP, Griffith M, Islam MM, Forrester JV, Kuffová L. Activation of dendritic cells by crosslinked collagen hydrogels (artificial corneas) varies with their composition. J Tissue Eng Regen Med 2019; 13:1528-1543. [PMID: 31144475 DOI: 10.1002/term.2903] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 05/01/2019] [Accepted: 05/24/2019] [Indexed: 12/13/2022]
Abstract
Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen-containing matrices, MatrigelTM and de-cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a "tolerogenic" phenotype. The same applied to singly crosslinked CMP-PEG gels. RHCIII gels singly crosslinked using either N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide with the coinitiator N-hydroxy succinimide (EDC-NHS) or N-cyclohexyl-N-(2-morpholinoethyl)carbodiimide metho-p-toulenesulfonate with NHS (CMC-NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2-methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte-associated immunoglobulin-like receptor-1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.
Collapse
Affiliation(s)
- Christine Mölzer
- School of Medicine and Dentistry, Section of Immunology, Inflammation and Infection, Institute of Medical Sciences, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK
| | - Sucharita P Shankar
- School of Medicine and Dentistry, Section of Immunology, Inflammation and Infection, Institute of Medical Sciences, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK
| | - May Griffith
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.,Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC, Canada
| | - Mirazul M Islam
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.,Schepens Eye Research Institute and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - John V Forrester
- School of Medicine and Dentistry, Section of Immunology, Inflammation and Infection, Institute of Medical Sciences, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK
| | - Lucia Kuffová
- School of Medicine and Dentistry, Section of Immunology, Inflammation and Infection, Institute of Medical Sciences, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK
| |
Collapse
|
|
49
|
Mesenchymal stem cell therapy induces FLT3L and CD1c + dendritic cells in systemic lupus erythematosus patients. Nat Commun 2019; 10:2498. [PMID: 31175312 PMCID: PMC6555800 DOI: 10.1038/s41467-019-10491-8] [Citation(s) in RCA: 113] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 05/14/2019] [Indexed: 02/06/2023] Open
Abstract
Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs. Promising pilot clinical trials of mesenchymal stem cells (MSCs) therapy of lupus await validation in larger, controlled trials. Here the authors show that MSCs expand CD1c+ dendritic cells in cell culture by producing FLT3L, and that in lupus patients, circulating CD1c+ dendritic cells and FLT3L are increased following MSCs therapy.
Collapse
|
|
50
|
Onali S, Favale A, Fantini MC. The Resolution of Intestinal Inflammation: The Peace-Keeper's Perspective. Cells 2019; 8:cells8040344. [PMID: 30979024 PMCID: PMC6523641 DOI: 10.3390/cells8040344] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
The uncontrolled activation of the immune system toward antigens contained in the gut lumen in genetically predisposed subjects is believed to be the leading cause of inflammatory bowel disease (IBD). Two not mutually exclusive hypotheses can explain the pathogenic process leading to IBD. The first and mostly explored hypothesis states that the loss of tolerance toward gut microbiota antigens generates an aberrant inflammatory response that is perpetuated by continuous and unavoidable exposure to the triggering antigens. However, the discovery that the resolution of inflammation is not the mere consequence of clearing inflammatory triggers and diluting pro-inflammatory factors, but rather an active process in which molecular and cellular elements are involved, implies that a defect in the pro-resolving mechanisms might cause chronic inflammation in different immune-mediated diseases, including IBD. Here we review data on pro-resolving and counter-regulatory mechanisms involved in the resolution of inflammation, aiming to identify their possible involvement in the pathogenesis of IBD.
Collapse
Affiliation(s)
- Sara Onali
- Dep. of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Agnese Favale
- Dep. of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Massimo C Fantini
- Dep. of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| |
Collapse
|