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Miller S, Eizenberg-Magar I, Reich-Zeliger S, Rimer J, Zaretsky I, Reshef D, Kopitman E, Friedman N, Antebi YE. Independent and temporally separated dynamics for RORγt and Foxp3 during Th17 differentiation. Front Immunol 2025; 16:1462045. [PMID: 40356912 PMCID: PMC12066577 DOI: 10.3389/fimmu.2025.1462045] [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: 08/12/2024] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
T helper 17 and Regulatory T cells (Th17 and Treg, respectively) are two well-described lymphocyte subsets with opposing actions. The divergent fates of Th17 and Treg cells are accounted for, at least in part, by molecular antagonism that occurs between their respective specific transcription factors, RORγt and Foxp3. An imbalance between Th17 and Treg cells may lead to tissue inflammation and is associated with certain types of autoimmunity. In order to understand the heterogeneity and dynamics of the differentiation process, we studied Th17/Treg cell differentiation of naïve cells in vitro, using RORγtGFPFoxp3RFP dual-reporter mouse. Flow cytometry revealed the consistent emergence of a population of double positive RORγt+Foxp3+ (DP) cells during the early stages of Th17 cell differentiation. These DP cells are closely related to RORγt+ single positive (SPR) cells in terms of global gene expression. Nevertheless, for some genes, DP cells share an expression pattern with Foxp3+ single positive (SPF) Treg cells, most importantly by reducing IL17 levels. Using time-lapse microscopy, we could delineate the expression dynamics of RORγt and Foxp3 at a clonal level. While the RORγt expression level elevates early during differentiation, Foxp3 rises later and is more stable upon environmental changes. These distinct expression profiles are independent of each other. During differentiation and proliferation, individual cells transit between SPR, DP, and SPF states. Nevertheless, the differentiation of sister cells within a clone progeny was highly correlated. We further demonstrated that sorted SPR and DP populations were not significantly affected by changes in their environment, suggesting that the correlated fate decision emerged at early time points before the first division. Overall, this study provides the first quantitative analysis of differentiation dynamics during the generation of DP RORγt+Foxp3+ cells. Characterizing these dynamics and the differentiation trajectory could provide a profound understanding and be used to better define the distinct fates of T cells, critical mediators of the immune response.
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MESH Headings
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
- Animals
- Cell Differentiation/immunology
- Th17 Cells/immunology
- Th17 Cells/cytology
- Th17 Cells/metabolism
- Forkhead Transcription Factors/metabolism
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/immunology
- Mice
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/cytology
- Mice, Inbred C57BL
- Mice, Transgenic
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Affiliation(s)
- Stav Miller
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | | | | | - Jacob Rimer
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Irina Zaretsky
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Dan Reshef
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ekaterina Kopitman
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Nir Friedman
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Yaron E Antebi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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2
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Jagasia P, Taritsa I, Bagdady K, Shah S, Fracol M. Silicone breast implant-associated pathologies and T cell-mediated responses. Inflamm Res 2025; 74:33. [PMID: 39891670 DOI: 10.1007/s00011-025-02006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/21/2025] [Accepted: 01/28/2025] [Indexed: 02/03/2025] Open
Abstract
Silicone breast implants elicit a foreign body response (FBR) defined by a complex cascade of various immune cells. Studies have shown that the capsule around silicone breast implants that forms as a result of the FBR contains large T cell populations. T cells are implicated in pathologies such as capsular contracture, which is defined by an excessively fibrotic capsule, and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a non-Hodgkin's lymphoma. In this article, we provide a synthesis of 17 studies reporting on T cell-mediated responses to silicone breast implants and highlight recent developments on this topic. The lymphocytes present in the breast implant capsule are predominantly Th1 and Th17 cells. Patients with advanced capsular contracture had fewer T-regulatory (Treg) cells present in the capsules that were less able to suppress T effector cells such as Th17 cells, which can promote fibrosis in autoimmune conditions. Textured silicone implants, which are associated with BIA-ALCL, created a more robust T cell response, especially CD30 + T cells in the peri-implant fluid and CD4 + T cells in the capsule. Cultivating a deeper understanding of T cell-mediated responses to silicone breast implants may allow for novel treatments of breast implant-associated complications and malignancies.
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Affiliation(s)
- Puja Jagasia
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Iulianna Taritsa
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Kazimir Bagdady
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Shivani Shah
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Megan Fracol
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA.
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Złotkowska D, Markiewicz LH, Ogrodowczyk AM, Wróblewska B, Wasilewska E. Enhanced Effect of β-Lactoglobulin Immunization in Mice with Mild Intestinal Deterioration Caused by Low-Dose Dextran Sulphate Sodium: A New Experimental Approach to Allergy Studies. Nutrients 2024; 16:3430. [PMID: 39458426 PMCID: PMC11510979 DOI: 10.3390/nu16203430] [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: 08/28/2024] [Revised: 09/26/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Cow's milk allergy is one of the most common food allergies in children, and its pathomechanism is still under investigation. Recently, an increasing number of studies have linked food allergy to intestinal barrier dysfunction. The present study aimed to investigate changes in the intestinal microenvironment during the development of β-lactoglobulin (β-lg) allergy under conditions of early intestinal dysfunction. METHODS BALB/c mice received intraperitoneal β-lg with Freund's adjuvant, followed by oral β-lg while receiving dextran sulphate sodium salt (DSS) in their drinking water (0.2% w/v). The immunized group without DSS and the groups receiving saline, oral β-lg, or DSS served as controls. RESULTS The study showed that the immunization effect was greater in mice with mild intestinal barrier dysfunction. Although DSS did not affect the mice's humoral response to β-lg, in combination with β-lg, it significantly altered their cellular response, affecting the induction and distribution of T cells in the inductive and peripheral tissues and the activation of immune mediators. Administration of β-lg to sensitized mice receiving DSS increased disease activity index (DAI) scores and pro-inflammatory cytokine activity, altered the distribution of claudins and zonulin 1 (ZO-1) in the colonic tissue, and negatively affected the balance and activity of the gut microbiota. CONCLUSIONS The research model used appears attractive for studying food allergen sensitization, particularly in relation to the initial events leading to mucosal inflammation and the development of food hypersensitivity.
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Affiliation(s)
| | | | | | | | - Ewa Wasilewska
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland
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Wu Q, Liu Y, Liang J, Dai A, Du B, Xi X, Jin L, Guo Y. Baricitinib relieves DSS-induced ulcerative colitis in mice by suppressing the NF-κB and JAK2/STAT3 signalling pathways. Inflammopharmacology 2024; 32:849-861. [PMID: 38227095 DOI: 10.1007/s10787-023-01396-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/14/2023] [Indexed: 01/17/2024]
Abstract
Ulcerative colitis (UC) is a relapsing inflammatory disease with a unique aetiology. The treatment of UC is challenging, and the current clinical therapeutics for colitis have limited efficacy. Thus, finding new and effective treatment options remains urgent. Baricitinib, an inhibitor of Janus kinase (JAK), has been clinically used to treat rheumatoid arthritis (RA). However, its potential effects on UC have not been fully elucidated. In this study, we aimed to explore the effects of baricitinib on UC and its underlying mechanism. Dextran sulphate sodium (DSS)-induced murine model of chronic colitis was used to investigate the intervention efficacy following oral administration of baricitinib. The levels of key cytokines, such as IL-6, IFN-γ and IL-17A, were determined. Moreover, western blotting for IκBα, p-IκBα, JAK2, p-JAK2, STAT3 and p-STAT3 protein expression was performed to investigate the associated signalling pathways. Our findings demonstrated that baricitinib can significantly relieve DSS-induced UC in mice. After baricitinib intervention, IL-6, IFN-γ and IL-17A levels were decreased both in vitro and in vivo. Moreover, the elevated expression levels of p-IκBα, p-JAK2, and p-STAT3 were significantly reduced after treatment. Collectively, these results suggest that baricitinib is a potential therapeutic agent for alleviation of DSS-induced colitis. This study provides a method for subsequent investigations on potential curative drugs development of the for colitis.
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Affiliation(s)
- Qiong Wu
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Yangyang Liu
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Jinmeiqi Liang
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Ao Dai
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Boyu Du
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
| | - Xueyan Xi
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Lan Jin
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
| | - Yang Guo
- Department of Immunology, School of Basic Medical Sciences, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, People's Republic of China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
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Barnes JL, Yoshida M, He P, Worlock KB, Lindeboom RGH, Suo C, Pett JP, Wilbrey-Clark A, Dann E, Mamanova L, Richardson L, Polanski K, Pennycuick A, Allen-Hyttinen J, Herczeg IT, Arzili R, Hynds RE, Teixeira VH, Haniffa M, Lim K, Sun D, Rawlins EL, Oliver AJ, Lyons PA, Marioni JC, Ruhrberg C, Tuong ZK, Clatworthy MR, Reading JL, Janes SM, Teichmann SA, Meyer KB, Nikolić MZ. Early human lung immune cell development and its role in epithelial cell fate. Sci Immunol 2023; 8:eadf9988. [PMID: 38100545 PMCID: PMC7615868 DOI: 10.1126/sciimmunol.adf9988] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 11/03/2023] [Indexed: 12/17/2023]
Abstract
Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.
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Affiliation(s)
- Josephine L Barnes
- UCL Respiratory, Division of Medicine, University College London, London, UK
| | - Masahiro Yoshida
- UCL Respiratory, Division of Medicine, University College London, London, UK
- Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Peng He
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK
| | - Kaylee B Worlock
- UCL Respiratory, Division of Medicine, University College London, London, UK
| | - Rik G H Lindeboom
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Chenqu Suo
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - J Patrick Pett
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | | | - Emma Dann
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Lira Mamanova
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- Enhanc3D Genomics Ltd, Cambridge, UK
| | - Laura Richardson
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | | | - Adam Pennycuick
- UCL Respiratory, Division of Medicine, University College London, London, UK
| | | | - Iván T Herczeg
- UCL Respiratory, Division of Medicine, University College London, London, UK
| | - Romina Arzili
- UCL Respiratory, Division of Medicine, University College London, London, UK
| | - Robert E Hynds
- Epithelial Cell Biology in ENT Research (EpiCENTR) Group, Developmental Biology and Cancer Department, Great Ormond Street UCL Institute of Child Health, University College London, London, UK
- CRUK Lung Cancer Centre Of Excellence, UCL Cancer Institute, University College London, London, UK
| | - Vitor H Teixeira
- UCL Respiratory, Division of Medicine, University College London, London, UK
| | - Muzlifah Haniffa
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Kyungtae Lim
- Wellcome Trust/CRUK Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
- Department of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Dawei Sun
- Wellcome Trust/CRUK Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Emma L Rawlins
- Wellcome Trust/CRUK Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Amanda J Oliver
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Paul A Lyons
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
| | - John C Marioni
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
| | | | - Zewen Kelvin Tuong
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
- Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Menna R Clatworthy
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - James L Reading
- CRUK Lung Cancer Centre Of Excellence, UCL Cancer Institute, University College London, London, UK
- Tumour Immunodynamics and Interception Laboratory, Cancer Institute, University College London, London, UK
| | - Sam M Janes
- UCL Respiratory, Division of Medicine, University College London, London, UK
- CRUK Lung Cancer Centre Of Excellence, UCL Cancer Institute, University College London, London, UK
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
- Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Department of Physics/Cavendish Laboratory, University of Cambridge, Cambridge, UK
| | - Kerstin B Meyer
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Marko Z Nikolić
- UCL Respiratory, Division of Medicine, University College London, London, UK
- University College London Hospitals NHS Foundation Trust, London, UK
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6
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Gao J, Zhang H, Yang Y, Tao J. Therapeutic Potential of Targeting the NLRP3 Inflammasome in Rheumatoid Arthritis. Inflammation 2023; 46:835-852. [PMID: 36897552 DOI: 10.1007/s10753-023-01795-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/10/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic multiprotein complex composed of the innate immune receptor protein NLRP3, the adapter protein apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC), and the inflammatory protease cysteine-1. Pathogen-associated molecular patterns (PAMPs) or other endogenous danger-associated molecular patterns (DAMPs) activate the NLRP3 inflammasome. As part of the innate immune response, activated NLRP3 promotes GSDMD-dependent pyroptosis, and IL-1β and IL-18 are released during inflammation. Aberrantly activated NLRP3 is deeply involved in various inflammatory diseases. Due to its interaction with adaptive immunity. NLRP3 inflammation has increasingly received attention in autoimmune diseases. Rheumatoid arthritis (RA) is a classic autoimmune disease, which mainly causes bone and cartilage damage. Elevated levels of NLRP3 can be detected in the synovium of RA patients. NLRP3 overactivation is strongly associated with RA activity. Mouse models of spontaneous arthritis has shown that NLRP3/IL-1β axis is implicated in periarticular inflammation in RA. In this review, we describe the current understanding of NLRP3 activation in RA pathogenesis and dissect its impact on innate and adaptive immunity. We also discuss the potential application of specific inhibitors of NLRP3 to provide new therapeutic strategies for treating RA.
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Affiliation(s)
- Jie Gao
- Department of Rheumatology and Immunology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, People's Republic of China
| | - Hongliang Zhang
- Department of Rheumatology and Immunology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, People's Republic of China
- College of Medicine and Health, Lishui University, Liandu District, No. 1 Xueyuan Road, Lishui, 323000, China
| | - Yanyan Yang
- Department of Rheumatology and Immunology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, People's Republic of China
| | - Jinhui Tao
- Department of Rheumatology and Immunology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, People's Republic of China.
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Bessho S, Grando KCM, Kyrylchuk K, Miller A, Klein-Szanto AJ, Zhu W, Gallucci S, Tam V, Tükel Ç. Systemic exposure to bacterial amyloid curli alters the gut mucosal immune response and the microbiome, exacerbating Salmonella-induced arthritis. Gut Microbes 2023; 15:2221813. [PMID: 37317012 PMCID: PMC10269392 DOI: 10.1080/19490976.2023.2221813] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/16/2023] Open
Abstract
The Salmonella biofilm-associated amyloid protein, curli, is a dominant instigator of systemic inflammation and autoimmune responses following Salmonella infection. Systemic curli injections or infection of mice with Salmonella Typhimurium induce the major features of reactive arthritis, an autoimmune disorder associated with Salmonella infection in humans. In this study, we investigated the link between inflammation and microbiota in exacerbating autoimmunity. We studied C57BL/6 mice from two sources, Taconic Farms and Jackson Labs. Mice from Taconic Farms have been reported to have higher basal levels of the inflammatory cytokine IL - 17 than do mice from Jackson Labs due to the differences in their microbiota. When we systemically injected mice with purified curli, we observed a significant increase in diversity in the microbiota of Jackson Labs mice but not in that of the Taconic mice. In Jackson Labs, mice, the most striking effect was the expansion of Prevotellaceae. Furthermore, there were increases in the relative abundance of the family Akkermansiaceae and decreases in families Clostridiaceae and Muribaculaceae in Jackson Labs mice. Curli treatment led to significantly aggravated immune responses in the Taconic mice compared to Jackson Labs counterparts. Expression and production of IL - 1β, a cytokine known to promote IL - 17 production, as well as expression of Tnfa increased in the gut mucosa of Taconic mice in the first 24 hours after curli injections, which correlated with significant increases in the number of neutrophils and macrophages in the mesenteric lymph nodes. A significant increase in the expression of Ccl3 in colon and cecum of Taconic mice injected with curli was detected. Taconic mice injected with curli also had elevated levels of inflammation in their knees. Overall, our data suggest that autoimmune responses to bacterial ligands, such as curli, are amplified in individuals with a microbiome that promote inflammation.
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Affiliation(s)
- Shingo Bessho
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Kaitlyn C. M. Grando
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Kathrine Kyrylchuk
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Amanda Miller
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | | | - Wenhan Zhu
- Department of Pathology Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Stefania Gallucci
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Vincent Tam
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Çagla Tükel
- Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, USA
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8
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Nour-Eldine W, Ltaief SM, Abdul Manaph NP, Al-Shammari AR. In search of immune cellular sources of abnormal cytokines in the blood in autism spectrum disorder: A systematic review of case-control studies. Front Immunol 2022; 13:950275. [PMID: 36268027 PMCID: PMC9578337 DOI: 10.3389/fimmu.2022.950275] [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: 05/22/2022] [Accepted: 09/21/2022] [Indexed: 12/04/2022] Open
Abstract
Abnormal cytokine levels in circulating blood have been repeatedly reported in autism; however, the underlying cause remains unclear. This systematic review aimed to investigate cytokine levels in peripheral blood compartments and identify their potential immune cellular sources in subjects with autism through comparison with controls. We conducted an electronic database search (PubMed, Scopus, ProQuest Central, Ovid, SAGE Journals, and Wiley Online Library) from inception (no time limits) to July 9, 2020, and identified 75 relevant articles. Our qualitative data synthesis focused on results consistently described in at least three independent studies, and we reported the results according to the PRISMA protocol. We found that compared with controls, in subjects with autism, cytokines IL-6, IL-17, TNF-α, and IL-1β increased in the plasma and serum. We also identified monocytes, neutrophils, and CD4+ T cells as potential sources of these elevated cytokines in autism. Cytokines IFN-γ, TGF-β, RANTES, and IL-8 were increased in the plasma/serum of subjects with autism, and IFN-γ was likely produced by CD4+ T cells and natural killer (NK) cells, although conflicting evidence is present for IFN-γ and TGF-β. Other cytokines-IL-13, IL-10, IL-5, and IL-4-were found to be unaltered in the plasma/serum and post-stimulated blood immune cells in autistic individuals as compared with controls. The frequencies of T cells, monocytes, B cells, and NK cells were unchanged in subjects with autism as opposed to controls, suggesting that abnormal cytokines were unlikely due to altered cell numbers but might be due to altered functioning of these cells in autism. Our results support existing studies of abnormal cytokines in autism and provide comprehensive evidence of potential cellular sources of these altered cytokines in the context of autism. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205224, identifier [CRD42020205224].
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Affiliation(s)
| | | | | | - Abeer R. Al-Shammari
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
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Androgen Plays a Potential Novel Hormonal Therapeutic Role in Th17 Cells Predominant Neutrophilic Severe Asthma by Attenuating BECs Regulated Th17 Cells Differentiation via MBD2 Expression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3096528. [PMID: 36062195 PMCID: PMC9436621 DOI: 10.1155/2022/3096528] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/02/2022] [Indexed: 12/05/2022]
Abstract
T helper 17 (Th17) cells subtype of non-T2 asthma is less responsive (resistant) to inhaled corticosteroids (ICS), so also called severe asthma. Methyl-CpG-binding domain protein 2 (MBD2) regulates the differentiation of the Th17 cells, showing the possibility of a therapeutic target in severe asthma. Androgen tends to show beneficial therapeutic effects and is a “hot research topic,” but its role in the differentiation and expression of Th17 cells via MBD2 is still unknown. The aim of this study was to evaluate how sex hormone interacts with MBD2 and affects the differentiation and expression of Th17 cells in severe asthma. Here, first, we measured the concentration of androgen, estrogen, and androgen estrogen ratio from subjects and correlated it with severe asthma status. Then, we established an animal model and bronchial epithelial cells (BECs) model of severe asthma to evaluate the role of MBD2 in the differentiation and expression of Th17 cells (IL-17), the therapeutic potential of sex hormones in severe asthma, and the effect of sex hormones in BECs regulated Th17 cells differentiation via MBD2 at the cellular level. Increased MBD2 expression and Th17 cells differentiation were noted in the animal and the BECs severe asthma models. Th17 cell differentiation and expression were MBD2 dependent. Androgen attenuated the differentiation of BECs regulated Th17 cells via MBD2 showing BECs as a therapeutic target of androgen, and these findings postulate the novel role of androgen in Th17 cells predominant neutrophilic severe asthma therapy through targeting MBD2.
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10
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Duarte I, de Souza MCM, Curinga RM, Mendonça HM, de Lacerda de Oliveira L, Milenkovic D, Hassimotto NMA, Costa AM, Malaquias JV, Dos Santos Borges TK. Effect of Passiflora setacea juice and its phenolic metabolites on insulin resistance markers in overweight individuals and on microglial cell activity. Food Funct 2022; 13:6498-6509. [PMID: 35621054 DOI: 10.1039/d1fo04334j] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Passiflora setacea (PS) is a species of wild Brazilian passion fruit, rich in bioactive compounds. Scientific evidence suggests that food rich in polyphenols can modulate inflammation, thereby playing an important role in preventing chronic non-communicable diseases, such as type 2 diabetes (DT2) and cardiovascular diseases (CVD). This study aimed to investigate the effect of PS consumption on metabolic and inflammatory biomarkers in overweight male volunteers and to identify the underlying mechanism of action using an in vitro study using phenolic metabolites isolated from the plasma of volunteers at physiologically relevant concentrations. Volunteers participated in a double-blind, placebo-controlled (PB) study with two phases: phase I (acute study) and phase II (chronic study). In phase I, 15 volunteers ingested a single dose of 50 g, 150 g of PS pulp and PB in three different interventions. In phase II, nine volunteers ingested 50 g of PS or PB for 14 days. Blood samples were collected before (T0 h) and 3 h (T3 h) (phase I) or 15 days after (phase II) ingestion of PS or PB. Blood biochemical markers, HOMA IR, and inflammatory markers were analyzed and data on BMI, waist circumference, and consumption of polyphenol-rich foods were collected. Phenolic metabolites were extracted from plasma by solid-phase separation and were used to treat BV-2 cells stimulated by LPS or anacardic acid to assess p50, p65 and PPAR-γ activation. It was observed that the consumption of a single dose of PS juice significantly reduced basal insulin levels and HOMA IR. After prolonged consumption for two weeks, PS contributed to the reduction of circulating levels of IL-6. BV-2 cells treated with PS phenolic metabolites showed increased PPAR-γ activity, which resulted in an anti-inflammatory and anti-diabetic effect of PS metabolites. In conclusion, PS juice consumption exerts beneficial effects on inflammatory markers in overweight individuals, being a possible and important tool in the prevention of T2D and CVD in risk groups.
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Affiliation(s)
- Isabella Duarte
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, DF, 70.910-900, Brazil.
| | - Maria Carolina Miranda de Souza
- Department of Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, DF, 70.910-900, Brazil
| | - Rafaela Moura Curinga
- Laboratory of Cellular Immunology, Faculty of Medicine, University of Brasilia, Brasilia, DF, 70.910-900, Brazil
| | - Henrique Matos Mendonça
- Laboratory of Cellular Immunology, Faculty of Medicine, University of Brasilia, Brasilia, DF, 70.910-900, Brazil
| | - Livia de Lacerda de Oliveira
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, DF, 70.910-900, Brazil.
| | - Dragan Milenkovic
- Department of Nutrition, University of California, Davis, Davis, CA, USA
| | - Neuza Mariko Aymoto Hassimotto
- Food Research Center (FoRC-CEPID) and Department of Food Science and Experimental Nutrition, School of Pharmaceutical Science, University of São Paulo, São Paulo, SP, Brazil
| | - Ana Maria Costa
- Embrapa Cerrados, BR 020, Km18, Laboratory of Food Science, Planaltina, DF, 73.310-970, Brazil
| | - Juaci Vitorio Malaquias
- Embrapa Cerrados, BR 020, Km18, Laboratory of Food Science, Planaltina, DF, 73.310-970, Brazil
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11
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Jiang Z, Zhu H, Wang P, Que W, Zhong L, Li X, Du F. Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity. MedComm (Beijing) 2022; 3:e137. [PMID: 35474948 PMCID: PMC9023873 DOI: 10.1002/mco2.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022] Open
Abstract
CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery The Affiliated Hospital of Guizhou Medical University Guizhou P. R. China
| | - Pusen Wang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Weitao Que
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Lin Zhong
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Xiao‐Kang Li
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
- Division of Transplantation Immunology National Research Institute for Child Health and Development Tokyo Japan
| | - Futian Du
- Department of Hepatobiliary Surgery Weifang People's Hospital Shandong P. R. China
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12
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Longo V, Parrinello D, Longo A, Parisi MG, Parrinello N, Colombo P, Cammarata M. The conservation and diversity of ascidian cells and molecules involved in the inflammatory reaction: The Ciona robusta model. FISH & SHELLFISH IMMUNOLOGY 2021; 119:384-396. [PMID: 34687879 DOI: 10.1016/j.fsi.2021.10.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/27/2021] [Accepted: 10/16/2021] [Indexed: 06/13/2023]
Abstract
Ascidians are marine invertebrate chordates belonging to the earliest branch (Tunicata) in the chordate phylum, therefore, they are of interest for studying the evolution of immune systems. Due to the known genome, the non-colonial Ciona robusta, previously considered to be C. intestinalis type A, is a model species for the study of inflammatory response. The internal defense of ascidians mainly relies on hemocytes circulating in the hemolymph and pharynx. Hemocytes can be in vivo challenged by LPS injection and various granulocyte and vacuolated cell populations differentiated to produce and release inflammatory factors. Molecular biology and gene expression studies revealed complex defense mechanisms involving different inflammatory hemocytes. Furthermore, cloning procedures allowed sequence analyses and molecular studies disclose immune-related gene families including TOLL-like receptors, galectins, C-type lectins, collectins, interlectins, pentraxine-like, peroxinectins, complement factors-like, TNFα-like, IL-17-like, TGF-like, MIF-like. These genes are promptly upregulated by the inflammatory stimulus and show a time course of transcription similar to each other. Domains sequence similarity and phylogenetic relationships with the vertebrate counterparts are shedding some light on immune-related gene evolution. Selective bioassays as well as bioinformatic approaches have allowed the characterization of antimicrobial peptides and the identification of post transcriptional molecular mechanisms able of influencing dynamics of gene regulation are described. In synthesis, the purpose of this article is to further explore the topic of hemocyte and molecules related to internal defence of ascidians involved in the inflammatory reaction, as well as to discuss current and future study options through a detailed literature review.
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Affiliation(s)
- Valeria Longo
- Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy
| | | | - Alessandra Longo
- Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy
| | | | - Nicolò Parrinello
- Department of Earth and Marine Science, University of Palermo, Italy
| | - Paolo Colombo
- Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy.
| | - Matteo Cammarata
- Department of Earth and Marine Science, University of Palermo, Italy
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13
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de Araújo Esteves Duarte I, Milenkovic D, Borges TK, de Lacerda de Oliveira L, Costa AM. Brazilian passion fruit as a new healthy food: from its composition to health properties and mechanisms of action. Food Funct 2021; 12:11106-11120. [PMID: 34651638 DOI: 10.1039/d1fo01976g] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The Brazilian biodiversity is one of the largest in the world, with about 41 000 species cataloged within two global biodiversity hotspots: Atlantic Forest and Cerrado, the Brazilian savannah. Passiflora, known also as passion flowers, is a genus of which 96% of its species are distributed in the Americas, mainly Brazil and Colombia. Passion fruit extracts have a commercial value on a global scale through the pharmaceutical, nutraceutical, self-care, and food and beverage industries. Passiflora are widely studied due to their potential antioxidant, anti-inflammatory, anxiolytic, antidepressant and vascular and neuronal protective effects, probably owing to their content of polyphenols. Passiflora setacea DC is a species of wild passion fruit from the Brazilian Cerrado, rich in flavonoid C-glycosides, homoorientin, vitexin, isovitexin and orientin. Intake of these plant food bioactives has been associated with protection against chronic non-communicable diseases (CNDCs), including cardiovascular diseases, cancers, and neurodegenerative diseases. In this review, we aimed to discuss the varieties of Passiflora, their content in plant food bioactives and their potential molecular mechanisms of action in preventing or reversing CNDCs.
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Affiliation(s)
- Isabella de Araújo Esteves Duarte
- Postgraduate Program in Human Nutrition, College of Health Sciences, Campus Universitário Darcy Ribeiro, University of Brasilia, Brasília DF 70.910-900, Brazil.
| | - Dragan Milenkovic
- Unité de Nutrition Humaine, Université Clermont Auvergne, INRAE, UNH, F-63000 Clermont-Ferrand, France.,Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, USA
| | - Tatiana Karla Borges
- Laboratory of Cellular Immunology, Faculty of Medicine, University of Brasilia, Brasília DF 70.910-900, Brazil
| | - Livia de Lacerda de Oliveira
- Postgraduate Program in Human Nutrition, College of Health Sciences, Campus Universitário Darcy Ribeiro, University of Brasilia, Brasília DF 70.910-900, Brazil.
| | - Ana Maria Costa
- Laboratory of Food Science, Embrapa Cerrados, Planaltina DF 73.310-970, Brazil
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14
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Feng Z, Jiao L, Wu Z, Xu J, Gu P, Xu S, Liu Z, Hu Y, Liu J, Wu Y, Wang D. A Novel Nanomedicine Ameliorates Acute Inflammatory Bowel Disease by Regulating Macrophages and T-Cells. Mol Pharm 2021; 18:3484-3495. [PMID: 34310145 DOI: 10.1021/acs.molpharmaceut.1c00415] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Ramulus mori polysaccharide (RMP), one of the most important active components of R. mori, has been attracting increasing interest because of its potent bioactive properties, including anti-inflammatory, antitumor, and antidiabetic effects. Despite the great therapeutic potential of RMP, its inherent properties of low bioavailability and brief biological half-life have limited its applications to the clinic. Thus, RMP was packaged by poly(lactic-co-glycolic acid) (PLGA) nanoparticles to develop a novel anti-inflammatory nanomedicine (PLGA-RMP) in this study. The nanoparticles were synthesized via a double-emulsion solvent evaporation technique, and the average diameter of PLGA-RMP was about 202 nm. PLGA-RMP nanoparticles reduced the expression of inflammatory cytokines while promoting the production of IL-10, and boosted the phenotypic shift in macrophages in vitro. Furthermore, lipopolysaccharide (LPS)-induced inflammatory bowel disease (IBD) in mouse was used to examine the anti-inflammatory effect of PLGA-RMP in vivo. Oral administration of PLGA-RMP in LPS-induced IBD mice substantially mitigated the intestinal inflammation compared to treatment with LPS alone, as evidenced by attenuation of disease activity index scores and inflammatory damage in the intestine. Meanwhile, PLGA-RMP suppressed the expression and secretion of specific inflammatory cytokines including TNF-α, IL-6, IL-1β, and PGE2 in the inflamed intestine while inhibiting the activation of CD3+CD8+ T-cells and increasing the number of activated Tregs in the intestine. These results indicated that PLGA-RMP deserves further consideration as a potential therapeutic nanomedicine to treat various inflammatory diseases, including IBD.
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Affiliation(s)
- Zian Feng
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Lina Jiao
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Zhiyong Wu
- Nanjing Traditional Chinese Veterinary Medicine Research Center, Building 1, Weigang, Xuanwu District, Nanjing 210095, P. R. China
| | - Jiameng Xu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Pengfei Gu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Shuwen Xu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Zhenguang Liu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Yuanliang Hu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Jiaguo Liu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Yi Wu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - Deyun Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
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15
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Phloretin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice by regulating the gut microbiota. Pharmacol Res 2019; 150:104489. [PMID: 31689519 DOI: 10.1016/j.phrs.2019.104489] [Citation(s) in RCA: 182] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 10/04/2019] [Accepted: 10/10/2019] [Indexed: 02/06/2023]
Abstract
Phloretin, extracted from the pericarp and velamen of apples or pears, is a dihydrochalcone flavonoid with anti-bacterial and anti-inflammatory activities. It has been reported that phloretin has anti-inflammatory effects in ulcerative colitis (UC) mice. However, the role of the gut microbiota in the phloretin anti-UC process remains unclear. In this study, we observed that the anti-UC effect of phloretin was affected by co-housing, probably because of the transmissible nature of the gut micobiota. Through fecal micobiota transplantation (FMT), the effects of the gut microbiota on the anti-UC of phloretin were further confirmed. UC was induced in mice by administrating 3% dextran sulfate sodium (DSS) in drinking water for 7 days. Phloretin (60 mg/kg) was administered by gavage every day during the experiment. Fecal microbes (109 CFU/mL) from phloretin-treated UC mice were administered by gavage to non-phloretin-treated UC mice for 7 days. The results showed that FMT, like phloretin, ameliorated UC by improving disease symptoms and colon inflammation, balancing inflammatory cytokines, maintaining intestinal barrier integrity, restoring systemic immune function, inhibiting NF-κB and NLRP3 inflammasome activation and ameliorating the oxidant stress. Both FMT and phloretin treatment increased the levels of Bacteroidetes, Alistipes and Lactobacillus and decreased those of Firmicutes, Oscillibacter and Ruminiclostridium_6. Correlation analysis between gut microbes and micro-environmental factors revealed that Alistipes abundance was negatively correlated with DAI, pathological score, and TNF-α, IL-6 and IL-1β levels, and Alistipes was more abundant in phloretin or FMT treated UC mice. Oscillibacter abundance was significantly positively correlated with IL-6 and IL-1β levels and pathological score, and Oscillibacter was increased in UC mice. Furthermore, network analysis of the dominant genera revealed that Alistipes abundance was negatively related to Oscillibacter abundance. In conclusion, this study suggests that the anti-UC effects of phloretin are achieved through regulation of the gut microbiota and phloretin has the potential to be developed as a promising agent for the treatment of UC.
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Lissoni P, Rovelli F, Vigorè L, Messina G, Lissoni A, Porro G, Di Fede G. How to Monitor the Neuroimmune Biological Response in Patients Affected by Immune Alteration-Related Systemic Diseases. Methods Mol Biol 2019; 1781:171-191. [PMID: 29705848 DOI: 10.1007/978-1-4939-7828-1_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The clinical management of patients affected by systemic diseases, including cancer and autoimmune diseases, is generally founded on the evaluation of the only markers related to the single disease rather than the biological immuno-inflammatory response of patients, despite the fundamental role of cytokine network in the pathogenesis of cancer and autoimmunity is well known. Cancer progression has appeared to be associated with a progressive decline in the blood levels of the main antitumor cytokines, including IL-2 and IL-12, in association with an increase in those of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1-beta, and immunosuppressive cytokines, namely TGF-beta and IL-10. On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN-gamma, and IL-18, in association with low levels of TGF-beta and IL-10. However, because of excessive cost and complexity of analyzing the data regarding the secretion of the single cytokines, the relation between lymphocyte-induced immune activation and monocyte-macrophage-mediated immunosuppression has been recently proven to be expressed by the simple lymphocyte-to-monocyte ratio (LMR). The evidence of low LMR values has appeared to correlate with a poor prognosis in cancer and with a disease control in the autoimmune diseases. Moreover, since the in vivo immunoinflammatory response is physiologically under a neuroendocrine modulation, for the evaluation of patient biological response it would be necessary to investigate the function of at least the two main neuroendocrine structures involved in the neuroendocrine modulation of the immune responses, consisting of the hypothalamic-pituitary-adrenal axis and the pineal gland, since the lack of physiological circadian rhythm of cortisol and pineal hormone melatonin has appeared to be associated with a worse prognosis in the human systemic diseases.
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17
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Hu S, Cheng M, Fan R, Wang Z, Wang L, Zhang T, Zhang M, Louis E, Zhong J. Beneficial effects of dual TORC1/2 inhibition on chronic experimental colitis. Int Immunopharmacol 2019; 70:88-100. [PMID: 30797172 DOI: 10.1016/j.intimp.2019.02.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/12/2019] [Accepted: 02/12/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM AZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation. METHODS Dextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis. RESULTS AZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria. CONCLUSIONS These findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.
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Affiliation(s)
- Shurong Hu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Translational Gastroenterology Research Unit, GIGA-R, University of Liège, Belgium
| | - Mengmeng Cheng
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, PR China
| | - Rong Fan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China
| | - Lei Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China
| | - Tianyu Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China
| | - Maochen Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China
| | - Edouard Louis
- Translational Gastroenterology Research Unit, GIGA-R, University of Liège, Belgium; Hepato-Gastroenterology and Digestive Oncology Unit, University Hospital, CHU Liege, Domaine du Sart Tilman, 4000 Liege, Belgium.
| | - Jie Zhong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China.
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18
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Ooi KGJ, Khoo P, Vaclavik V, Watson SL. Statins in ophthalmology. Surv Ophthalmol 2019; 64:401-432. [PMID: 30703407 DOI: 10.1016/j.survophthal.2019.01.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 01/14/2019] [Accepted: 01/17/2019] [Indexed: 01/07/2023]
Abstract
Statins, 3-hydroxy-3-methyl-gutaryl coenzyme A reductase inhibitors, are a class of lipid-lowering drugs with anti-inflammatory, immunomodulatory, and vascular effects. Statins are increasingly being used in the treatment of a variety of medical conditions. We examine the actions of statins on the eye and its associated ophthalmic disorders. Statins can be synthetic or nonsynthetic, and their differentiating derivations may contribute to their varying cholesterol-lowering and pleiotropic effects. There is conflicting evidence on the ocular therapeutic and adverse effects of the statins. Statins may play a role in reducing the burden of dry eye, corneal ulcer scarring, thyroid-associated orbitopathy, glaucoma, uveitis and other associated ocular inflammatory states, cataract, proliferative vitreoretinopathy, diabetic retinopathy, macular degeneration, and choroidal melanoma. Topical preparations of statins can be formulated, thereby extending the range of ocular diseases that may be amenable to treatment. Statins have a relatively safe side effect profile, but rare and serious adverse reactions have been reported with their usage in ophthalmology, including myopathies and rhabdomyolysis with acute renal failure.
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Affiliation(s)
- Kenneth G-J Ooi
- Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia.
| | - Pauline Khoo
- Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Veronika Vaclavik
- Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
| | - Stephanie L Watson
- Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia
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Merkley SD, Chock CJ, Yang XO, Harris J, Castillo EF. Modulating T Cell Responses via Autophagy: The Intrinsic Influence Controlling the Function of Both Antigen-Presenting Cells and T Cells. Front Immunol 2018; 9:2914. [PMID: 30619278 PMCID: PMC6302218 DOI: 10.3389/fimmu.2018.02914] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/28/2018] [Indexed: 12/17/2022] Open
Abstract
Autophagy is a homeostatic and inducible process affecting multiple aspects of the immune system. This intrinsic cellular process is involved in MHC-antigen (Ag) presentation, inflammatory signaling, cytokine regulation, and cellular metabolism. In the context of T cell responses, autophagy has an influential hand in dictating responses to self and non-self by controlling extrinsic factors (e.g., MHC-Ag, cytokine production) in antigen-presenting cells (APC) and intrinsic factors (e.g., cell signaling, survival, cytokine production, and metabolism) in T cells. These attributes make autophagy an attractive therapeutic target to modulate T cell responses. In this review, we examine the impact autophagy has on T cell responses by modulating multiple aspects of APC function; the importance of autophagy in the activation, differentiation and homeostasis of T cells; and discuss how the modulation of autophagy could influence T cell responses.
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Affiliation(s)
- Seth D Merkley
- Clinical and Translational Science Center, University of New Mexico Health Sciences Albuquerque, NM, United States
| | - Cameron J Chock
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Albuquerque, NM, United States
| | - Xuexian O Yang
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Albuquerque, NM, United States.,Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Albuquerque, NM, United States
| | - James Harris
- Rheumatology Group, Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University Clayton, VIC, Australia
| | - Eliseo F Castillo
- Clinical and Translational Science Center, University of New Mexico Health Sciences Albuquerque, NM, United States.,Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Albuquerque, NM, United States.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico School of Medicine Albuquerque, NM, United States
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Lu Y, Kim NM, Jiang YW, Zhang H, Zheng D, Zhu FX, Liang R, Li B, Xu HX. Cambogin suppresses dextran sulphate sodium-induced colitis by enhancing Treg cell stability and function. Br J Pharmacol 2018; 175:1085-1099. [PMID: 29352742 PMCID: PMC5843713 DOI: 10.1111/bph.14150] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 12/22/2022] Open
Abstract
Background and Purpose Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract, and an impaired immune response plays a critical role in IBD. The current drugs and therapies for IBD treatment are of limited use, therefore, there is a need to find novel drugs or therapies for this disease. We investigated the effect of cambogin in a mouse model of dextran sulphate sodium (DSS)‐induced colitis and whether cambogin attenuates inflammation via a Treg‐cell‐mediated effect on the immune response. Experimental Approach Chronic colitis was established in mice using 2% DSS, and cambogin (10 mg·kg−1, p.o.) was administered for 10 days. Body weight, colon length and colon histology were assessed. Cytokine production was measured using elisa and quantitative real‐time PCR. To evaluate the mechanism of cambogin, human CD4+CD25hiCD127lo Treg cells were isolated from peripheral blood mononuclear cells. Major signalling profiles involved in Treg cell stability were measured. Key Results Cambogin attenuated diarrhoea, colon shortening and colon histological injury and IL‐6, IFN‐γ and TNF‐α production in DSS‐treated mice. Cambogin also up‐regulated Treg cell numbers in both the spleen and mesenteric lymph nodes. Furthermore, cambogin (10 μM) prevented Foxp3 loss in human primary Treg cells in vitro, and promoted USP7‐mediated Foxp3 deubiquitination and increased Foxp3 protein expression in LPS‐treated cells. Conclusions and Implications The effect of cambogin on DSS‐induced colitis is expedited by a Treg‐cell‐mediated modification of the immune response, suggesting that cambogin could be applied as a novel agent for treating colitis and other Treg cell‐related diseases.
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Affiliation(s)
- Yue Lu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Na-Mi Kim
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi-Wen Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fu-Xiang Zhu
- Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Rui Liang
- Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Bin Li
- Unit of Molecular Immunology, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai JiaoTong University, Shanghai, China
| | - Hong-Xi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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21
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Yan B, Liu Y, Bai H, Chen M, Xie S, Li D, Liu M, Zhou J. HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies. Am J Cancer Res 2017; 7:1002-1009. [PMID: 28382171 PMCID: PMC5381261 DOI: 10.7150/thno.17615] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Accepted: 01/03/2017] [Indexed: 11/05/2022] Open
Abstract
The pro-inflammatory cytokine interleukin 17 (IL-17) is critically involved in immunity and inflammation. T-helper 17 and γδ T cells are the predominant sources of IL-17 in the immune system. However, the mechanisms by which the expression of IL-17 is regulated in T cells remain elusive. Here, we demonstrate that loss of histone deacetylase 6 (HDAC6) in mice does not affect the generation of CD4+ or CD8+ T cells, but stimulates the development of IL-17-producing γδ T cells. Our data further show that HDAC6 deficiency increases the production of IL-17 by Vγ4+ γδ T cells in the spleen and lymph nodes. Consistent with these observations, small-molecule inhibition of HDAC6 activity in γδ T cells promotes the expression of IL-17 in vitro. These data thus reveal that HDAC6 represses IL-17 production in T cells, providing novel insights into the role of HDAC6 in the immune system. These findings also have important implications for the clinical investigation of HDAC6-targeted therapies.
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22
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Hyung KE, Moon BS, Kim B, Park ES, Park SY, Hwang KW. Lactobacillus plantarum isolated from kimchi suppress food allergy by modulating cytokine production and mast cells activation. J Funct Foods 2017. [DOI: 10.1016/j.jff.2016.12.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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23
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Mahmoudian-Sani MR, Asadi-Samani M, Luther T, Saeedi-Boroujeni A, Gholamian N. A new approach for treatment of type 1 diabetes: Phytotherapy and phytopharmacology of regulatory T cells. J Renal Inj Prev 2017. [DOI: 10.15171/jrip.2017.31] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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Sharma J, Bhar S, Devi CS. A review on interleukins: The key manipulators in rheumatoid arthritis. Mod Rheumatol 2017; 27:723-746. [DOI: 10.1080/14397595.2016.1266071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jatin Sharma
- School of Biosciences and Technology, VIT University, Vellore, India
| | - Sutonuka Bhar
- School of Biosciences and Technology, VIT University, Vellore, India
| | - C. Subathra Devi
- School of Biosciences and Technology, VIT University, Vellore, India
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25
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Liu Y, Zou H, Zhao P, Sun B, Wang J, Kong Q, Mu L, Zhao S, Wang G, Wang D, Zhang Y, Zhao J, Yin P, Liu L, Zhao X, Li H. Activation of the adenosine A2A receptor attenuates experimental autoimmune encephalomyelitis and is associated with increased intracellular calcium levels. Neuroscience 2016; 330:150-61. [DOI: 10.1016/j.neuroscience.2016.05.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 05/12/2016] [Accepted: 05/13/2016] [Indexed: 02/01/2023]
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Zhao HM, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Lu AP, Liu DY. Curcumin improves regulatory T cells in gut-associated lymphoid tissue of colitis mice. World J Gastroenterol 2016; 22:5374-5383. [PMID: 27340353 PMCID: PMC4910658 DOI: 10.3748/wjg.v22.i23.5374] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the probable pathway by which curcumin (Cur) regulates the function of Treg cells by observing the expression of costimulatory molecules of dendritic cells (DCs).
METHODS: Experimental colitis was induced by administering 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Forty male C57BL/6 mice were randomly divided into four groups: normal, TNBS + Cur, TNBS + mesalazine (Mes) and TNBS groups. The mice in the TNBS + Cur and TNBS +Mes groups were treated with Cur and Mes, respectively, while those in the TNBS group were treated with physiological saline for 7 d. After treatment, the curative effect of Cur was evaluated by colonic weight, colonic length, weight index of the colon, and histological observation and score. The levels of CD4+CD25+Foxp3+ T cells (Treg cells) and costimulatory molecules of DCs were measured by flow cytometry. Also, related cytokines were analyzed by enzyme-linked immunosorbent assay.
RESULTS: Cur alleviated inflammatory injury of the colonic mucosa, decreased colonic weigh and histological score, and restored colonic length. The number of Treg cells was increased, while the secretion of TNF-α, IL-2, IL-6, IL-12 p40, IL-17 and IL-21 and the expression of costimulatory molecules (CD205, CD54 [ICAM-1], TLR4, CD252[OX40 L], CD256 [RANK] and CD254 [RANK L]) of DCs were notably inhibited in colitis mice treated with Cur.
CONCLUSION: Cur potentially modulates activation of DCs to enhance the suppressive functions of Treg cells and promote the recovery of damaged colonic mucosa in inflammatory bowel disease.
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Gu L, Deng WS, Sun XF, Zhou H, Xu Q. Rapamycin ameliorates CCl4-induced liver fibrosis in mice through reciprocal regulation of the Th17/Treg cell balance. Mol Med Rep 2016; 14:1153-61. [PMID: 27315465 PMCID: PMC4940054 DOI: 10.3892/mmr.2016.5392] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 04/11/2016] [Indexed: 01/04/2023] Open
Abstract
Previous investigations have suggested that the activation of Th17 cells and/or deficiency of regulatory T cells (Tregs) are involved in the pathogenesis of liver fibrosis. The aim of the present study was to investigate the effect of rapamycin on immune responses in a carbon tetrachloride (CCl4)-induced murine liver fibrosis model. Liver fibrosis was induced by intraperitoneal administration with CCl4. Following injection of CCl4, the mice were treated intraperitoneally with rapamycin (1.25 mg/kg/day) for 8 weeks. Hematoxylin and eosin staining and Masson's trichrome staining were used for histological examination. The protein levels of forkhead/winged helix transcription factor P3, retinoic-acid-related orphan receptor (ROR)-γt in liver tissue were determined by western blotting, the frequency of Th17 and Treg cells in the liver was evaluated by flow cytometry, and a suppression assay was measured by incorporating [3H]-thymidine. In addition, to explore the effect of Tregs expanded with rapamycin on hepatic stellate cells (HSC), HSCs were co-cultured with Tregs from rapamycin or phosphate-buffered saline-treated mice. It was found that rapamycin treatment led to a significant reduction in the number of Th17 cells and in the expression levels of ROR-γt in the liver tissues. Simultaneously, the results of the present study showed a significant increase in the frequency of Tregs and a marked enhancement in the expression of forkhead/winged helix transcription factor P3 in the rapamycin-treated mice. Furthermore, the Tregs in rapamycin-treated mice had significantly higher suppressive effects, compared with the cells from mice treated with phospphate-buffered saline. Consequently, rapamycin treatment prevented the development of CCl4-induced hepatic fibrosis, which was shown by its histological appearances. These results suggested that the immunosuppressive effect of rapamycin on liver fibrosis was associated with the suppression of hepatic fibrogenesis and regulation of the Th17/Treg cell balance.
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Affiliation(s)
- Lei Gu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
| | - Wen-Sheng Deng
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
| | - Xiao-Fei Sun
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Hong Zhou
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
| | - Qing Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
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Ramesh Kumar SG, Aswath Narayanan MB, Jayanthi D. Comparative assessment of the prevalence of periodontal disease in subjects with and without systemic autoimmune diseases: A case-control study. Contemp Clin Dent 2016; 7:170-5. [PMID: 27307662 PMCID: PMC4906858 DOI: 10.4103/0976-237x.183069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Immune mechanism shares a common pathway both for systemic autoimmune diseases and periodontal diseases. Scientific exploration of literature revealed limited studies on the association between systemic autoimmune diseases and periodontal diseases in India. AIM The aim of the study is to find whether the presence of systemic autoimmune diseases in an individual is a risk factor for the development of periodontal disease. SETTINGS AND DESIGN This was a hospital-based case-control study. MATERIALS AND METHODS A sample of 253 patients with systemic autoimmune diseases, attending the Rheumatology Department of Government General Hospital, Chennai-3, and 262 patients without systemic autoimmune diseases, attending the outpatient department of the Tamil Nadu Government Dental College and Hospital, Chennai-3, constituted the case and control groups, respectively. Age, gender, and oral hygiene status matching was done. Oral hygiene status was assessed using oral hygiene index (OHI) and periodontal status was assessed using community periodontal index (CPI) and loss of attachment (LOA) index. STATISTICAL ANALYSIS Statistical analysis was done using SPSS version 15 (SPSS Inc, 2006, Chicago). RESULTS Results showed 99.2% and 73.9% prevalence of gingivitis and periodontitis, respectively, in the case group as compared to 85.5% and 14.9%, respectively, in the control group. There is no linear relationship between OHI scores and prevalence of periodontitis (CPI and LOA scores) in the case group. Patients suffering from systemic autoimmune diseases showed more prevalence of periodontal diseases irrespective of oral hygiene scores. CONCLUSION It is postulated that the presence of systemic autoimmune diseases may pose a risk for the development of periodontal diseases.
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Affiliation(s)
- S. G. Ramesh Kumar
- Department of Public Health Dentistry, Tamil Nadu Government Dental College and Hospital, Chennai, Tamil Nadu, India
| | - M. B. Aswath Narayanan
- Department of Public Health Dentistry, Tamil Nadu Government Dental College and Hospital, Chennai, Tamil Nadu, India
| | - D. Jayanthi
- Department of Public Health Dentistry, Tamil Nadu Government Dental College and Hospital, Chennai, Tamil Nadu, India
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Imani S, Salimian J, Bozorgmehr M, Vahedi E, Ghazvini A, Ghanei M, Panahi Y. Assessment of Treg/Th17 axis role in immunopathogenesis of chronic injuries of mustard lung disease. J Recept Signal Transduct Res 2016; 36:531-41. [DOI: 10.3109/10799893.2016.1141953] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Saber Imani
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran and
| | - Jafar Salimian
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran and
| | - Mahmood Bozorgmehr
- Department of Immunology, Ebn-e-Sina Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ensieh Vahedi
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran and
| | - Ali Ghazvini
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran and
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran and
| | - Yunes Panahi
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran and
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Effects of Synthetic Anti-Inflammatory Sterol in CB3V-Induced Myocarditis: A Morphological Study on Heart Muscle Tissue. J Funct Morphol Kinesiol 2016. [DOI: 10.3390/jfmk1010069] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Vizzini A, Di Falco F, Parrinello D, Sanfratello MA, Cammarata M. Transforming growth factor β (CiTGF-β) gene expression is induced in the inflammatory reaction of Ciona intestinalis. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2016; 55:102-110. [PMID: 26493014 DOI: 10.1016/j.dci.2015.10.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 10/15/2015] [Accepted: 10/15/2015] [Indexed: 06/05/2023]
Abstract
Transforming growth factor (TGF-β) is a well-known component of a regulatory cytokines superfamily that has pleiotropic functions in a broad range of cell types and is involved, in vertebrates, in numerous physiological and pathological processes. In the current study, we report on Ciona intestinalis molecular characterisation and expression of a transforming growth factor β homologue (CiTGF-β). The gene organisation, phylogenetic tree and modelling supported the close relationship with the mammalian TGF suggesting that the C. intestinalis TGF-β gene shares a common ancestor in the chordate lineages. Functionally, real-time PCR analysis showed that CiTGF-β was transcriptionally upregulated in the inflammatory process induced by LPS inoculation, suggesting that is involved in the first phase and significant in the secondary phase of the inflammatory response in which cell differentiation occurs. In situ hybridisation assays revealed that the genes transcription was upregulated in the pharynx, the main organ of the ascidian immune system, and expressed by cluster of hemocytes inside the pharynx vessels. These data supported the view that CiTGF-β is a potential molecule in immune defence systems against bacterial infection.
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Affiliation(s)
- Aiti Vizzini
- Marine Immunobiology Laboratory, Department of Biological Chemical Pharmaceutical Science and Technology, University of Palermo, Via Archirafi 18, Palermo, Italy
| | - Felicia Di Falco
- Marine Immunobiology Laboratory, Department of Biological Chemical Pharmaceutical Science and Technology, University of Palermo, Via Archirafi 18, Palermo, Italy
| | - Daniela Parrinello
- Marine Immunobiology Laboratory, Department of Biological Chemical Pharmaceutical Science and Technology, University of Palermo, Via Archirafi 18, Palermo, Italy
| | - Maria Antonietta Sanfratello
- Marine Immunobiology Laboratory, Department of Biological Chemical Pharmaceutical Science and Technology, University of Palermo, Via Archirafi 18, Palermo, Italy
| | - Matteo Cammarata
- Marine Immunobiology Laboratory, Department of Biological Chemical Pharmaceutical Science and Technology, University of Palermo, Via Archirafi 18, Palermo, Italy.
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Atkinson SM, Hoffmann U, Hamann A, Bach E, Danneskiold-Samsøe NB, Kristiansen K, Serikawa K, Fox B, Kruse K, Haase C, Skov S, Nansen A. Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade. Dis Model Mech 2016; 9:427-40. [PMID: 26822477 PMCID: PMC4852503 DOI: 10.1242/dmm.022905] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 01/22/2016] [Indexed: 12/19/2022] Open
Abstract
Rodent models of arthritis have been extensively used in the elucidation of rheumatoid arthritis (RA) pathogenesis and are instrumental in the development of therapeutic strategies. Here we utilise delayed-type hypersensitivity arthritis (DTHA), a model in C57BL/6 mice affecting one paw with synchronised onset, 100% penetrance and low variation. We investigate the role of regulatory T cells (Tregs) in DTHA through selective depletion of Tregsand the role of IL-17 in connection with Tregdepletion. Given the relevance of Tregsin RA, and the possibility of developing Treg-directed therapies, this approach could be relevant for advancing the understanding of Tregsin inflammatory arthritis. Selective depletion of Tregswas achieved using aFoxp3-DTR-eGFPmouse, which expresses the diphtheria toxin receptor (DTR) and enhanced green fluorescent protein (eGFP) under control of theFoxp3gene. Anti-IL-17 monoclonal antibody (mAb) was used for IL-17 blockade. Numbers and activation of Tregsincreased in the paw and its draining lymph node in DTHA, and depletion of Tregsresulted in exacerbation of disease as shown by increased paw swelling, increased infiltration of inflammatory cells, increased bone remodelling and increased production of inflammatory mediators, as well as increased production of anti-citrullinated protein antibodies. Anti-IL-17 mAb treatment demonstrated that IL-17 is important for disease severity in both the presence and absence of Tregs, and that IL-17 blockade is able to rescue mice from the exacerbated disease caused by Tregdepletion and caused a reduction in RANKL, IL-6 and the number of neutrophils. We show that Tregsare important for the containment of inflammation and bone remodelling in DTHA. To our knowledge, this is the first study using theFoxp3-DTR-eGFPmouse on a C57BL/6 background for Tregdepletion in an arthritis model, and we here demonstrate the usefulness of the approach to study the role of Tregsand IL-17 in arthritis.
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Affiliation(s)
- Sara Marie Atkinson
- Department of Diabetes Complications Research, Global Research, Novo Nordisk A/S, Maaloev 2760, Denmark Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Ute Hoffmann
- Experimentelle Rheumatologie, Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Alf Hamann
- Experimentelle Rheumatologie, Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Emil Bach
- Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark
| | | | - Karsten Kristiansen
- Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark
| | | | - Brian Fox
- Immunexpress, Seattle, WA 98109, USA
| | - Kim Kruse
- Department of Diabetes Complications Research, Global Research, Novo Nordisk A/S, Maaloev 2760, Denmark
| | - Claus Haase
- Department of Diabetes Complications Research, Global Research, Novo Nordisk A/S, Maaloev 2760, Denmark
| | - Søren Skov
- Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Anneline Nansen
- Department of Pharmacology, Zealand Pharma, Glostrup 2600, Denmark
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Valiathan R, Asthana D. Increase in frequencies of circulating Th-17 cells correlates with microbial translocation, immune activation and exhaustion in HIV-1 infected patients with poor CD4 T-cell reconstitution. Immunobiology 2016; 221:670-8. [PMID: 26817581 DOI: 10.1016/j.imbio.2016.01.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 12/16/2015] [Accepted: 01/12/2016] [Indexed: 12/31/2022]
Abstract
We analyzed the association of circulating Th-17 cells (cTh-17) with immune activation (IA), immune exhaustion (IE) and regulatory T-cells (T-regs) in 20 human immunodeficiency virus-1 (HIV-1) infected patients with impaired restoration of CD4 T-cell counts despite prolonged suppression of plasma viremia (discordant) and compared it with 20 HIV-1 infected patients showing good immunologic and virologic responses (concordant) following highly active antiretroviral therapy (HAART). Discordant HIV-1 infected patients showed significantly higher frequencies of cTh-17 cells compared to concordant patients and healthy controls after PMA+Ionomicin stimulation. Discordant patients also showed higher CD4 T-cell immune activation (HLA-DR+CD38+) than concordant patients which directly correlated with microbial translocation. Additionally, CD4 T-cells of discordant patients showed higher frequencies of CD4 T-cells expressing multiple immune exhaustion markers (Tim3+PD-1+) which correlated with immune activation indicating that combined analysis of inhibitory molecules along with PD-1 might be a better predictor for immune exhaustion of CD4 T-cells. Increased cTh-17 cell frequency correlated inversely with CD4 T-cell percentages and absolute counts and directly with CD4 T-cell immune activation and T-reg frequencies. Persistent CD4 T-cell immune activation might favor differentiation of activated CD4 T-cells toward cTh-17 phenotype in discordant patients. Discordant patients had significantly lower baseline CD4 T-cell counts and higher viral load at the initiation of HAART and higher immune activation and immune exhaustion after being on HAART for long time indicating that these factors might be associated with an increase in cTh-17 cell frequency, thus, increasing the risk of disease progression despite virologic control.
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Affiliation(s)
- Ranjini Valiathan
- Department of Pathology, University of Miami-Miller School of Medicine, Miami, FL, USA; Laboratory for Clinical and Biological Studies, University of Miami-Miller School of Medicine, Miami, FL, USA
| | - Deshratn Asthana
- Department of Pathology, University of Miami-Miller School of Medicine, Miami, FL, USA; Laboratory for Clinical and Biological Studies, University of Miami-Miller School of Medicine, Miami, FL, USA; Department of Psychiatry and Behavioral Science, University of Miami-Miller School of Medicine, Miami, FL, USA.
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Chung BH, Kim KW, Kim BM, Doh KC, Cho ML, Yang CW. Increase of Th17 Cell Phenotype in Kidney Transplant Recipients with Chronic Allograft Dysfunction. PLoS One 2015; 10:e0145258. [PMID: 26717145 PMCID: PMC4696852 DOI: 10.1371/journal.pone.0145258] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 11/30/2015] [Indexed: 01/08/2023] Open
Abstract
This study was performed to determine the association of Th17 cell phenotype with chronic allograft dysfunction in kidney transplant recipients (KTRs). We compared the expression of Th17 cell phenotype in KTRs with chronic allograft dysfunction group (CAD, n = 52) with four control groups (long-term stable KTRs (LTS, n = 67), early stable KTRs (ES, n = 28), end stage renal disease (ESRD, n = 45), and healthy control (HC, n = 26). We also performed in vitro study using human proximal renal tubular epithelial cell line (HPRTEpiC) to evaluate the effect of IL-17 on human renal tubular epithelial cells. The CAD group showed increased percentage of Th17 cells out of CD4+ T cells and also increased proportion of IL-17 producing cells out of effector memory T cells or out of CCR4+CCR6+/CD4+ T cells compared to the LTS group and other control groups. Also, the serum level of IL-17, IL-33, and RAGE, and the expression of IL-1beta, RAGE, and HMGB1 mRNA showed an increase in the CAD group compared to the LTS group. In vitro study revealed that IL-17 increased production of IL-6 and IL-8 and up-regulated profibrotic gene expression such as ACTA-2 and CTGF in HPRTEpiC in a dose-dependent manner, which suggests that IL-17 has a role in the development of renal tubular cell injury. The results of our study may suggest that increase of Th17 cell phenotype could be a marker for the chronic allograft injury; hence there is a need to develop diagnostic and therapeutic tools targeting the Th17 cells pathway.
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Affiliation(s)
- Byung Ha Chung
- Convergent Research Consortium for Immunologic disease, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Transplant research center, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
| | - Kyoung Woon Kim
- Convergent Research Consortium for Immunologic disease, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Transplant research center, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
| | - Bo-Mi Kim
- Convergent Research Consortium for Immunologic disease, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Transplant research center, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
| | - Kyoung Chan Doh
- Convergent Research Consortium for Immunologic disease, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Transplant research center, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
| | - Mi-La Cho
- Convergent Research Consortium for Immunologic disease, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
| | - Chul Woo Yang
- Convergent Research Consortium for Immunologic disease, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Transplant research center, St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Seoul, Korea
- * E-mail:
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Okamoto S, Fujiwara H, Nishimori H, Matsuoka KI, Fujii N, Kondo E, Tanaka T, Yoshimura A, Tanimoto M, Maeda Y. Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells. THE JOURNAL OF IMMUNOLOGY 2014; 194:1357-63. [PMID: 25527789 DOI: 10.4049/jimmunol.1400973] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17(-)) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.
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Affiliation(s)
- Sachiyo Okamoto
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hideaki Fujiwara
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hisakazu Nishimori
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Ken-ichi Matsuoka
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Nobuharu Fujii
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Eisei Kondo
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan; and
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 108-8345, Japan
| | - Mitsune Tanimoto
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan;
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Baicalin attenuates TNBS-induced colitis in rats by modulating the Th17/Treg paradigm. Arch Pharm Res 2014; 38:1873-87. [PMID: 25269538 DOI: 10.1007/s12272-014-0486-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 09/23/2014] [Indexed: 12/12/2022]
Abstract
Baicalin, a flavonoid, has a wide range of pharmacological properties, including immunomodulation. The objective of this study was to investigate the effect of baicalin on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in a colitis model. The rat colitis model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Baicalin (10 ml/kg, each) or mesalazine (positive control) was then administered orally for 7 days. Inflammatory and immunological responses were evaluated by pathology, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, western blot analysis, and flow cytometry. Our study showed that baicalin not only significantly attenuated TNBS-induced colitis by reducing the disease activity index as well as macroscopic and microscopic scores, but it also improved the weight loss and shortening of the colon. Baicalin treatment also induced a significant decrease in the levels of inflammatory mediators, including the myeloperoxidase activity, the levels of tumor necrosis factor α, IL-1β, and Th1-related cytokines IL-12 and IFN-γ. Furthermore, the beneficial effects of baicalin seem to be associated with regulation of the Th17 and Treg paradigm. We found that administration of baicalin significantly downregulated the number of Th17 cells and the levels of Th17-related cytokines (IL-17 and IL-6) and retinoic acid receptor-related orphan receptor γt. In contrast, there was an increase in Treg cells numbers, Treg-related cytokines transforming growth factor-β and IL-10, and forkhead box P3. Our results suggest that the anti-inflammatory effect of baicalin may be linked to modulation of the balance between Th17 and Treg cells in TNBS-induced ulcerative colitis.
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Haque M, Fino K, Lei F, Xiong X, Song J. Utilizing regulatory T cells against rheumatoid arthritis. Front Oncol 2014; 4:209. [PMID: 25152867 PMCID: PMC4125784 DOI: 10.3389/fonc.2014.00209] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 07/23/2014] [Indexed: 01/07/2023] Open
Abstract
Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4+CD25+ Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3− Treg cells include Tr1, Th3, CD8+CD28−/−, and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3+ Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3+ Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3+ Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
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Affiliation(s)
- Mohammad Haque
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine , Hershey, PA , USA
| | - Kristin Fino
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine , Hershey, PA , USA
| | - Fengyang Lei
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine , Hershey, PA , USA
| | - Xiaofang Xiong
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine , Hershey, PA , USA
| | - Jianxun Song
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine , Hershey, PA , USA
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Calvaruso M, Gulino A, Buffa S, Guarnotta C, Franco G, Cacciatore M, Bonura MG, Franco V, Florena AM. Challenges and new prospects in hepatosplenic γδ T-cell lymphoma. Leuk Lymphoma 2014; 55:2457-65. [PMID: 24506469 DOI: 10.3109/10428194.2014.889821] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid neoplasms characterized by aggressive clinical behavior and dismal prognosis. Hepatosplenic γδ T-cell lymphoma (γδ-HSTL) is a particular form of PTCL that arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. γδ-HSTL has a rapidly progressive course and poor outcome due also to its refractoriness to conventional chemotherapy regimens. The very low incidence of γδ-HSTL, along with its propensity to mimic different pathological entities, makes this lymphoma a true diagnostic challenge. In this review, we highlight the biological and clinical features of γδ-HSTL that contribute to making this lymphoma a mostly incurable disease. Moreover, we provide a new insight into the crosstalk between HSTL clones and the bone marrow, liver and spleen vascular microenvironment, in which neoplastic cells reside and proliferate. We further discuss γδ-HSTL associated molecules that might be proposed as potential targets for novel therapeutic approaches.
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Affiliation(s)
- Marco Calvaruso
- Laboratorio di Tecnologie Oncologiche - HSR Giglio, C. da Pietrapollastra-Pisciotto , Cefalù , Italy
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Chen X, Oppenheim JJ. Th17 cells and Tregs: unlikely allies. J Leukoc Biol 2014; 95:723-731. [PMID: 24563509 DOI: 10.1189/jlb.1213633] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Revised: 01/29/2014] [Accepted: 02/02/2014] [Indexed: 01/14/2023] Open
Abstract
Identification of CD4+Foxp3+ Tregs and Th17 modified the historical Th1-Th2 paradigm. Currently, the Th17-Tregs dichotomy provides a dominant conceptual framework for the comprehension of immunity/inflammation and tolerance/immunosuppression in an increasing number of diseases. Targeting proinflammatory Th17 cells or immunosuppressive Tregs has been widely considered as a promising therapeutic strategy in the treatment of major human diseases, including autoimmunity and cancer. The efficacy and safety of such therapy rely on a thorough understanding of immunobiology and interaction of these two subsets of Th cells. In this article, we review recent progress concerning complicated interplay of Th17 cells and Tregs There is compelling evidence that Tregs potently inhibit Th1 and Th2 responses; however, the inhibitory effect of Tregs on Th17 responses is a controversial subject. There is increasing evidence showing that Tregs actually promote the differentiation of Th17 cells in vitro and in vivo and consequently, enhanced the functional consequences of Th17 cells, including the protective effect in host defense, as well as detrimental effect in inflammation and in the support of tumor growth. On the other hand, Th17 cells were also the most potent Th subset in the stimulation and support of expansion and phenotypic stability of Tregs in vivo. These results indicate that these two subsets of Th cells reciprocally stimulate each other. This bidirectional crosstalk is largely dependent on the TNF-TNFR2 pathway. These mutual stimulatory effects should be considered in devising future Th17 cell- and Treg-targeting therapy.
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Affiliation(s)
- Xin Chen
- Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA; and .,Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Joost J Oppenheim
- Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
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Sugimoto K, Itoh T, Takita M, Shimoda M, Chujo D, SoRelle JA, Naziruddin B, Levy MF, Shimada M, Matsumoto S. Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors. Transpl Int 2014; 27:408-15. [PMID: 24410777 DOI: 10.1111/tri.12265] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 07/01/2013] [Accepted: 01/07/2014] [Indexed: 12/23/2022]
Abstract
Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor-specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T-cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN-g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation.
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Affiliation(s)
- Koji Sugimoto
- Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA; The Departments of Surgery, Tokushima University, Tokushima, Japan
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41
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Increased Th17/Treg ratio in chronic liver GVHD. Bone Marrow Transplant 2014; 49:539-44. [PMID: 24419519 DOI: 10.1038/bmt.2013.215] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 10/04/2013] [Accepted: 11/10/2013] [Indexed: 12/21/2022]
Abstract
The contribution of Th17 cells to chronic GVHD (cGVHD) has been demonstrated in cGVHD mouse models. However, their contribution to human liver cGVHD remains unclear. We evaluated Th17 cells in biopsies from a cohort of 17 patients with liver cGVHD. We observed a significant increase in Th17 cells in the liver of patients with cGVHD, as demonstrated by an increase in CCR6+, CD161+ and RORγt+ T cells (P=0.03, P=0.0001 and P=0.03, respectively). We also assessed the presence of Th1 and regulatory (Treg) T cells: the numbers of Th1 and Treg cells were very low, with no difference between the two groups (P=0.88 and P=0.12, respectively). Furthermore, Th17/Th1 and Th17/Treg ratios were significantly increased in the liver of patients with liver cGVHD (P=0.005 and P=0.002, respectively). This study provides evidence for an infiltration by Th17 cells in the liver of patients with cGVHD and an increased Th17/Treg ratio, suggesting a defect in the regulatory mechanism driven by Treg cells or an inappropriate activation of effectors cells, especially Th17 cells, or both mechanisms, in human liver cGVHD.
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42
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Sun B, Zhang Y. Overview of orchestration of CD4+ T cell subsets in immune responses. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 841:1-13. [PMID: 25261202 DOI: 10.1007/978-94-017-9487-9_1] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adaptive immunity plays an important role in the host defense of pathogens, among which CD4+ T helper cell takes a major part. The regulation of Th cell differentiation, the function they exerts in immune response, autoimmune diseases, and allergic conditions, has long attracted much attention. Naive CD4+ T cells differentiate into distinct subsets after receiving TCR and costimulation signaling for activation and cytokine signaling to direct their differentiation. In this chapter, we will have a broad overview of all Th cell subsets, including Th1, Th2, Th17, Treg, Tfh, as well as Th9 and Th22.
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Affiliation(s)
- Bing Sun
- State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China,
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Li L, Liu S, Xu Y, Zhang A, Jiang J, Tan W, Xing J, Feng G, Liu H, Huo F, Tang Q, Gu Z. Human umbilical cord-derived mesenchymal stem cells downregulate inflammatory responses by shifting the Treg/Th17 profile in experimental colitis. Pharmacology 2013; 92:257-64. [PMID: 24280970 DOI: 10.1159/000354883] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 08/06/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS The aim of this study was to evaluate the effect and mechanisms of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on immune responses in murine colitis. METHODS Mice with dextran sulfate sodium (DSS)-induced colitis were injected intraperitoneally with hUC-MSCs or human bone marrow-derived MSCs. The cytokine levels from lamina propria mononuclear cells (LPMCs) and colon tissue were measured using ELISA. Treg and Th17 cells were analyzed using flow cytometry. The proliferation of LPMCs was assessed using Cell Counting Kit-8. RESULTS hUC-MSCs ameliorate DSS-induced colitis via the downregulation of colon inflammatory responses. Furthermore, hUC-MSCs adjusted modulation of Treg/Th17 cells in the spleen and mesenteric lymph nodes. hUC-MSCs also inhibited LPMCs in vitro. CONCLUSION hUC-MSCs may be an alternative source of stem cells and are worthy of study in long-term clinical trials.
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Affiliation(s)
- Liren Li
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
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Nissen JC, Selwood DL, Tsirka SE. Tuftsin signals through its receptor neuropilin-1 via the transforming growth factor beta pathway. J Neurochem 2013; 127:394-402. [PMID: 24033337 DOI: 10.1111/jnc.12404] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 08/09/2013] [Accepted: 08/14/2013] [Indexed: 01/13/2023]
Abstract
Tuftsin (Thr-Lys-Pro-Arg) is a natural immunomodulating peptide found to stimulate phagocytosis in macrophages/microglia. Tuftsin binds to the receptor neuropilin-1 (Nrp1) on the surface of cells. Nrp1 is a single-pass transmembrane protein, but its intracellular C-terminal domain is too small to signal independently. Instead, it associates with a variety of coreceptors. Despite its long history, the pathway through which tuftsin signals has not been described. To investigate this question, we employed various inhibitors to Nrp1's coreceptors to determine which route is responsible for tuftsin signaling. We use the inhibitor EG00229, which prevents tuftsin binding to Nrp1 on the surface of microglia and reverses the anti-inflammatory M2 shift induced by tuftsin. Furthermore, we demonstrate that blockade of transforming growth factor beta (TGFβ) signaling via TβR1 disrupts the M2 shift similar to EG00229. We report that tuftsin promotes Smad3 phosphorylation and reduces Akt phosphorylation. Taken together, our data show that tuftsin signals through Nrp1 and the canonical TGFβ signaling pathway. Despite the 40-year history of the tetrapeptide tuftsin (TKPR), a macrophage and microglial activator, its mechanism of action has not been defined. Here, we report that the tuftsin-mediated anti-inflammatory M2 shift in microglia is caused specifically by tuftsin binding to the receptor neuropilin-1 (Nrp1) and signaling through TGFβ receptor-1, a coreceptor of Nrp1. We further show that tuftsin signals via the canonical TGFβ pathway and promotes TGFβ release from target cells.
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Affiliation(s)
- Jillian C Nissen
- Program in Molecular and Cellular Pharmacology, Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA
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45
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Wang J, Zheng S, Xin N, Dou C, Fu L, Zhang X, Chen J, Zhang Y, Geng D, Xiao C, Cui G, Shen X, Lu Y, Wang J, Dong R, Qiao Y, Zhang Y. Identification of Novel MicroRNA Signatures Linked to Experimental Autoimmune Myasthenia Gravis Pathogenesis: Down-Regulated miR-145 Promotes Pathogenetic Th17 Cell Response. J Neuroimmune Pharmacol 2013; 8:1287-302. [DOI: 10.1007/s11481-013-9498-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 08/26/2013] [Indexed: 12/21/2022]
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Yin H, Li X, Zhang B, Liu T, Yuan B, Ni Q, Hu S, Gu H. Sirolimus ameliorates inflammatory responses by switching the regulatory T/T helper type 17 profile in murine colitis. Immunology 2013; 139:494-502. [PMID: 23480027 DOI: 10.1111/imm.12096] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Revised: 02/25/2013] [Accepted: 02/27/2013] [Indexed: 12/29/2022] Open
Abstract
Inflammatory bowel disease is characterized by dysregulated immune responses in inflamed intestine, with dominance of interleukin-17 (IL-17)--producing cells and deficiency of regulatory T (Treg) cells. The aim of this study was to investigate the effect and mechanisms of sirolimus, an inhibitor of the mammalian target of rapamycin, on immune responses in a murine model of Crohn's disease. Murine colitis was induced by intrarectal administration of 2,4,6-trinitrobenzene sulphonic acid at day 0. Mice were then treated intraperitoneally with sirolimus daily for 3 days. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. Sirolimus treatment significantly decreased all macroscopic, microscopic and histopathological parameters of colitis that were analysed. The therapeutic effects of sirolimus were associated with a down-regulation of pro-inflammatory cytokines tumour necrosis factor-α, IL-6 and IL-17A. Intriguingly, sirolimus administration resulted in a prominent up-regulation of the regulatory cytokine transforming growth factor-β. Supporting the hypothesis that sirolimus directly affects the functional activity of CD4+ CD25+ Treg cells, we observed a remarkable enhancement of FoxP3 expression in colon tissues and isolated CD4+ T cells of sirolimus-treated mice. Simultaneously, sirolimus treatment led to a significant reduction in the number of CD4+ IL-17A+ T cells in the mesenteric lymph node cells as well as IL-17A production in mesenteric lymph node cells. Therefore, sirolimus may offer a promising new therapeutic strategy for the treatment of inflammatory bowel disease.
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Affiliation(s)
- Hui Yin
- Department of Microbiology and Immunology, Guangdong Pharmaceutical University, Guangzhou, China.
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47
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Eric Gershwin M, Shoenfeld Y. Abul Abbas: An epitome of scholarship. J Autoimmun 2013; 45:1-6. [DOI: 10.1016/j.jaut.2013.07.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 07/14/2013] [Indexed: 11/29/2022]
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Cheng H, Tian J, Zeng L, Pan B, Li Z, Song G, Chen W, Xu K. Halofugine prevents cutaneous graft versus host disease by suppression of Th17 differentiation. Hematology 2013; 17:261-7. [PMID: 22971531 DOI: 10.1179/1607845412y.0000000016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Hai Cheng
- Department of HematologyThe Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Jing Tian
- Xuzhou Children's Hospital, Xuzhou, China
| | - Lingyu Zeng
- Department of HematologyThe Affiliated Hospital of Xuzhou Medical College, Xuzhou, China; and Laboratory of Transplantation and Immunology, Xuzhou Medical College, Xuzhou, China
| | - Bin Pan
- Laboratory of Transplantation and ImmunologyXuzhou Medical College, Xuzhou, China
| | - Zhenyu Li
- Department of HematologyThe Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Guoliang Song
- Laboratory of Transplantation and ImmunologyXuzhou Medical College, Xuzhou, China
| | - Wei Chen
- Department of HematologyThe Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Kailin Xu
- Department of HematologyThe Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
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Wehrens EJ, Prakken BJ, van Wijk F. T cells out of control--impaired immune regulation in the inflamed joint. Nat Rev Rheumatol 2013; 9:34-42. [PMID: 23390638 DOI: 10.1038/nrrheum.2012.149] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Since the discovery of FOXP3+ regulatory T (T(REG)) cells over 15 years ago, intensive research has focused on their presence, phenotype and function in autoimmune disease. Whether deficiencies in T(REG) cells underlie autoimmune pathology and whether, or how, therapeutic approaches based on these cells might be successful is still the subject of debate. The potential role of T(REG)-cell extrinsic factors, such as proinflammatory cytokines and resistance of effector T cells to suppression, as the cause of regulatory defects in chronic autoimmune inflammation is an intensive area of research. It is now clear that, at the site of inflammation, antigen presenting cells (APCs) and proinflammatory cytokines drive effector T cell skewing and plasticity, and that these T cells can become unresponsive to regulation. In addition, expansion and function of T(REG) cells is affected by the inflammatory environment; indeed, new data suggest that, in certain conditions, T(REG) cells promote inflammation. This Review summarizes the latest findings on changes in effector T cell homeostasis in autoimmune disease and focuses on how mechanisms that normally regulate these cells are affected in the inflamed joints of patients with arthritis. These findings have important clinical implications and will affect the development of new therapeutic strategies for autoimmune arthritis.
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Affiliation(s)
- Ellen J Wehrens
- Center for Molecular and Cellular Intervention, Department of Paediatric Immunology, University Medical Centre Utrecht, P.O., AB Utrecht, The Netherlands
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Walter GJ, Evans HG, Menon B, Gullick NJ, Kirkham BW, Cope AP, Geissmann F, Taams LS. Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127(low) regulatory T cells. ACTA ACUST UNITED AC 2013; 65:627-38. [PMID: 23280063 DOI: 10.1002/art.37832] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 12/11/2012] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Despite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127(low) FoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Treg cells are converted into proinflammatory interleukin-17 (IL-17)-producing cells by inflammatory mediators and thereby lose their suppressive function. The aim of this study was to investigate whether activated monocytes, which are potent producers of inflammatory cytokines and are abundantly present in the rheumatic joint, induce proinflammatory cytokine expression in human Treg cells and impair their regulatory function. METHODS The presence and phenotype of CD4+CD45RO+CD25+CD127(low) T cells (memory Treg cells) and CD14+ monocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with RA were investigated by flow cytometry. Memory Treg cells obtained from healthy control subjects underwent fluorescence-activated cell sorting and then were cocultured with autologous activated monocytes and stimulated with anti-CD3 monoclonal antibodies. Intracellular cytokine expression, phenotype, and function of cells were determined by flow cytometry, enzyme-linked immunosorbent assay, and proliferation assays. RESULTS In patients with RA, the frequencies of CD4+CD45RO+CD25+CD127(low) Treg cells and activated CD14+ monocytes were higher in SF compared with PB. In vitro-activated monocytes induced an increase in the percentage of IL-17-positive, interferon-γ (IFNγ)-positive, and tumor necrosis factor α (TNFα)-positive Treg cells as well as IL-10-positive Treg cells. The observed increase in IL-17-positive and IFNγ-positive Treg cells was driven by monocyte-derived IL-1β, IL-6, and TNFα and was mediated by both CD14+CD16- and CD14+CD16+ monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25+FoxP3+CD39+ Treg cell phenotype and showed an enhanced capacity to suppress T cell proliferation and IL-17 production. CONCLUSION Treg cells exposed to a proinflammatory environment show increased cytokine expression as well as enhanced suppressive activity.
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