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Lu J, Qin H, Liang L, Fang J, Hao K, Song Y, Sun T, Hui G, Xie Y, Zhao Y. Yam protein ameliorates cyclophosphamide-induced intestinal immunosuppression by regulating gut microbiota and its metabolites. Int J Biol Macromol 2024; 279:135415. [PMID: 39245119 DOI: 10.1016/j.ijbiomac.2024.135415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/21/2024] [Accepted: 09/05/2024] [Indexed: 09/10/2024]
Abstract
Yam is a dual-purpose crop used in both medicine and food that is commonly used as a dietary supplement in food processing. Since yam proteins are often lost during the production of yam starch, elucidating the functionally active value of yam proteins is an important guideline for fully utilizing yam in industrial production processes. This study aimed to explore the potential protective effect of yam protein (YP) on cyclophosphamide (CTX)-induced immunosuppression in mice. The results showed that YP can reduce immune damage caused by CTX by reversing immunoglobulins (IgA, IgG and IgM), cytokines (TNF-α, IL-6, etc.) in the intestines of mice. Moreover, YPs were found to prevent CTX-induced microbiota dysbiosis by enhancing the levels of beneficial bacteria within the microbiome, such as Lactobacillus, and lowering those of Desulfovibrio_R and Helicobacter_A. Metabolomics analyses showed that YP significantly altered differential metabolites (tryptophan, etc.) and metabolic pathways (ABC transporter protein, etc.) associated with immune responses in the gut. Furthermore, important connections were noted between particular microbiomes and metabolites, shedding light on the immunoprotective effects of YPs by regulating gut flora and metabolism. These findings deepen our understanding of the functional properties of YPs and lay a solid foundation for the utilization of yam.
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Affiliation(s)
- Jiahong Lu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Huacong Qin
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Lili Liang
- Obstetrics and Gynecology Diagnosis and Treatment Center, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130031, China
| | - Jiaqi Fang
- College of Food Science and Engineering, Jilin University, Changchun 130062, China
| | - Kaiwen Hao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Yuting Song
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Tianxia Sun
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Ge Hui
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Yunfei Xie
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Yu Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China.
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2
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Larange A, Takazawa I, Kakugawa K, Thiault N, Ngoi S, Olive ME, Iwaya H, Seguin L, Vicente-Suarez I, Becart S, Verstichel G, Balancio A, Altman A, Chang JT, Taniuchi I, Lillemeier B, Kronenberg M, Myers SA, Cheroutre H. A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function. Immunity 2023; 56:2054-2069.e10. [PMID: 37597518 PMCID: PMC10552917 DOI: 10.1016/j.immuni.2023.07.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/08/2023] [Accepted: 07/25/2023] [Indexed: 08/21/2023]
Abstract
Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome. RA interfered with extranuclear RARα signaling, causing suboptimal TCR activation while enhancing FOXP3+ regulatory T cell conversion. TCR activation induced the expression of CRABP2, which translocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resulting in impaired anti-pathogen immunity and suppressed autoimmune disease. Our findings underscore the significance of subcellular RA/RARα signaling in T cells and identify extranuclear RARα as a component of the TCR signalosome and a determinant of immune responses.
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Affiliation(s)
- Alexandre Larange
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Ikuo Takazawa
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Kiyokazu Kakugawa
- Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Nicolas Thiault
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - SooMun Ngoi
- School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Meagan E Olive
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Hitoshi Iwaya
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Laetitia Seguin
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Ildefonso Vicente-Suarez
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Stephane Becart
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Greet Verstichel
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Ann Balancio
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Amnon Altman
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - John T Chang
- School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Ichiro Taniuchi
- Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Bjorn Lillemeier
- Immunobiology and Microbial Pathogenesis Laboratory, IMPL-L, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Mitchell Kronenberg
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Samuel A Myers
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Laboratory for Immunochemical Circuits, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
| | - Hilde Cheroutre
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Center for Cancer Immunotherapy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.
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3
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Wang J, Zhao X, Wan YY. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell Mol Immunol 2023; 20:1002-1022. [PMID: 37217798 PMCID: PMC10468540 DOI: 10.1038/s41423-023-01036-7] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023] Open
Abstract
Balanced immunity is pivotal for health and homeostasis. CD4+ helper T (Th) cells are central to the balance between immune tolerance and immune rejection. Th cells adopt distinct functions to maintain tolerance and clear pathogens. Dysregulation of Th cell function often leads to maladies, including autoimmunity, inflammatory disease, cancer, and infection. Regulatory T (Treg) and Th17 cells are critical Th cell types involved in immune tolerance, homeostasis, pathogenicity, and pathogen clearance. It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease. Cytokines are instrumental in directing Treg and Th17 cell function. The evolutionarily conserved TGF-β (transforming growth factor-β) cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory, pathogenic, and immune regulatory. How TGF-β superfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades. Here, we introduce the fundamental biology of TGF-β superfamily signaling, Treg cells, and Th17 cells and discuss in detail how the TGF-β superfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.
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Affiliation(s)
- Junying Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Xingqi Zhao
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yisong Y Wan
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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Immune Impairment Associated with Vitamin A Deficiency: Insights from Clinical Studies and Animal Model Research. Nutrients 2022; 14:nu14235038. [PMID: 36501067 PMCID: PMC9738822 DOI: 10.3390/nu14235038] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Vitamin A (VA) is critical for many biological processes, including embryonic development, hormone production and function, the maintenance and modulation of immunity, and the homeostasis of epithelium and mucosa. Specifically, VA affects cell integrity, cytokine production, innate immune cell activation, antigen presentation, and lymphocyte trafficking to mucosal surfaces. VA also has been reported to influence the gut microbiota composition and diversity. Consequently, VA deficiency (VAD) results in the imbalanced production of inflammatory and immunomodulatory cytokines, intestinal inflammation, weakened mucosal barrier functions, reduced reactive oxygen species (ROS) and disruption of the gut microbiome. Although VAD is primarily known to cause xerophthalmia, its role in the impairment of anti-infectious defense mechanisms is less defined. Infectious diseases lead to temporary anorexia and lower dietary intake; furthermore, they adversely affect VA status by interfering with VA absorption, utilization and excretion. Thus, there is a tri-directional relationship between VAD, immune response and infections, as VAD affects immune response and predisposes the host to infection, and infection decreases the intestinal absorption of the VA, thereby contributing to secondary VAD development. This has been demonstrated using nutritional and clinical studies, radiotracer studies and knockout animal models. An in-depth understanding of the relationship between VAD, immune response, gut microbiota and infections is critical for optimizing vaccine efficacy and the development of effective immunization programs for countries with high prevalence of VAD. Therefore, in this review, we have comprehensively summarized the existing knowledge regarding VAD impacts on immune responses to infections and post vaccination. We have detailed pathological conditions associated with clinical and subclinical VAD, gut microbiome adaptation to VAD and VAD effects on the immune responses to infection and vaccines.
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5
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van der Veeken J, Campbell C, Pritykin Y, Schizas M, Verter J, Hu W, Wang ZM, Matheis F, Mucida D, Charbonnier LM, Chatila TA, Rudensky AY. Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells. Immunity 2022; 55:1173-1184.e7. [PMID: 35700740 PMCID: PMC9885886 DOI: 10.1016/j.immuni.2022.05.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 01/19/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023]
Abstract
Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4+ T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells suppress autoimmunity, pTreg cells enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms supporting their differentiation remain poorly understood. Here, we used genetic tracing to identify microbiota-induced pTreg cells and found that many of their distinguishing features were Foxp3 independent. Lineage-committed, microbiota-dependent pTreg-like cells persisted in the colon in the absence of Foxp3. While Foxp3 was critical for the suppression of a Th17 cell program, colitis, and mastocytosis, pTreg cells suppressed colonic effector T cell expansion in a Foxp3-independent manner. Thus, Foxp3 and the tolerogenic signals that precede and promote its expression independently confer distinct facets of pTreg functionality.
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Affiliation(s)
- Joris van der Veeken
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA; Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
| | - Clarissa Campbell
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA,CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Yuri Pritykin
- Lewis-Sigler Institute for Integrative Genomics and Computer Science Department, Princeton University, Princeton, NJ, USA
| | - Michail Schizas
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jacob Verter
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wei Hu
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zhong-Min Wang
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA,Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Fanny Matheis
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA
| | - Daniel Mucida
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA
| | - Louis-Marie Charbonnier
- Division of Immunology, Boston Children’s Hospital; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Talal A Chatila
- Division of Immunology, Boston Children’s Hospital; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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6
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Gürbüz M, Aktaç Ş. Understanding the role of vitamin A and its precursors in the immune system. NUTR CLIN METAB 2022. [DOI: 10.1016/j.nupar.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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7
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Sarohan AR, Kızıl M, İnkaya AÇ, Mahmud S, Akram M, Cen O. A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder. Cell Signal 2021; 87:110121. [PMID: 34438017 PMCID: PMC8380544 DOI: 10.1016/j.cellsig.2021.110121] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 02/08/2023]
Abstract
The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.
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Affiliation(s)
- Aziz Rodan Sarohan
- Department of Obstetrics and Gynecology, Medicina Plus Medical Center, 75. Yıl Mah., İstiklal Cad. 1305 Sk., No: 16 Sultangazi, İstanbul, Turkey.
| | - Murat Kızıl
- Department of Chemistry, Faculty of Science, Dicle University. Diyarbakır, Turkey
| | - Ahmet Çağkan İnkaya
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey
| | - Shokhan Mahmud
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
| | - Muhammad Akram
- Department of Eastern Medicine Government College, University Faisalabad, Pakistan
| | - Osman Cen
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America; Department of Natural Sciences and Engineering, John Wood College, Quincy, IL, United States of America
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8
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van Daal MT, Folkerts G, Garssen J, Braber S. Pharmacological Modulation of Immune Responses by Nutritional Components. Pharmacol Rev 2021; 73:198-232. [PMID: 34663688 DOI: 10.1124/pharmrev.120.000063] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The incidence of noncommunicable diseases (NCDs) has increased over the last few decades, and one of the major contributors to this is lifestyle, especially diet. High intake of saturated fatty acids and low intake of dietary fiber is linked to an increase in NCDs. Conversely, a low intake of saturated fatty acids and a high intake of dietary fiber seem to have a protective effect on general health. Several mechanisms have been identified that underlie this phenomenon. In this review, we focus on pharmacological receptors, including the aryl hydrocarbon receptor, binding partners of the retinoid X receptor, G-coupled protein receptors, and toll-like receptors, which can be activated by nutritional components and their metabolites. Depending on the nutritional component and the receptors involved, both proinflammatory and anti-inflammatory effects occur, leading to an altered immune response. These insights may provide opportunities for the prevention and treatment of NCDs and their inherent (sub)chronic inflammation. SIGNIFICANCE STATEMENT: This review summarizes the reported effects of nutritional components and their metabolites on the immune system through manipulation of specific (pharmacological) receptors, including the aryl hydrocarbon receptor, binding partners of the retinoid X receptor, G-coupled protein receptors, and toll-like receptors. Nutritional components, such as vitamins, fibers, and unsaturated fatty acids are able to resolve inflammation, whereas saturated fatty acids tend to exhibit proinflammatory effects. This may aid decision makers and scientists in developing strategies to decrease the incidence of noncommunicable diseases.
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Affiliation(s)
- Marthe T van Daal
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
| | - Gert Folkerts
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
| | - Saskia Braber
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
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9
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Kartasheva-Ebertz DM, Pol S, Lagaye S. Retinoic Acid: A New Old Friend of IL-17A in the Immune Pathogeny of Liver Fibrosis. Front Immunol 2021; 12:691073. [PMID: 34211477 PMCID: PMC8239722 DOI: 10.3389/fimmu.2021.691073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
Despite all the medical advances mortality due to cirrhosis and hepatocellular carcinoma, the end stages of fibrosis, continuously increases. Recent data suggest that liver fibrosis is guided by type 3 inflammation with IL-17A at the top of the line. The storage of vitamin A and its active metabolites, as well as genetics, can influence the development and progression of liver fibrosis and inflammation. Retinoic acid (active metabolite of vitamin A) is able to regulate the differentiation of IL-17A+/IL-22–producing cells as well as the expression of profibrotic markers. IL-17A and its pro-fibrotic role in the liver is the most studied, while the interaction and communication between IL-17A, IL-22, and vitamin A–active metabolites has not been investigated. We aim to update what is known about IL-17A, IL-22, and retinoic acid in the pathobiology of liver diseases.
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Affiliation(s)
| | - Stanislas Pol
- Institut Pasteur, INSERM U1223, Paris, France.,Université de Paris, Paris, France.,APHP, Groupe Hospitalier Cochin, Département d'Hépatologie, Paris, France
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10
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Blagih J, Hennequart M, Zani F. Tissue Nutrient Environments and Their Effect on Regulatory T Cell Biology. Front Immunol 2021; 12:637960. [PMID: 33868263 PMCID: PMC8050341 DOI: 10.3389/fimmu.2021.637960] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Regulatory T cells (Tregs) are essential for mitigating inflammation. Tregs are found in nearly every tissue and play either beneficial or harmful roles in the host. The availability of various nutrients can either enhance or impair Treg function. Mitochondrial oxidative metabolism plays a major role in supporting Treg differentiation and fitness. While Tregs rely heavily on oxidation of fatty acids to support mitochondrial activity, they have found ways to adapt to different tissue types, such as tumors, to survive in competitive environments. In addition, metabolic by-products from commensal organisms in the gut also have a profound impact on Treg differentiation. In this review, we will focus on the core metabolic pathways engaged in Tregs, especially in the context of tissue nutrient environments, and how they can affect Treg function, stability and differentiation.
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Affiliation(s)
| | | | - Fabio Zani
- The Francis Crick Institute, London, United Kingdom
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11
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Hao X, Zhong X, Sun X. The effects of all-trans retinoic acid on immune cells and its formulation design for vaccines. AAPS JOURNAL 2021; 23:32. [DOI: 10.1208/s12248-021-00565-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
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12
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Zhou Y, Wang H, Zhou J, Qiu S, Cai T, Li H, Shen Z, Hu Y, Ding B, Luo M, Huang R, Yan R, Xu W, He C, Zhang Y, Li F, Sun Z, Ma J. Vitamin A and Its Multi-Effects on Pancreas: Recent Advances and Prospects. Front Endocrinol (Lausanne) 2021; 12:620941. [PMID: 33679618 PMCID: PMC7930481 DOI: 10.3389/fendo.2021.620941] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, β-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.
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Affiliation(s)
- Yunting Zhou
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Huiying Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Junming Zhou
- Department of Cadre Gastroenterology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Shanhu Qiu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
- Department of Endocrinology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Tingting Cai
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Huiqin Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ziyang Shen
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yun Hu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bo Ding
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Menghui Luo
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rong Huang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rengna Yan
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wei Xu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, China
| | - Cong He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Yumin Zhang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Fengfei Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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13
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Friesen L, Gu B, Kim C. A ligand-independent fast function of RARα promotes exit from metabolic quiescence upon T cell activation and controls T cell differentiation. Mucosal Immunol 2021; 14:100-112. [PMID: 32518366 PMCID: PMC7725911 DOI: 10.1038/s41385-020-0311-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 04/22/2020] [Accepted: 05/20/2020] [Indexed: 02/04/2023]
Abstract
Vitamin A metabolites play important roles in T cell activation and differentiation. A conventional model of RARα function relies upon retinoic acid (RA)-liganded RARα binding to specific DNA motifs to regulate gene expression in the nucleus. However, this genomic function fails to explain many of the biological responses of the RA-RARα axis on T cells. We generated a mouse line where RARα is over-expressed in T cells to probe RARα function with unprecedented sensitivity. Using this model together with mice specifically lacking RARα in T cells, we found that RARα is required for prompt exit from metabolic quiescence in resting T cells upon T cell activation. The positive effect of RARα on metabolism is mediated through PI3K and subsequent activation of the Akt and mTOR signaling pathway. This largely non-genomic function of RARα is surprisingly ligand-independent and controls the differentiation of effector and regulatory T cell subsets.
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Affiliation(s)
- L.R. Friesen
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109,Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine, Ann Arbor, MI 48109
| | - B. Gu
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47906
| | - C.H. Kim
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109,Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine, Ann Arbor, MI 48109,Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI 48109
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14
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Shojadoost B, Alizadeh M, Taha-Abdelaziz K, Shoja Doost J, Astill J, Sharif S. In Ovo Inoculation of Vitamin A Modulates Chicken Embryo Immune Functions. J Interferon Cytokine Res 2021; 41:20-28. [PMID: 33471614 DOI: 10.1089/jir.2020.0212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Vitamin A mediates many important biological functions in humans and animals. Presence of vitamin A receptors on immune system cells emphasizes their role in immune functions. To assess the effects of in ovo inoculation of vitamin A on the immune system of chicken embryos, 18 days old embryonated eggs were inoculated with 3 different concentrations of retinoic acid (the active form of vitamin A) at 30, 90, and 270 μmol/egg via the amniotic sac. After 6, 18, and 24 h, the spleen and bursa of the embryos were collected for RNA extraction and real-time polymerase chain reaction. The results were dose dependant. After 24 h, inoculation with 270 μmol/egg downregulated relative expression of interferon IFN-α, IFN-β, IFN-γ, interleukin (IL)-1β, IL-2, CXCLi2, IL-12, and IL-13 compared to control in the spleen, indicating an anti-inflammatory effect at this concentration. In comparison, 90 μmol/egg induced greater expressions of the above genes at the same timepoint compared to the 270 μmol. The results of this study indicate that in ovo inoculation of vitamin A can modulate immune functions of the chicken embryo, which might be beneficial for induction of immune responses by in ovo vaccines.
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Affiliation(s)
- Bahram Shojadoost
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - Mohammadali Alizadeh
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - Khaled Taha-Abdelaziz
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
- Pathology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Janan Shoja Doost
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - Jake Astill
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - Shayan Sharif
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
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15
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Möhn N, Bruni E, Schröder A, Frömmel S, Gueler F, Vieten G, Prinz I, Kuebler JF, Petersen C, Klemann C. Synthetic retinoid AM80 inhibits IL-17 production of gamma delta T cells and ameliorates biliary atresia in mice. Liver Int 2020; 40:3031-3041. [PMID: 33463083 DOI: 10.1111/liv.14639] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/03/2020] [Accepted: 08/10/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Recent evidence suggests that Interleukin (IL)-17-producing gamma delta ( γδ ) T cells are the dominant pathogenic cellular component in designated autoimmune or inflammatory diseases, including biliary atresia (BA). We have previously demonstrated that retinoids effectively suppress T-helper cell (Th) 17 differentiation. METHODS Here, we established an in vitro system, enabling investigations of the effect of AM80 on the IL-17 production of γδ T cells. Additionally, we tested the therapeutic effect of AM80 in the Rotavirus-induced mouse model of BA. Co-incubation of γδ T cells with IL-23 and anti-CD28 mAb proved most effective in inducing an IL-17 response in vitro. The effect of AM80 on human CCR6+CD26+ V δ 2 cells was assessed by flow cytometry. RESULTS AM80 efficiently reduced IL-17 production by murine γδ T cells and the expression of the master transcription factor Retinoid-Orphan-Receptor- γ t (ROR γτ ) in a dose-dependent manner. The fraction of human CCR6+CD26+ V δ 2 cells was significantly reduced by co-incubation with AM80. Moreover, AM80 also inhibited IL-17 production by liver-infiltrating γδ T cells isolated from animals suffering from BA. Intraperitoneal treatment with AM80 ameliorated BA-associated inflammation. However, AM80 treatment was not sufficient to control disease progression in the murine model, despite reduced inflammatory activity in the animals. CONCLUSIONS Retinoids are very efficient in down-regulating IL-17 production by γδ T cells in vitro and, to a lesser extent, in the BA mouse model. However, retinoids do not suffice for the control of disease progression. Thus, our data suggest that IL-17 is not the only factor contributing to the pathogenesis of BA. LAY SUMMARY Biliary atresia (BA) is a rare disease which affects infants, causing progressive liver failure in most children, and is the most common indication for paediatric liver transplantation. We have previously demonstrated that IL-17, produced by γδ T cells, contributes to hepatic inflammation in the murine model of BA and is increased in the livers of infants suffering from the disease. In the study at hand, we demonstrate that treatment with AM80, a synthetic retinoid with superior pharmacological properties, effectively inhibits the IL-17 production of gamma delta T cells without generating systemic immunosuppression. Although all-trans retinoic acid (ATRA) has been demonstrated to suppress differentiation of IL-17-producing conventional T-helper cells (Th17) in vitro, the therapeutic application of ATRA in vivo is limited by the compound's potential side effects caused by its instability and lack of receptor specificity. Our study is the first to show that AM80 suppresses the IL-17 production of γδ T cells in a very efficient manner and that hepatic inflammation is ameliorated in mice suffering from BA. However, AM80 treatment does not suffice to block the disease progression. We conclude that factors other than IL-17 drive the progressive inflammation in BA. The addition of retinoids to the treatment regime of children suffering from BA might decrease the disease burden; however, further research is needed to clarify the pathomechanism and possible therapeutic interventions in humans.
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Affiliation(s)
- Nora Möhn
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Elena Bruni
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Arne Schröder
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Stephanie Frömmel
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Faikah Gueler
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Gertrud Vieten
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Joachim F Kuebler
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Christian Klemann
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.,Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany
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16
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Ahmad SM, Huda MN, Raqib R, Qadri F, Alam MJ, Afsar MNA, Peerson JM, Tanumihardjo SA, Stephensen CB. High-Dose Neonatal Vitamin A Supplementation to Bangladeshi Infants Increases the Percentage of CCR9-Positive Treg Cells in Infants with Lower Birthweight in Early Infancy, and Decreases Plasma sCD14 Concentration and the Prevalence of Vitamin A Deficiency at Two Years of Age. J Nutr 2020; 150:3005-3012. [PMID: 32939553 PMCID: PMC7675026 DOI: 10.1093/jn/nxaa260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/08/2020] [Accepted: 08/04/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Vitamin A (VA) stores are low in early infancy and may impair development of the immune system. OBJECTIVE This study determined if neonatal VA supplementation (VAS) affects the following: 1) development of regulatory T (Treg) cells; 2) chemokine receptor 9 (CCR9) expression, which directs mucosal targeting of immune cells; and 3) systemic endotoxin exposure as indicated by changed plasma concentrations of soluble CD14 (sCD14). Secondarily, VA status, growth, and systemic inflammation were investigated. METHODS In total, 306 Bangladeshi infants were randomly assigned to receive 50,000 IU VA or placebo (PL) within 48 h of birth, and immune function was assessed at 6 wk, 15 wk, and 2 y. Primary outcomes included the following: 1) peripheral blood Treg cells; 2) percentage of Treg, T, and B cells expressing CCR9; and 3) plasma sCD14. Secondary outcomes included the following: 4) VA status measured using the modified relative dose-response (MRDR) test and plasma retinol; 5) infant growth; and 6) plasma C-reactive protein (CRP). Statistical analysis identified group differences and interactions with sex and birthweight. RESULTS VAS increased (P = 0.004) the percentage of CCR9+ Treg cells (13.2 ± 1.37%) relative to PL (9.17 ± 1.15%) in children below the median birthweight but had the opposite effect (P = 0.04) in those with higher birthweight (VA, 9.13 ± 0.89; PL, 12.1 ± 1.31%) at 6 and 15 wk (values are combined mean ± SE). VAS decreased (P = 0.003) plasma sCD14 (1.56 ± 0.025 mg/L) relative to PL (1.67 ± 0.032 mg/L) and decreased (P = 0.034) the prevalence of VA deficiency (2.3%) relative to PL (9.2%) at 2 y. CONCLUSIONS Neonatal VAS enhanced mucosal targeting of Treg cells in low-birthweight infants. The decreased systemic exposure to endotoxin and improved VA status at 2 y may have been due to VA-mediated improvements in gut development resulting in improved barrier function and nutrient absorption. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.
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Affiliation(s)
- Shaikh M Ahmad
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh
| | - M Nazmul Huda
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh
- USDA Western Human Nutrition Research Center at University of California, Davis, CA, USA
- Nutrition Department, University of California, Davis, CA, USA
| | - Rubhana Raqib
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh
| | - Firdausi Qadri
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh
| | - Md Jahangir Alam
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh
| | - Md Nure Alam Afsar
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh
| | - Janet M Peerson
- USDA Western Human Nutrition Research Center at University of California, Davis, CA, USA
| | - Sherry A Tanumihardjo
- University of Wisconsin–Madison, Department of Nutritional Sciences, Madison, WI, USA
| | - Charles B Stephensen
- USDA Western Human Nutrition Research Center at University of California, Davis, CA, USA
- Nutrition Department, University of California, Davis, CA, USA
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17
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Koprivica I, Gajic D, Saksida T, Cavalli E, Auci D, Despotovic S, Pejnovic N, Stosic-Grujicic S, Nicoletti F, Stojanovic I. Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice. Eur J Pharmacol 2019; 864:172721. [DOI: 10.1016/j.ejphar.2019.172721] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/01/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
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18
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Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A. Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. Int Immunol 2019; 30:357-373. [PMID: 29982622 DOI: 10.1093/intimm/dxy043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 06/28/2018] [Indexed: 12/16/2022] Open
Abstract
T helper type 1 (Th1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated Th1 to regulatory T (Treg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from Th1 cells of mice and humans. This is achieved simply by resting Th1 cells without T-cell receptor ligation before stimulation in the presence of transforming growth factor-beta (TGF-β). We named the resulting Th1-derived Foxp3+ cells Th1reg cells. Mouse Th1reg cells showed an inducible Treg-like phenotype and suppressive ability both in vitro and in vivo. Th1reg cells could also be induced from in vivo-developed mouse Th1 cells. Unexpectedly, the resting process enabled Foxp3 expression not through epigenetic changes at the locus, but through metabolic change resulting from reduced mammalian target of rapamycin complex 1 (mTORC1) activity. mTORC1 suppressed TGF-β-induced phosphorylation of Smad2/3 in Th1 cells, which was restored in rested cells. Our study warrants future research aiming at development of immunotherapy with Th1reg cells.
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Affiliation(s)
- Mitsuhiro Kanamori
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hiroko Nakatsukasa
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Minako Ito
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Shunsuke Chikuma
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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19
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Xiang J, Wang H, Li T. Comorbidity of Vitamin A and Vitamin D Deficiency Exacerbates the Severity of Atopic Dermatitis in Children. Dermatology 2019; 235:196-204. [DOI: 10.1159/000496603] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
Abstract
<b><i>Background:</i></b> Several studies have suggested that vitamin D (VD) deficiency (VDD) is associated with atopic dermatitis (AD). However, little is known about the relationship between AD and vitamin A (VA). The interaction between VA and VD on AD requires further study. <b><i>Objective:</i></b> We detected serum levels of VA and VD in children with AD to explore how VA deficiency (VAD) and VDD affect AD severity. <b><i>Methods:</i></b> We assessed the SCORing Atopic Dermatitis (SCORAD) index, total immunoglobin E levels and peripheral blood eosinophil counts. VA and VD levels were determined with high-performance liquid chromatography. Correlations among variables were investigated with Pearson’s correlation analysis. <b><i>Results:</i></b> The VD and VA levels were significantly lower in children with AD than in normal children (p < 0.001, p = 0.0423). Both VD and VA levels were negatively correlated with SCORAD scores. The SCORAD scores were significantly higher in AD patients with both VDD and VAD (co-deficiency) than in other AD patients. Significant inverse correlations were observed between peripheral blood eosinophil counts and serum VA and VD levels. <b><i>Conclusions:</i></b> VA and VD co-deficiency may exacerbate AD symptoms in children, but the specific mechanism underlying this relationship requires further study. These findings may indicate the need for studies evaluating the use of VD and VA as potential treatments for AD patients.
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20
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Huang Z, Liu Y, Qi G, Brand D, Zheng SG. Role of Vitamin A in the Immune System. J Clin Med 2018; 7:E258. [PMID: 30200565 PMCID: PMC6162863 DOI: 10.3390/jcm7090258] [Citation(s) in RCA: 289] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 08/23/2018] [Accepted: 08/31/2018] [Indexed: 12/20/2022] Open
Abstract
Vitamin A (VitA) is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. VitA is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. VitA is involved in the development of the immune system and plays regulatory roles in cellular immune responses and humoral immune processes. VitA has demonstrated a therapeutic effect in the treatment of various infectious diseases. To better understand the relationship between nutrition and the immune system, the authors review recent literature about VitA in immunity research and briefly introduce the clinical application of VitA in the treatment of several infectious diseases.
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Affiliation(s)
- Zhiyi Huang
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, Guangxi, China.
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, Guangxi, China.
| | - Yu Liu
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, Guangxi, China.
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, Guangxi, China.
| | - Guangying Qi
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, Guangxi, China.
- Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, Guangxi, China.
| | - David Brand
- Research Service, VA Medical Center, Memphis, TN 38104, USA.
| | - Song Guo Zheng
- Department of Medicine, Division of Rheumatology, Milton S. Hershey Medical Center at Penn State University, Hershey, PA 17033, USA.
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21
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The Aryl Hydrocarbon Receptor Preferentially Marks and Promotes Gut Regulatory T Cells. Cell Rep 2018; 21:2277-2290. [PMID: 29166616 DOI: 10.1016/j.celrep.2017.10.114] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/20/2017] [Accepted: 10/29/2017] [Indexed: 12/15/2022] Open
Abstract
The local environment may affect the development and function of tissue-resident T regulatory cells (Tregs), which are crucial for controlling inflammation. Although the aryl hydrocarbon receptor (Ahr), an environmental sensor, is expressed by Tregs, its role in Treg cell development and/or function remains elusive. Here, we generated mouse genetic models to ablate or activate Ahr expression specifically in Tregs. We showed that Ahr was expressed more abundantly by peripherally induced Tregs (pTregs) in the gut and that its expression was independent of microbiota. Ahr was important for Treg gut homing and function. Ahr inhibited pro-inflammatory cytokines produced by Tregs but was dispensable for Treg stability. Furthermore, Ahr-expressing Tregs had enhanced in vivo suppressive activity compared with Tregs lacking Ahr expression in a T cell transfer model of colitis. Our data suggest that Ahr signaling in Tregs may be important for gut immune homeostasis.
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22
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Feng Q, Liu W, Baker SS, Li H, Chen C, Liu Q, Tang S, Guan L, Tsompana M, Kozielski R, Baker RD, Peng J, Liu P, Zhu R, Hu Y, Zhu L. Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of non-alcoholic fatty liver disease. Oncotarget 2018; 8:27820-27838. [PMID: 28416740 PMCID: PMC5438611 DOI: 10.18632/oncotarget.15482] [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: 12/28/2016] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
Beneficial effects of the Chinese herbal medicine Qushi Huayu Decoction (QHD) were observed with non-alcoholic fatty liver disease (NAFLD) patients and animal models. The impact of QHD or its active components (geniposide and chlorogenic acid, GC) on NAFLD liver transcriptome and gut microbiota was examined with NAFLD rats. Increased expression for genes required for glutathione production and decreased expression for genes required for lipid synthesis was observed in NAFLD livers treated with QHD and GC. GC treatment decreased serum LPS, which could be explained by reduced mucosal damage in the colon of GC-treated rats. Further, our data suggest an increased abundance of Treg-inducing bacteria that stimulated the Treg activity in GC treated colon, which in turn down-regulated inflammatory signals, improved gut barrier function and consequently reduced hepatic exposure to microbial products. Our study suggests that QHD simultaneously enhanced the hepatic anti-oxidative mechanism, decreased hepatic lipid synthesis, and promoted the regulatory T cell inducing microbiota in the gut.
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Affiliation(s)
- Qin Feng
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, NY, USA.,Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA
| | - Wensheng Liu
- Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, NY, USA.,Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA
| | - Susan S Baker
- Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, NY, USA.,Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA
| | - Hongshan Li
- Ningbo No.2 Hospital, Ningbo, Zhejiang Province, China
| | - Cheng Chen
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qian Liu
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shijie Tang
- Department of Bioinformatics, Tongji University, Shanghai, China
| | - Lingyu Guan
- Department of Bioinformatics, Tongji University, Shanghai, China
| | - Maria Tsompana
- Center of Excellence in Bioinformatics and Life Sciences, The State University of New York at Buffalo, Buffalo, New York, USA
| | - Rafal Kozielski
- Women and Children's Hospital of Buffalo, Buffalo, NY, USA.,Department of Pathology, The State University of New York at Buffalo, Buffalo, New York, USA
| | - Robert D Baker
- Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, NY, USA.,Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA
| | - Jinghua Peng
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Liu
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ruixin Zhu
- Department of Bioinformatics, Tongji University, Shanghai, China
| | - Yiyang Hu
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lixin Zhu
- Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, Buffalo, NY, USA.,Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA.,Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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23
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Burrows K, Antignano F, Bramhall M, Chenery A, Scheer S, Korinek V, Underhill TM, Zaph C. The transcriptional repressor HIC1 regulates intestinal immune homeostasis. Mucosal Immunol 2017; 10:1518-1528. [PMID: 28327618 DOI: 10.1038/mi.2017.17] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/09/2017] [Indexed: 02/04/2023]
Abstract
The intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T-cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T-cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.
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Affiliation(s)
- K Burrows
- The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - F Antignano
- The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - M Bramhall
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
| | - A Chenery
- The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - S Scheer
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
| | - V Korinek
- Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - T M Underhill
- The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Cellular &Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - C Zaph
- The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
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24
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He X, Koenen HJ, Slaats JH, Joosten I. Stabilizing human regulatory T cells for tolerance inducing immunotherapy. Immunotherapy 2017; 9:735-751. [PMID: 28771099 DOI: 10.2217/imt-2017-0017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Many autoimmune diseases develop as a consequence of an altered balance between autoreactive immune cells and suppressive FOXP3+ Treg. Restoring this balance through amplification of Treg represents a promising strategy to treat disease. However, FOXP3+ Treg might become unstable especially under certain inflammatory conditions, and might transform into proinflammatory cytokine-producing cells. The issue of heterogeneity and instability of Treg has caused considerable debate in the field and has important implications for Treg-based immunotherapy. In this review, we discuss how Treg stability is defined and what the molecular mechanisms underlying the maintenance of FOXP3 expression and the regulation of Treg stability are. Also, we elaborate on current strategies used to stabilize human Treg for clinical purposes. This review focuses on human Treg, but considering that cell-intrinsic mechanisms to regulate Treg stability in mice and in humans might be similar, data derived from mice studies are also discussed in this paper.
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Affiliation(s)
- Xuehui He
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,College of Computer Science, Qinghai Normal University, Xining, Qinghai, China
| | - Hans Jpm Koenen
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen Hr Slaats
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Irma Joosten
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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25
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Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells. PLoS One 2017; 12:e0182009. [PMID: 28746369 PMCID: PMC5529012 DOI: 10.1371/journal.pone.0182009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 07/11/2017] [Indexed: 12/29/2022] Open
Abstract
Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.
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26
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Chiasson VL, Pakanati AR, Hernandez M, Young KJ, Bounds KR, Mitchell BM. Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice. Hypertension 2017; 70:183-191. [PMID: 28584011 DOI: 10.1161/hypertensionaha.117.09374] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 03/22/2017] [Accepted: 05/02/2017] [Indexed: 12/20/2022]
Abstract
The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4+/FoxP3+ regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.
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Affiliation(s)
- Valorie L Chiasson
- From the Department of Internal Medicine (V.L.C., A.R.P., M.H., K.J.Y., K.R.B., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center, College of Medicine, Baylor Scott & White Health, Temple
| | - Abhinandan R Pakanati
- From the Department of Internal Medicine (V.L.C., A.R.P., M.H., K.J.Y., K.R.B., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center, College of Medicine, Baylor Scott & White Health, Temple
| | - Marcos Hernandez
- From the Department of Internal Medicine (V.L.C., A.R.P., M.H., K.J.Y., K.R.B., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center, College of Medicine, Baylor Scott & White Health, Temple
| | - Kristina J Young
- From the Department of Internal Medicine (V.L.C., A.R.P., M.H., K.J.Y., K.R.B., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center, College of Medicine, Baylor Scott & White Health, Temple
| | - Kelsey R Bounds
- From the Department of Internal Medicine (V.L.C., A.R.P., M.H., K.J.Y., K.R.B., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center, College of Medicine, Baylor Scott & White Health, Temple
| | - Brett M Mitchell
- From the Department of Internal Medicine (V.L.C., A.R.P., M.H., K.J.Y., K.R.B., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center, College of Medicine, Baylor Scott & White Health, Temple.
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27
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Kuttkat N, Mohs A, Ohl K, Hooiveld G, Longerich T, Tenbrock K, Cubero FJ, Trautwein C. Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease. Gut 2017; 66:908-919. [PMID: 27686093 PMCID: PMC5531221 DOI: 10.1136/gutjnl-2015-311119] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 08/17/2016] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Th17 cells are a subset of CD4+ T-helper cells characterised by interleukin 17 (IL-17) production, a cytokine that plays a crucial role in inflammation-associated diseases. The cyclic AMP-responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis, which contributes to increased IL-17 expression in patients with autoimmune disorders. Since an increased Th17 response is associated with a poor prognosis in patients with chronic liver injury, we investigated the relevance of Th17 cells for chronic liver disease (CLD) and hepatocarcinogenesis. DESIGN Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (NemoΔhepa) to generate NemoΔhepa/CREMαTg mice. The impact of CREMαTg on CLD progression was examined. Additionally, soft agar colony formation assays, in vitro studies, adoptive transfer of bone marrow-derived cells (BMDCs) and T cells, and gene arrays in T cells were performed. RESULTS 8-week-old NemoΔhepa/CREMαTg mice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b+ dendritic cells and CD8+ T cells. CREMαTg overexpression in NemoΔhepa mice was associated with significantly reduced hepatic fibrogenesis and carcinogenesis at 52 weeks. Interestingly, hepatic stellate cell-derived retinoic acid induced a regulatory T-cell (Treg) phenotype in CREMαTg hepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMαTg into NemoΔhepa mice ameliorated markers of liver injury and hepatitis. CONCLUSIONS Our results demonstrate that overexpression of CREMα in T cells changes the inflammatory milieu, attenuating initiation and progression of CLD. Unexpectedly, our study indicates that CREMα transgenic T cells shift chronic inflammation in NemoΔhepa livers towards a protective Treg response.
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Affiliation(s)
- Nadine Kuttkat
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Antje Mohs
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Kim Ohl
- Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany
| | - Guido Hooiveld
- Institute for Nutrition, Metabolism & Genomics, Wageningen University & Research Centre, Wageningen, Netherlands
| | - Thomas Longerich
- Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany
| | - Klaus Tenbrock
- Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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28
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Bauché D, Marie JC. Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions. Clin Transl Immunology 2017; 6:e136. [PMID: 28523126 PMCID: PMC5418590 DOI: 10.1038/cti.2017.9] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 02/20/2017] [Accepted: 02/20/2017] [Indexed: 12/12/2022] Open
Abstract
The relationship between host organisms and their microbiota has co-evolved towards an inter-dependent network of mutualistic interactions. This interplay is particularly well studied in the gastrointestinal tract, where microbiota and host immune cells can modulate each other directly, as well as indirectly, through the production and release of chemical molecules and signals. In this review, we define the functional impact of transforming growth factor-beta (TGF-β) on this complex interplay, especially through its modulation of the activity of local regulatory T cells (Tregs), type 17 helper (Th17) cells, innate lymphoid cells (ILCs) and B cells.
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Affiliation(s)
- David Bauché
- Department of Immunology, Virology and Inflammation, Cancer Research Center of Lyon UMR INSERM1052, CNRS 5286, Centre Léon Bérard Hospital, Université de Lyon, Equipe labellisée LIGUE, Lyon, France.,TGF-β and Immuno-evasion Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julien C Marie
- Department of Immunology, Virology and Inflammation, Cancer Research Center of Lyon UMR INSERM1052, CNRS 5286, Centre Léon Bérard Hospital, Université de Lyon, Equipe labellisée LIGUE, Lyon, France.,TGF-β and Immuno-evasion Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
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29
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Bhaumik S, Basu R. Cellular and Molecular Dynamics of Th17 Differentiation and its Developmental Plasticity in the Intestinal Immune Response. Front Immunol 2017; 8:254. [PMID: 28408906 PMCID: PMC5374155 DOI: 10.3389/fimmu.2017.00254] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/21/2017] [Indexed: 01/15/2023] Open
Abstract
After emerging from the thymus, naive CD4 T cells circulate through secondary lymphoid tissues, including gut-associated lymphoid tissue of the intestine. The activation of naïve CD4 T cells by antigen-presenting cells offering cognate antigen initiate differentiation programs that lead to the development of highly specialized T helper (Th) cell lineages. Although initially believed that developmental programing of effector T cells such as T helper 1 (Th1) or T helper 2 (Th2) resulted in irreversible commitment to a fixed fate, subsequent studies have demonstrated greater flexibility, or plasticity, in effector T cell stability than originally conceived. This is particularly so for the Th17 subset, differentiation of which is a highly dynamic process with overlapping developmental axes with inducible regulatory T (iTreg), T helper 22 (Th22), and Th1 cells. Accordingly, intermediary stages of Th17 cells are found in various tissues, which co-express lineage-specific transcription factor(s) or cytokine(s) of developmentally related CD4 T cell subsets. A highly specialized tissue like that of the intestine, which harbors the largest immune compartment of the body, adds several layers of complexity to the intricate process of Th differentiation. Due to constant exposure to millions of commensal microbes and periodic exposure to pathogens, the intestinal mucosa maintains a delicate balance between regulatory and effector T cells. It is becoming increasingly clear that equilibrium between tolerogenic and inflammatory axes is maintained in the intestine by shuttling the flexible genetic programming of a developing CD4 T cell along the developmental axis of iTreg, Th17, Th22, and Th1 subsets. Currently, Th17 plasticity remains an unresolved concern in the field of clinical research as targeting Th17 cells to cure immune-mediated disease might also target its related subsets. In this review, we discuss the expanding sphere of Th17 plasticity through its shared developmental axes with related cellular subsets such as Th22, Th1, and iTreg in the context of intestinal inflammation and also examine the molecular and epigenetic features of Th17 cells that mediate these overlapping developmental programs.
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Affiliation(s)
- Suniti Bhaumik
- Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Rajatava Basu
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
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30
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Metabolites: deciphering the molecular language between DCs and their environment. Semin Immunopathol 2016; 39:177-198. [PMID: 27921148 DOI: 10.1007/s00281-016-0609-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 11/14/2016] [Indexed: 02/07/2023]
Abstract
Dendritic cells (DCs) determine the outcome of the immune response based on signals they receive from the environment. Presentation of antigen under various contexts can lead to activation and differentiation of T cells for immunity or dampening of immune responses by establishing tolerance, primarily through the priming of regulatory T cells. Infections, inflammation and normal cellular interactions shape DC responses through direct contact or via cytokine signaling. Although it is widely accepted that DCs sense microbial components through pattern recognition receptors (PRRs), increasing evidence advocates for the existence of a set of signals that can profoundly shape DC function via PRR-independent pathways. This diverse group of host- or commensal-derived metabolites represents a newly appreciated code from which DCs can interpret environmental cues. In this review, we discuss the existing information on the effect of some of the most studied metabolites on DC function, together with the implications this may have in immune-mediated diseases.
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31
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Morel PA, Lee REC, Faeder JR. Demystifying the cytokine network: Mathematical models point the way. Cytokine 2016; 98:115-123. [PMID: 27919524 DOI: 10.1016/j.cyto.2016.11.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 11/21/2016] [Indexed: 12/22/2022]
Abstract
Cytokines provide the means by which immune cells communicate with each other and with parenchymal cells. There are over one hundred cytokines and many exist in families that share receptor components and signal transduction pathways, creating complex networks. Reductionist approaches to understanding the role of specific cytokines, through the use of gene-targeted mice, have revealed further complexity in the form of redundancy and pleiotropy in cytokine function. Creating an understanding of the complex interactions between cytokines and their target cells is challenging experimentally. Mathematical and computational modeling provides a robust set of tools by which complex interactions between cytokines can be studied and analyzed, in the process creating novel insights that can be further tested experimentally. This review will discuss and provide examples of the different modeling approaches that have been used to increase our understanding of cytokine networks. This includes discussion of knowledge-based and data-driven modeling approaches and the recent advance in single-cell analysis. The use of modeling to optimize cytokine-based therapies will also be discussed.
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Affiliation(s)
- Penelope A Morel
- Department of Immunology, University of Pittsburgh, Pittsburgh, USA.
| | - Robin E C Lee
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, USA
| | - James R Faeder
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, USA
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32
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Yokota-Nakatsuma A, Ohoka Y, Takeuchi H, Song SY, Iwata M. Beta 1-integrin ligation and TLR ligation enhance GM-CSF-induced ALDH1A2 expression in dendritic cells, but differentially regulate their anti-inflammatory properties. Sci Rep 2016; 6:37914. [PMID: 27897208 PMCID: PMC5126582 DOI: 10.1038/srep37914] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 11/03/2016] [Indexed: 12/11/2022] Open
Abstract
Retinoic acid (RA)–producing CD103+ mature dendritic cells (DCs) in mesenteric lymph nodes (MLNs) play crucial roles in gut immunity. GM-CSF and RA contribute to the expression of the RA-producing enzyme ALDH1A2. However, additional signals appeared to be required for inducing ALDH1A2high mature DCs from immature DCs. We found here that TLR ligands (Ls) and immobilized E-cadherin could provide such signals in FLT3-L–generated bone marrow (BM)–derived DCs after treatment with GM-CSF and the RA receptor agonist Am80. The TLR-L-treated DCs produced proinflammatory cytokines unlike normal ALDH1A2high MLN-DCs, whereas the E-cadherin-treated DCs did not. Immobilized VCAM-1 and semaphorin 7 A exerted effects similar to those of E-cadherin. Soluble anti-integrin β1 antibodies or inhibitors of integrin signaling molecules suppressed the effects of these immobilized proteins, whereas immobilized anti-integrin β1 antibodies enhanced the GM-CSF/Am80-induced ALDH1A2 expression without inducing proinflammatory cytokines. Sequential stimulation of splenic pre-DCs with GM-CSF/Am80 and immobilized E-cadherin or anti-integrin β1 antibody also induced differentiation to mature DCs with high ALDH activity. The E-cadherin-treated BM-DCs induced gut-tropic Foxp3+ T cells and alleviated DSS–induced colitis, whereas the TLR-L-treated DCs aggravated DSS–induced colitis. The results suggest that integrin β1-mediated signals contribute to the differentiation and maturation of RA-producing anti-inflammatory DCs.
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Affiliation(s)
- Aya Yokota-Nakatsuma
- Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.,Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan
| | - Yoshiharu Ohoka
- Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.,Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan
| | - Hajime Takeuchi
- Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.,Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan
| | - Si-Young Song
- Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.,Institute of Neuroscience, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan
| | - Makoto Iwata
- Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.,Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan
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33
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Ghali JR, Alikhan MA, Holdsworth SR, Kitching AR. Induced regulatory T cells are phenotypically unstable and do not protect mice from rapidly progressive glomerulonephritis. Immunology 2016; 150:100-114. [PMID: 27606831 DOI: 10.1111/imm.12671] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 08/10/2016] [Accepted: 09/02/2016] [Indexed: 12/15/2022] Open
Abstract
Regulatory T (Treg) cells are a suppressive CD4+ T-cell subset. We generated induced Treg (iTreg) cells and explored their therapeutic potential in a murine model of rapidly progressive glomerulonephritis. Polyclonal naive CD4+ T cells were cultured in vitro with interleukin-2 (IL-2), transforming growth factor-β1, all-trans-retinoic acid and monoclonal antibodies against interferon-γ and IL-4, generating Foxp3+ iTreg cells. To enhance their suppressive phenotype, iTreg cultures were modified with the addition of a monoclonal antibody against IL-12p40 or by using RORγt-/- CD4+ T cells. Induced Treg cells were transferred into models of delayed-type hypersensitivity and experimental glomerulonephritis. The iTreg cells exhibited comparable surface receptor expression and in vitro suppressive ability to natural Treg cells, but did not regulate antigen-specific delayed-type hypersensitivity or systemic inflammatory immune responses, losing Foxp3 expression in vivo. In glomerulonephritis, transferred iTreg cells did not prevent renal injury or modulate systemic T helper type 1 immune responses. Induced Treg cells cultured with anti-IL-12p40 had an enhanced suppressive phenotype in vitro and regulated dermal delayed-type hypersensitivity in vivo, but were not protective against renal injury, losing Foxp3 expression, especially in the transferred cells recruited to the kidney. Use of RORγt-/- CD4+ T cells or iTreg cells generated from sensitized CD4+ Foxp3- cells did not regulate renal or systemic inflammatory responses in vivo. In conclusion, iTreg cells suppress T-cell proliferation in vitro, but do not regulate experimental glomerulonephritis, being unstable in this inflammatory milieu in vivo.
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Affiliation(s)
- Joanna R Ghali
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.,Department of Nephrology, Monash Health, Clayton, Victoria, Australia
| | - Maliha A Alikhan
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia
| | - Stephen R Holdsworth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.,Department of Nephrology, Monash Health, Clayton, Victoria, Australia
| | - A Richard Kitching
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.,Department of Nephrology, Monash Health, Clayton, Victoria, Australia.,Department of Paediatric Nephrology, Monash Health, Clayton, Victoria, Australia
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34
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Farhangi MA, Saboor-Yaraghi AA, Keshavarz SA. Vitamin A supplementation reduces the Th17-Treg - Related cytokines in obese and non-obese women. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2016; 60:29-35. [PMID: 26909479 PMCID: PMC10118919 DOI: 10.1590/2359-3997000000125] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 09/29/2015] [Indexed: 11/21/2022]
Abstract
OBJECTIVE The objective of the present study was to investigate the effect of vitamin A supplementation on serum Th17 (IL-6, IL-17, IFNγ) and Treg (TGF-β, IL-10) related cytokines in obese and non-obese women. SUBJECTS AND METHODS In a randomized double blind placebo controlled design, 56 obese women were randomly assigned to receive either an oral dose of 25,000 IU retinyl palmitate or placebo per day for 4 months. Twenty eight ages matched non-obese women were also received vitamin A. At the study entry, anthropometric variables were measured and serum Th17 and Treg related cytokine profile were determined at baseline and 4 months after intervention. RESULTS Significantly higher baseline concentrations of IL-6 were observed in obese compared with non-obese women (P < 0.05). However, the initial concentrations of other cytokines were not significantly different between groups. The mean concentrations of IL-17 and TGF-β were significantly decreased after vitamin A supplementation in non-obese and obese women respectively. Positive relationships between IL-17 and IL-10 (r = 0.42, P < 0.001), TGF-β and IL-17 (r = 0.35, P < 0.001) and between IL-10 and IFN-γ (r = 0.41, P = 0.002) in total participants were also observed. CONCLUSIONS The results of the present study showed for the first time that vitamin A supplementation reduces serum concentrations of IL-17 and TGF-β in reproductive age women. Further studies are needed to explore the possible underlying mechanisms.
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Affiliation(s)
| | - Ali Akbar Saboor-Yaraghi
- Department of Cellular and Molecular Nutrition, School of Nutrition and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed Ali Keshavarz
- Department of Clinical Nutrition, School of Nutrition and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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35
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The Molecular Mechanisms of Vitamin A Deficiency in Multiple Sclerosis. J Mol Neurosci 2016; 60:82-90. [DOI: 10.1007/s12031-016-0781-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 06/17/2016] [Indexed: 10/24/2022]
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36
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Bono MR, Tejon G, Flores-Santibañez F, Fernandez D, Rosemblatt M, Sauma D. Retinoic Acid as a Modulator of T Cell Immunity. Nutrients 2016; 8:E349. [PMID: 27304965 PMCID: PMC4924190 DOI: 10.3390/nu8060349] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 05/20/2016] [Accepted: 06/01/2016] [Indexed: 12/30/2022] Open
Abstract
Vitamin A, a generic designation for an array of organic molecules that includes retinal, retinol and retinoic acid, is an essential nutrient needed in a wide array of aspects including the proper functioning of the visual system, maintenance of cell function and differentiation, epithelial surface integrity, erythrocyte production, reproduction, and normal immune function. Vitamin A deficiency is one of the most common micronutrient deficiencies worldwide and is associated with defects in adaptive immunity. Reports from epidemiological studies, clinical trials and experimental studies have clearly demonstrated that vitamin A plays a central role in immunity and that its deficiency is the cause of broad immune alterations including decreased humoral and cellular responses, inadequate immune regulation, weak response to vaccines and poor lymphoid organ development. In this review, we will examine the role of vitamin A in immunity and focus on several aspects of T cell biology such as T helper cell differentiation, function and homing, as well as lymphoid organ development. Further, we will provide an overview of the effects of vitamin A deficiency in the adaptive immune responses and how retinoic acid, through its effect on T cells can fine-tune the balance between tolerance and immunity.
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Affiliation(s)
- Maria Rosa Bono
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Gabriela Tejon
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Felipe Flores-Santibañez
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Dominique Fernandez
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
| | - Mario Rosemblatt
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
- Fundacion Ciencia & Vida, Santiago 7780272, Chile.
- Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago 8370146, Chile.
| | - Daniela Sauma
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.
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Yosaee S, Akbari Fakhrabadi M, Shidfar F. Positive evidence for vitamin A role in prevention of type 1 diabetes. World J Diabetes 2016; 7:177-188. [PMID: 27162582 PMCID: PMC4856890 DOI: 10.4239/wjd.v7.i9.177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 03/23/2016] [Accepted: 04/07/2016] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) as one of the most well-known autoimmune disease, results from the destruction of β-cells in pancreas by autoimmune process. T1DM is fatal without insulin treatment. The expansion of alternative treatment to insulin is a dream to be fulfilled. Currently autoimmunity is considered as main factor in development of T1DM. So manipulation of the immune system can be considered as alternative treatment to insulin. For the past decades, vitamin A has been implicated as an essential dietary micronutrient in regulator of immune function. Despite major advantage in the knowledge of vitamin A biology, patients who present T1DM are at risk for deficiency in vitamin A and carotenoids. Applying such evidences, vitamin A treatment may be the key approach in preventing T1DM.
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Retinoic acid suppresses IL‐17 production and pathogenic activity of γδ T cells in CNS autoimmunity. Immunol Cell Biol 2016; 94:763-73. [DOI: 10.1038/icb.2016.39] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 04/12/2016] [Accepted: 04/13/2016] [Indexed: 12/26/2022]
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Ferretti C, La Cava A. Adaptive immune regulation in autoimmune diabetes. Autoimmun Rev 2016; 15:236-41. [DOI: 10.1016/j.autrev.2015.11.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 11/19/2015] [Indexed: 12/16/2022]
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Vitamin D improves cognitive function and modulates Th17/T reg cell balance after hepatectomy in mice. Inflammation 2015; 38:500-9. [PMID: 24958015 DOI: 10.1007/s10753-014-9956-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
It is known that surgery-induced tissue damage activates the peripheral immune system resulting in the release of inflammatory mediators and cognitive impairment in aged mice. Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we mainly investigated the efficacy and mechanism of vitamin D against postoperative cognitive dysfunction (POCD). The treatment of C57BL mice with vitamin D significantly preserves postoperative cognitive function, markedly inhibits surgery-induced interleukin (IL)-17, IL-6, transforming growth factor beta (TGF-β), and retinoic acid-related orphan receptor (RORγt) production, and obviously induces IL-10 and forkhead box p3 (Foxp3) expression. These findings indicate that vitamin D amelioration of POCD is, to a large extent, due to inhibit inflammatory CD4_T cell lineage, T helper 17 (Th17) cells, accompanied with expansion in regulatory T cells (Treg cells), a subset of CD4_T cells that are important in inhibiting inflammation. Our results suggest that Th17 and Treg cell imbalance may play a role in the development of POCD. Vitamin D is useful in the control of inflammatory diseases.
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Park BV, Pan F. The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases. Cell Mol Immunol 2015; 12:533-42. [PMID: 25958843 PMCID: PMC4579653 DOI: 10.1038/cmi.2015.21] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 02/20/2015] [Accepted: 02/21/2015] [Indexed: 12/15/2022] Open
Abstract
Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis,and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD41 T-cell type 17 (Th17) and regulatory T cells (Treg). Th17 and Treg are closely related cell fates that are determined by orchestrated cytokine signaling. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how such interaction affects Th17/Treg development and function.This review will focus on the most recent discoveries concerning the roles of nuclear receptors in the context of therapeutic applications in autoimmune diseases.
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Liu ZM, Wang KP, Ma J, Guo Zheng S. The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells. Cell Mol Immunol 2015; 12:553-7. [PMID: 25640656 PMCID: PMC4579645 DOI: 10.1038/cmi.2014.133] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 12/14/2014] [Accepted: 12/16/2014] [Indexed: 12/14/2022] Open
Abstract
Regulatory T (Treg) cells are necessary for immune system homeostasis and the prevention of autoimmune diseases. Foxp3 is specifically expressed in Treg cells and plays a key role in their differentiation and function. Foxp3(+) Treg cells are consisted of naturally occurring, thymus-derived Treg (nTreg) and peripheral-induced Treg (iTreg) cells that may have different functional characteristics or synergistic roles. All-trans retinoic acid (atRA), a vitamin A metabolite, regulates a wide range of biological processes, including cell differentiation and proliferation. Recent studies demonstrated that atRA also regulates the differentiation of T helper (Th) cells and Treg cells. Moreover, atRA also sustains nTreg stability under inflammatory conditions. In this review, we summarize the significant progress of our understanding of the role(s) and mechanisms of atRA in Treg biology.
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Affiliation(s)
- Zhong-Min Liu
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kun-Peng Wang
- Division of Rheumatology, Penn State Hershey College of Medicine, Hershey, PA, USA
- Division of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jilin Ma
- Division of Rheumatology, Penn State Hershey College of Medicine, Hershey, PA, USA
- Division of Rheumatology, Immunology and Nephrology, Zhejiang Provincial Traditional Chinese Medicine and Western Medicine Hospital, Hangzhou, China
| | - Song Guo Zheng
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
- Division of Rheumatology, Penn State Hershey College of Medicine, Hershey, PA, USA
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Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis. J Mol Neurosci 2015; 57:605-13. [PMID: 26319266 DOI: 10.1007/s12031-015-0643-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 08/17/2015] [Indexed: 01/30/2023]
Abstract
Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS). The immunopathogenesis of this disease involves an impaired balance of T helper (Th) 17 cells and regulatory T (Tregs) cells. MS is an autoinflammatory disease characterized by the degeneration of the CNS. For many years, MS has been considered to be an autoreactive Th1 and Th17 cell-dominated disease. The activity and number of Th17 cells are increased in MS; however, the function and number of Treg cells are reduced. Therefore, in MS, the balance between Th17 cells and Treg cells is impaired. Th17 cells produce pro-inflammatory cytokines, which play a role in experimental autoimmune encephalomyelitis (EAE) and MS. However, Treg cell-mediated production of cytokines maintains immune homeostasis and can ameliorate the progression of MS. These observations, therefore, confirm the pathogenic and protective role of Th17 and Treg cells, respectively, and highlight the importance of maintaining the balance of both of these cell types. Evidence suggests that vitamin A and its active metabolites (all-trans-retinoic acid and 9-cis-retinoic acid) modulate the imbalance of Th17 and Treg cells through multiple molecular pathways and can be considered as a promising target in the prevention and treatment of MS.
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Zhou HY, Zhong W, Zhang H, Bi MM, Wang S, Zhang WS. Potential role of nuclear receptor ligand all-trans retinoic acids in the treatment of fungal keratitis. Int J Ophthalmol 2015; 8:826-32. [PMID: 26309886 DOI: 10.3980/j.issn.2222-395.2015.04.32] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Accepted: 02/04/2015] [Indexed: 12/17/2022] Open
Abstract
Fungal keratitis (FK) is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to a variety of immune cells, including macrophages, helper T cells, neutrophils, dendritic cells, and Treg cells, and is associated with proinflammatory, chemotactic and regulatory cytokines. All-trans retinoic acids (ATRA) have diverse immunomodulatory actions in a number of inflammatory and autoimmune conditions. These retinoids regulate the transcriptional levels of target genes through the activation of nuclear receptors. Retinoic acid receptor α (RAR α), retinoic acid receptor γ (RAR γ), and retinoid X receptor α (RXR α) are expressed in the cornea and immune cells. This paper summarizes new findings regarding ATRA in immune and inflammatory diseases and analyzes the perspective application of ATRA in FK.
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Affiliation(s)
- Hong-Yan Zhou
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin Province, China
| | - Wei Zhong
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin Province, China
| | - Hong Zhang
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin Province, China
| | - Miao-Miao Bi
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin Province, China
| | - Shuang Wang
- Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin Province, China
| | - Wen-Song Zhang
- Department of Glaucoma, the Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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Kimura K, Orita T, Liu Y, Yang Y, Tokuda K, Kurakazu T, Noda T, Yanai R, Morishige N, Takeda A, Ishibashi T, Sonoda KH. Attenuation of EMT in RPE cells and subretinal fibrosis by an RAR-γ agonist. J Mol Med (Berl) 2015; 93:749-58. [PMID: 25947075 DOI: 10.1007/s00109-015-1289-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 01/28/2015] [Accepted: 03/30/2015] [Indexed: 10/23/2022]
Abstract
UNLABELLED Subretinal fibrosis contributes to the loss of vision associated with age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of AMD including the fibrotic reaction. We examined the role of retinoic acid receptor-γ (RAR-γ) in the epithelial-mesenchymal transition (EMT) and other fibrosis-related processes in mouse RPE cells cultured in a type I collagen gel. Transforming growth factor-β2 (TGF-β2)-induced collagen gel contraction mediated by the RPE cells was inhibited by the RAR-γ agonist R667 in a concentration- and time-dependent manner. Expression of the mesenchymal markers α-smooth muscle actin and fibronectin, the release of interleukin-6, and the phosphorylation of paxillin, mitogen-activated protein kinases (ERK, p38, and JNK), Smad2, and AKT induced by TGF-β2 were also suppressed by the RAR-γ agonist. Furthermore, gelatin zymography and immunoblot analysis revealed that the TGF-β2-induced release of matrix metalloproteinase (MMP)-2, MMP-3, MMP-8, and MMP-9 from RPE cells was inhibited by R667, and the MMP inhibitor GM6001 attenuated TGF-β2-induced RPE cell contraction. Finally, immunohistofluorescence analysis with antibodies to glial fibrillary acidic protein showed that R667 inhibited the development of subretinal fibrosis in a mouse model in vivo. Our results thus suggest that RAR-γ agonists may prove effective for the treatment of subretinal fibrosis associated with AMD. KEY MESSAGE RAR-γ agonist R667 suppressed collagen gel contraction mediated by RPE cells. Epithelial-mesenchymal transition (EMT) in RPE cells was inhibited by RAR-γ agonist R667. RAR-γ agonist R667 inhibited fibrosis-related processes in RPE cells. RAR-γ agonists may attenuate AMD-associated fibrosis.
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Affiliation(s)
- Kazuhiro Kimura
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube City, Yamaguchi, 755-8505, Japan,
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Khare A, Chakraborty K, Raundhal M, Ray P, Ray A. Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways. THE JOURNAL OF IMMUNOLOGY 2015; 195:431-5. [PMID: 26062999 DOI: 10.4049/jimmunol.1500474] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 05/17/2015] [Indexed: 01/15/2023]
Abstract
The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator-activated receptor γ (PPARγ) in CD11c(+) cells, we show that PPARγ performs two critical functions in CD11c(+) cells to induce tolerance, thereby preserving immune homeostasis. First, PPARγ was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103(+) dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4(+) T cells. Second, in all CD11c(+) cells, PPARγ was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARγ in CD11c(+) cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARγ favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation.
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Affiliation(s)
- Anupriya Khare
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and
| | - Krishnendu Chakraborty
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and
| | - Mahesh Raundhal
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Prabir Ray
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Anuradha Ray
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
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The Effect of Vitamin A Supplementation on FoxP3 and TGF-β Gene Expression in Avonex-Treated Multiple Sclerosis Patients. J Mol Neurosci 2015; 56:608-12. [PMID: 25985851 DOI: 10.1007/s12031-015-0549-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 03/23/2015] [Indexed: 01/07/2023]
Abstract
Multiple sclerosis (MS) is an autoinflammatory condition of the central nervous system with impaired T helper (Th)17 and regulatory T cell (Treg) balance that is involved in disease immunopathogenesis. The vitamin A active metabolite, retinoic acid, can re-establish this imbalance through the modulation of gene expression of specific nuclear receptors including Forkhead box P3 (FoxP3). At present, few data exist on the impact of vitamin A supplementation on T cell balance. This study reports the results of a clinical trial, over a 6-month period, of 36 relapsing-remitting MS (RRMS) patients that received vitamin A (25,000 IU retinyl palmitate) or placebo (one capsule of placebo per day). Peripheral blood mononuclear cells were isolated from patients, and the expression of FoxP3 and transforming growth factor (TGF)-β gene expression was measured using real-time PCR at the beginning and end of the study. The results of this study showed that vitamin A upregulated TGF-β and FoxP3 gene expression. Therefore, vitamin A supplementation can be considered as a new approach in MS prevention and treatment.
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48
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Park BV, Pan F. The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases. Cell Mol Immunol 2015. [DOI: 10.1038/cmi.2015.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Wang X, Wang W, Xu J, Wu S, Le Q. All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β. BMC Immunol 2015; 16:17. [PMID: 25887926 PMCID: PMC4395899 DOI: 10.1186/s12865-015-0082-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 03/09/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND All-trans retinoid acid (ATRA) has been proven to skew Regulatory T cell-T helper 17 cell (Treg-Th17) balance toward Treg in vitro, favoring graft acceptance. However, its in vivo effect after solid organ transplantation is under investigation. RESULTS BALB/c mice were given orthotopic corneal grafts from C57BL/6 donors, and recipient mice were administered with ATRA, TGF-β, and the combination of both agents for 8 weeks after surgery. We found that a mixed treatment of ATRA and TGF-β significantly promoted graft survival. Moreover, with the presence of TGF-β, ATRA upregulated CD4(+)CD25(+)Foxp3(+)Treg cells and suppressed Th17 cells in the blood, spleen and draining lymph nodes of recipient mice, as well as enhanced the Foxp3 expression and inhibited the RORγt expression in grafts and peripheral blood mononuclear cells (PBMCs). Simultaneously, increased number of Foxp3+ cells and decreased number of IL-17+ cells in conjunctiva were found in recipients with mixed treatment, along with reduced IL-17 level in serum and aqueous humor and increased IL-10 level in aqueous humor. Tregs isolated from recipient mice treated with ATRA + TGF-β presented the strongest suppressive activity in vitro. CONCLUSIONS Combined application of ATRA and TGF-β may shift the Th17-Treg balance toward Tregs, hence facilitating the induction of immunological tolerance after allogenic corneal transplantation and representing a potential therapeutic approach in the treatment of posttransplant rejection.
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Affiliation(s)
- Xin Wang
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China.
| | - Wentao Wang
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China. .,Research Center, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China.
| | - Jianjiang Xu
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China.
| | - Suqian Wu
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China.
| | - Qihua Le
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China. .,Research Center, Eye & ENT Hospital of Fudan University, Shanghai, 200031, China.
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