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Shi Y, Shao Q, Ren Z, Shang G, Han J, Cheng J, Zheng Y, Cheng F, Li C, Wang Q, Wang X. Mechanisms of pulmonary fibrosis and lung cancer induced by chronic PM 2.5 exposure: Focus on the airway epithelial barrier and epithelial-mesenchymal transition. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 297:118253. [PMID: 40311473 DOI: 10.1016/j.ecoenv.2025.118253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/25/2025] [Accepted: 04/26/2025] [Indexed: 05/03/2025]
Abstract
This study aims to provide new insights into PM2.5-induced lung diseases through a focus on the pulmonary epithelial barrier and epithelial-mesenchymal transition (EMT). Firstly, we analyzed the mechanisms by which PM2.5 damages the airway epithelial barrier, including inflammatory responses, immune imbalance, oxidative stress, apoptosis, and autophagy. Subsequently, we investigated the mechanisms by which PM2.5 induces EMT, which involve the synergistic effect of oxidative stress and inflammation, the activation of key signaling pathways, and the regulatory role of non-coding RNAs. Furthermore, we explored the interaction between the airway epithelial barrier and EMT, especially the induction of EMT by epithelial barrier damage and the impact of EMT on epithelial barrier repair. Regarding lung injury diseases, we focused on the roles of the epithelial barrier and EMT in the development of pulmonary fibrosis and lung cancer, providing evidence from in vitro and in vivo studies. Emphasizing the translational prospects from basic research to clinical applications, and we proposed new ideas for treating PM2.5-related lung diseases from four aspects-anti-inflammatory and antioxidant drugs, signaling pathway inhibitors, non-coding RNA-targeted therapies, and gene editing and cell therapies-by focusing on the two key links of the airway epithelial barrier and EMT.
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Affiliation(s)
- Yuyu Shi
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qi Shao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zilin Ren
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Guojiao Shang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jinhua Han
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jialin Cheng
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yuxiao Zheng
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Fafeng Cheng
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Changxiang Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Qingguo Wang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Xueqian Wang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
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2
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Palatella M, Kruse F, Glage S, Bleich A, Greweling-Pils M, Huehn J. Acsbg1 regulates differentiation and inflammatory properties of CD4+ T cells. Eur J Microbiol Immunol (Bp) 2025; 15:21-31. [PMID: 39937199 PMCID: PMC11925188 DOI: 10.1556/1886.2025.00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 01/28/2025] [Indexed: 02/13/2025] Open
Abstract
Epigenetic modifications are critical for the regulation of CD4+ T cell differentiation and function. Previously, we identified Acyl-CoA Synthetase Bubble Gum 1 (Acsbg1), a gene involved in fatty acid metabolism, as part of an epigenetic signature that was selectively demethylated in ex vivo isolated T helper 17 (TH17) cells. However, its functional relevance for CD4+ T cells remains incompletely understood. Here, we used in vitro differentiation assays and the adoptive transfer colitis model to investigate the role of Acsbg1 in the differentiation and function of TH1, TH17, and regulatory T (Treg) cells. In vitro, Acsbg1 was expressed in both TH17 and in vitro-induced Treg (iTreg) cells, whereas TH1 cells lacked Acsbg1 expression. Accordingly, Acsbg1 deficiency resulted in impaired TH17 and iTreg differentiation, whereas TH1 differentiation was unaffected. In vivo, upon adoptive transfer of Acsbg1⁻/⁻ Tnaïve cells, immunodeficient recipient mice exhibited an exacerbated colitis, characterized by an altered balance of TH17 and Treg cells, indicating that Acsbg1 expression is essential for optimal TH17 and Treg cell differentiation and function. Our findings highlight the importance of fatty acid (FA) metabolism in maintaining immune homeostasis by regulating T cell differentiation and provide novel insights into the metabolic targeting of inflammatory diseases.
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Affiliation(s)
- Martina Palatella
- 1Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Friederike Kruse
- 1Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Silke Glage
- 2Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - André Bleich
- 2Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Marina Greweling-Pils
- 3Mouse Pathology Platform, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Jochen Huehn
- 1Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- 4Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
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3
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Kaszycki J, Kim M. Epigenetic regulation of transcription factors involved in NLRP3 inflammasome and NF-kB signaling pathways. Front Immunol 2025; 16:1529756. [PMID: 40046056 PMCID: PMC11879833 DOI: 10.3389/fimmu.2025.1529756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 02/03/2025] [Indexed: 05/13/2025] Open
Abstract
The NLRP3 inflammasome and NF-κB signaling pathways play crucial roles in orchestrating inflammation and immune defense. This review explores the intricate relationship between these pathways and epigenetic regulation, a field of growing importance in understanding immune responses. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), significantly influence the activity of genes involved in these pathways, thereby modulating inflammatory responses. The review provides a comprehensive overview of current research on how epigenetic mechanisms interact with and regulate the NLRP3 inflammasome and NF-κB signaling pathways. It delves into advanced epigenetic concepts such as RNA modifications and 3D genome organization, and their impact on immune regulation. Furthermore, the implications of these findings for developing novel therapeutic strategies targeting epigenetic regulators in inflammatory diseases are discussed. By synthesizing recent advancements in this rapidly evolving field, this review underscores the critical role of epigenetic regulation in immune signaling and highlights the potential for epigenetic-based therapies in treating a wide range of inflammatory conditions, including autoimmune disorders and cancer.
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Affiliation(s)
- John Kaszycki
- Department of Biological Sciences, University of Connecticut, Storrs, CT, United States
| | - Minji Kim
- School of Pharmacy, University of Connecticut, Storrs, CT, United States
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Goldsmith C, Thevin V, Fesneau O, Matias MI, Perrault J, Abid AH, Taylor N, Dardalhon V, Marie JC, Hernandez-Vargas H. Single-Molecule DNA Methylation Reveals Unique Epigenetic Identity Profiles of T Helper Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1029-1039. [PMID: 38284984 PMCID: PMC11002815 DOI: 10.4049/jimmunol.2300091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 01/04/2024] [Indexed: 01/30/2024]
Abstract
Both identity and plasticity of CD4 T helper (Th) cells are regulated in part by epigenetic mechanisms. However, a method that reliably and readily profiles DNA base modifications is still needed to finely study Th cell differentiation. Cytosine methylation in CpG context (5mCpG) and cytosine hydroxymethylation (5hmCpG) are DNA modifications that identify stable cell phenotypes, but their potential to characterize intermediate cell transitions has not yet been evaluated. To assess transition states in Th cells, we developed a method to profile Th cell identity using Cas9-targeted single-molecule nanopore sequencing. Targeting as few as 10 selected genomic loci, we were able to distinguish major in vitro polarized murine T cell subtypes, as well as intermediate phenotypes, by their native DNA 5mCpG patterns. Moreover, by using off-target sequences, we were able to infer transcription factor activities relevant to each cell subtype. Detection of 5mCpG and 5hmCpG was validated on intestinal Th17 cells escaping transforming growth factor β control, using single-molecule adaptive sampling. A total of 21 differentially methylated regions mapping to the 10-gene panel were identified in pathogenic Th17 cells relative to their nonpathogenic counterpart. Hence, our data highlight the potential to exploit native DNA methylation profiling to study physiological and pathological transition states of Th cells.
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Affiliation(s)
- Chloe Goldsmith
- Tumor Escape Resistance and Immunity Department, Cancer Research Center of Lyon, The French League Against Cancer Certified Team, INSERM U1052, CNRS UMR 5286, Léon Bérard Centre and University of Lyon, Lyon, France
| | - Valentin Thevin
- Tumor Escape Resistance and Immunity Department, Cancer Research Center of Lyon, The French League Against Cancer Certified Team, INSERM U1052, CNRS UMR 5286, Léon Bérard Centre and University of Lyon, Lyon, France
| | - Olivier Fesneau
- Tumor Escape Resistance and Immunity Department, Cancer Research Center of Lyon, The French League Against Cancer Certified Team, INSERM U1052, CNRS UMR 5286, Léon Bérard Centre and University of Lyon, Lyon, France
| | - Maria I Matias
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Julie Perrault
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Ali Hani Abid
- Tumor Escape Resistance and Immunity Department, Cancer Research Center of Lyon, The French League Against Cancer Certified Team, INSERM U1052, CNRS UMR 5286, Léon Bérard Centre and University of Lyon, Lyon, France
| | - Naomi Taylor
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- Pediatric Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD
| | - Valérie Dardalhon
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Julien C Marie
- Tumor Escape Resistance and Immunity Department, Cancer Research Center of Lyon, The French League Against Cancer Certified Team, INSERM U1052, CNRS UMR 5286, Léon Bérard Centre and University of Lyon, Lyon, France
| | - Hector Hernandez-Vargas
- Tumor Escape Resistance and Immunity Department, Cancer Research Center of Lyon, The French League Against Cancer Certified Team, INSERM U1052, CNRS UMR 5286, Léon Bérard Centre and University of Lyon, Lyon, France
- Genomics Consulting, Bron, France
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5
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Cui H, Wang N, Li H, Bian Y, Wen W, Kong X, Wang F. The dynamic shifts of IL-10-producing Th17 and IL-17-producing Treg in health and disease: a crosstalk between ancient "Yin-Yang" theory and modern immunology. Cell Commun Signal 2024; 22:99. [PMID: 38317142 PMCID: PMC10845554 DOI: 10.1186/s12964-024-01505-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/28/2024] [Indexed: 02/07/2024] Open
Abstract
The changes in T regulatory cell (Treg) and T helper cell (Th) 17 ratios holds paramount importance in ensuring internal homeostasis and disease progression. Recently, novel subsets of Treg and Th17, namely IL-17-producing Treg and IL-10-producing Th17 have been identified. IL-17-producing Treg and IL-10-producing Th17 are widely considered as the intermediates during Treg/Th17 transformation. These "bi-functional" cells exhibit plasticity and have been demonstrated with important roles in multiple physiological functions and disease processes. Yin and Yang represent opposing aspects of phenomena according to the ancient Chinese philosophy "Yin-Yang" theory. Furthermore, Yin can transform into Yang, and vice versa, under specific conditions. This theory has been widely used to describe the contrasting functions of immune cells and molecules. Therefore, immune-activating populations (Th17, M1 macrophage, etc.) and immune overreaction (inflammation, autoimmunity) can be considered Yang, while immunosuppressive populations (Treg, M2 macrophage, etc.) and immunosuppression (tumor, immunodeficiency) can be considered Yin. However, another important connotation of "Yin-Yang" theory, the conversion between Yin and Yang, has been rarely documented in immune studies. The discovery of IL-17-producing Treg and IL-10-producing Th17 enriches the meaning of "Yin-Yang" theory and further promotes the relationship between ancient "Yin-Yang" theory and modern immunology. Besides, illustrating the functions of IL-17-producing Treg and IL-10-producing Th17 and mechanisms governing their differentiation provides valuable insights into the mechanisms underlying the dynamically changing statement of immune statement in health and diseases.
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Affiliation(s)
- Huantian Cui
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Ning Wang
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Hanzhou Li
- College of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yuhong Bian
- College of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Weibo Wen
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
| | - Xiangying Kong
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Fudi Wang
- The First Affiliated Hospital, Institute of Translational Medicine, The Second Affiliated Hospital, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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6
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Herppich S, Hoenicke L, Kern F, Kruse F, Smout J, Greweling-Pils MC, Geffers R, Burton OT, Liston A, Keller A, Floess S, Huehn J. Zfp362 potentiates murine colonic inflammation by constraining Treg cell function rather than promoting Th17 cell differentiation. Eur J Immunol 2023; 53:e2250270. [PMID: 37366299 DOI: 10.1002/eji.202250270] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 05/02/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023]
Abstract
Mucosal barrier integrity and pathogen clearance is a complex process influenced by both Th17 and Treg cells. Previously, we had described the DNA methylation profile of Th17 cells and identified Zinc finger protein (Zfp)362 to be uniquely demethylated. Here, we generated Zfp362-/- mice to unravel the role of Zfp362 for Th17 cell biology. Zfp362-/- mice appeared clinically normal, showed no phenotypic alterations in the T-cell compartment, and upon colonization with segmented filamentous bacteria, no effect of Zfp362 deficiency on Th17 cell differentiation was observed. By contrast, Zfp362 deletion resulted in increased frequencies of colonic Foxp3+ Treg cells and IL-10+ and RORγt+ Treg cell subsets in mesenteric lymph nodes. Adoptive transfer of naïve CD4+ T cells from Zfp362-/- mice into Rag2-/- mice resulted in a significantly lower weight loss when compared with controls receiving cells from Zfp362+/+ littermates. However, this attenuated weight loss did not correlate with alterations of Th17 cells but instead was associated with an increase of effector Treg cells in mesenteric lymph nodes. Together, these results suggest that Zfp362 plays an important role in promoting colonic inflammation; however, this function is derived from constraining the effector function of Treg cells rather than directly promoting Th17 cell differentiation.
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Affiliation(s)
- Susanne Herppich
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Lisa Hoenicke
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Fabian Kern
- Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, Saarland University, Saarbrücken, Germany
- Department of Clinical Bioinformatics, Saarland University, Homburg, Germany
| | - Friederike Kruse
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Justine Smout
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Oliver T Burton
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK
| | - Adrian Liston
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK
| | - Andreas Keller
- Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, Saarland University, Saarbrücken, Germany
- Department of Clinical Bioinformatics, Saarland University, Homburg, Germany
| | - Stefan Floess
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Jochen Huehn
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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7
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Wang Y, Xue N, Wang Z, Zeng X, Ji N, Chen Q. Targeting Th17 cells: a promising strategy to treat oral mucosal inflammatory diseases. Front Immunol 2023; 14:1236856. [PMID: 37564654 PMCID: PMC10410157 DOI: 10.3389/fimmu.2023.1236856] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/06/2023] [Indexed: 08/12/2023] Open
Abstract
With the improved quality of life, oral health is under increased pressure. Numerous common oral mucosal diseases, such as oral lichen planus(OLP) and gingivitis, are related to the destruction of the oral immune barrier. The cytokines secreted by T-helper 17 (Th17) cells are essential for maintaining oral immune homeostasis and play essential roles in immune surveillance. When antigens stimulate the epithelium, Th17 cells expand, differentiate, and generate inflammatory factors to recruit other lymphocytes, such as neutrophils, to clear the infection, which helps to maintain the integrity of the epithelial barrier. In contrast, excessive Th17/IL-17 axis reactions may cause autoimmune damage. Therefore, an in-depth understanding of the role of Th17 cells in oral mucosa may provide prospects for treating oral mucosal diseases. We reviewed the role of Th17 cells in various oral and skin mucosal systemic diseases with oral characteristics, and based on the findings of these reports, we emphasize that Th17 cellular response may be a critical factor in inflammatory diseases of the oral mucosa. In addition, we should pay attention to the role and relationship of "pathogenic Th17" and "non-pathogenic Th17" in oral mucosal diseases. We hope to provide a reference for Th17 cells as a potential therapeutic target for treating oral mucosal inflammatory disorders in the future.
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Affiliation(s)
| | | | | | | | - Ning Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Mladenov M, Lubomirov L, Grisk O, Avtanski D, Mitrokhin V, Sazdova I, Keremidarska-Markova M, Danailova Y, Nikolaev G, Konakchieva R, Gagov H. Oxidative Stress, Reductive Stress and Antioxidants in Vascular Pathogenesis and Aging. Antioxidants (Basel) 2023; 12:1126. [PMID: 37237992 PMCID: PMC10215600 DOI: 10.3390/antiox12051126] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/22/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
This review is focused on the mechanisms that regulate health, disease and aging redox status, the signal pathways that counteract oxidative and reductive stress, the role of food components and additives with antioxidant properties (curcumin, polyphenols, vitamins, carotenoids, flavonoids, etc.), and the role of the hormones irisin and melatonin in the redox homeostasis of animal and human cells. The correlations between the deviation from optimal redox conditions and inflammation, allergic, aging and autoimmune responses are discussed. Special attention is given to the vascular system, kidney, liver and brain oxidative stress processes. The role of hydrogen peroxide as an intracellular and paracrine signal molecule is also reviewed. The cyanotoxins β-N-methylamino-l-alanine (BMAA), cylindrospermopsin, microcystins and nodularins are introduced as potentially dangerous food and environment pro-oxidants.
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Affiliation(s)
- Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, “Ss. Cyril and Methodius” University, P.O. Box 162, 1000 Skopje, North Macedonia;
| | - Lubomir Lubomirov
- Institute of Physiology, Brandenburg Medical School Theodor Fontane, 16816 Neuruppin, Germany; (L.L.); (O.G.)
| | - Olaf Grisk
- Institute of Physiology, Brandenburg Medical School Theodor Fontane, 16816 Neuruppin, Germany; (L.L.); (O.G.)
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10003, USA;
| | - Vadim Mitrokhin
- Department of Physiology, Pirogov Russian National Research Medical University, 1 Ostrovityanova Street, 117997 Moscow, Russia;
| | - Iliyana Sazdova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria; (I.S.); (M.K.-M.); (Y.D.)
| | - Milena Keremidarska-Markova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria; (I.S.); (M.K.-M.); (Y.D.)
| | - Yana Danailova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria; (I.S.); (M.K.-M.); (Y.D.)
| | - Georgi Nikolaev
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tsankov Blvd., 1164 Sofia, Bulgaria; (G.N.); (R.K.)
| | - Rossitza Konakchieva
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tsankov Blvd., 1164 Sofia, Bulgaria; (G.N.); (R.K.)
| | - Hristo Gagov
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria; (I.S.); (M.K.-M.); (Y.D.)
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9
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Friedman MJ, Lee H, Lee JY, Oh S. Transcriptional and Epigenetic Regulation of Context-Dependent Plasticity in T-Helper Lineages. Immune Netw 2023; 23:e5. [PMID: 36911799 PMCID: PMC9995996 DOI: 10.4110/in.2023.23.e5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Th cell lineage determination and functional specialization are tightly linked to the activation of lineage-determining transcription factors (TFs) that bind cis-regulatory elements. These lineage-determining TFs act in concert with multiple layers of transcriptional regulators to alter the epigenetic landscape, including DNA methylation, histone modification and three-dimensional chromosome architecture, in order to facilitate the specific Th gene expression programs that allow for phenotypic diversification. Accumulating evidence indicates that Th cell differentiation is not as rigid as classically held; rather, extensive phenotypic plasticity is an inherent feature of T cell lineages. Recent studies have begun to uncover the epigenetic programs that mechanistically govern T cell subset specification and immunological memory. Advances in next generation sequencing technologies have allowed global transcriptomic and epigenomic interrogation of CD4+ Th cells that extends previous findings focusing on individual loci. In this review, we provide an overview of recent genome-wide insights into the transcriptional and epigenetic regulation of CD4+ T cell-mediated adaptive immunity and discuss the implications for disease as well as immunotherapies.
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Affiliation(s)
- Meyer J. Friedman
- Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Haram Lee
- College of Pharmacy Korea University, Sejong 30019, Korea
| | - June-Yong Lee
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
- Institute of Genetic Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soohwan Oh
- College of Pharmacy Korea University, Sejong 30019, Korea
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10
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Deyneko IV, Mustafaev ON, Tyurin AА, Zhukova KV, Varzari A, Goldenkova-Pavlova IV. Modeling and cleaning RNA-seq data significantly improve detection of differentially expressed genes. BMC Bioinformatics 2022; 23:488. [DOI: 10.1186/s12859-022-05023-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/29/2022] [Indexed: 11/17/2022] Open
Abstract
Abstract
Background
RNA-seq has become a standard technology to quantify mRNA. The measured values usually vary by several orders of magnitude, and while the detection of differences at high values is statistically well grounded, the significance of the differences for rare mRNAs can be weakened by the presence of biological and technical noise.
Results
We have developed a method for cleaning RNA-seq data, which improves the detection of differentially expressed genes and specifically genes with low to moderate transcription. Using a data modeling approach, parameters of randomly distributed mRNA counts are identified and reads, most probably originating from technical noise, are removed. We demonstrate that the removal of this random component leads to the significant increase in the number of detected differentially expressed genes, more significant pvalues and no bias towards low-count genes.
Conclusion
Application of RNAdeNoise to our RNA-seq data on polysome profiling and several published RNA-seq datasets reveals its suitability for different organisms and sequencing technologies such as Illumina and BGI, shows improved detection of differentially expressed genes, and excludes the subjective setting of thresholds for minimal RNA counts. The program, RNA-seq data, resulted gene lists and examples of use are in the supplementary data and at https://github.com/Deyneko/RNAdeNoise.
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11
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Beckstette M, Lu CW, Herppich S, Diem EC, Ntalli A, Ochel A, Kruse F, Pietzsch B, Neumann K, Huehn J, Floess S, Lochner M. Profiling of epigenetic marker regions in murine ILCs under homeostatic and inflammatory conditions. J Exp Med 2022; 219:213389. [PMID: 35938981 PMCID: PMC9386974 DOI: 10.1084/jem.20210663] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/26/2022] [Accepted: 07/14/2022] [Indexed: 12/03/2022] Open
Abstract
Epigenetic modifications such as DNA methylation play an essential role in imprinting specific transcriptional patterns in cells. We performed genome-wide DNA methylation profiling of murine lymph node–derived ILCs, which led to the identification of differentially methylated regions (DMRs) and the definition of epigenetic marker regions in ILCs. Marker regions were located in genes with a described function for ILCs, such as Tbx21, Gata3, or Il23r, but also in genes that have not been related to ILC biology. Methylation levels of the marker regions and expression of the associated genes were strongly correlated, indicating their functional relevance. Comparison with T helper cell methylomes revealed clear lineage differences, despite partial similarities in the methylation of specific ILC marker regions. IL-33–mediated challenge affected methylation of ILC2 epigenetic marker regions in the liver, while remaining relatively stable in the lung. In our study, we identified a set of epigenetic markers that can serve as a tool to study phenotypic and functional properties of ILCs.
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Affiliation(s)
- Michael Beckstette
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,Bielefeld Institute for Bioinformatics Infrastructure, Department of Technology, Bielefeld University, Bielefeld, Germany
| | - Chia-Wen Lu
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.,Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Susanne Herppich
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Elia C Diem
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Anna Ntalli
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Aaron Ochel
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friederike Kruse
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Beate Pietzsch
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jochen Huehn
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Stefan Floess
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Matthias Lochner
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.,Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
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12
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Abstract
Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a pathologically similar disease used to model MS in rodents, are typical CD4+ T cell-dominated autoimmune diseases. CD4+ interleukin (IL)17+ T cells (Th17 cells) have been well studied and have shown that they play a critical role in the pathogenesis of MS/EAE. However, studies have suggested that CD8+IL17+ T cells (Tc17 cells) have a similar phenotype and cytokine and transcription factor profiles to those of Th17 cells and have been found to be crucial in the pathogenesis of autoimmune diseases, including MS/EAE, psoriasis, type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus. However, the evidence for this is indirect and insufficient. Therefore, we searched for related publications and attempted to summarize the current knowledge on the role of Tc17 cells in the pathogenesis of MS/EAE, as well as in the pathogenesis of other autoimmune diseases, and to find out whether Tc17 cells or Th17 cells play a more critical role in autoimmune disease, especially in MS and EAE pathogenesis, or whether the interaction between these two cell types plays a critical role in the development of the disease.
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Affiliation(s)
- Yong Peng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
| | - Xiang Deng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
| | - Qiuming Zeng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yandan Tang
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
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13
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Szukiewicz D. Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity. Front Immunol 2022; 13:943839. [PMID: 35935991 PMCID: PMC9355085 DOI: 10.3389/fimmu.2022.943839] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Endometriosis is defined as the presence of endometrial-like glands and stroma located outside the uterine cavity. This common, estrogen dependent, inflammatory condition affects up to 15% of reproductive-aged women and is a well-recognized cause of chronic pelvic pain and infertility. Despite the still unknown etiology of endometriosis, much evidence suggests the participation of epigenetic mechanisms in the disease etiopathogenesis. The main rationale is based on the fact that heritable phenotype changes that do not involve alterations in the DNA sequence are common triggers for hormonal, immunological, and inflammatory disorders, which play a key role in the formation of endometriotic foci. Epigenetic mechanisms regulating T-cell responses, including DNA methylation and posttranslational histone modifications, deserve attention because tissue-resident T lymphocytes work in concert with organ structural cells to generate appropriate immune responses and are functionally shaped by organ-specific environmental conditions. Thus, a failure to precisely regulate immune cell transcription may result in compromised immunological integrity of the organ with an increased risk of inflammatory disorders. The coexistence of endometriosis and autoimmunity is a well-known occurrence. Recent research results indicate regulatory T-cell (Treg) alterations in endometriosis, and an increased number of highly active Tregs and macrophages have been found in peritoneal fluid from women with endometriosis. Elimination of the regulatory function of T cells and an imbalance between T helper cells of the Th1 and Th2 types have been reported in the endometria of women with endometriosis-associated infertility. This review aims to present the state of the art in recognition epigenetic reprogramming of T cells as the key factor in the pathophysiology of endometriosis in the context of T-cell-related autoimmunity. The new potential therapeutic approaches based on epigenetic modulation and/or adoptive transfer of T cells will also be outlined.
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14
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Abstract
T lymphocytes undergo carefully orchestrated programming during development in the thymus and subsequently during differentiation in the periphery. This intricate specification allows for cell-type and context-specific transcriptional programs that regulate immune responses to infection and malignancy. Epigenetic changes, including histone modifications and covalent modification of DNA itself through DNA methylation, are now recognized to play a critical role in these cell-fate decisions. DNA methylation is mediated primarily by the actions of the DNA methyltransferase (DNMT) and ten-eleven-translocation (TET) families of epigenetic enzymes. In this review, we discuss the role of DNA methylation and its enzymatic regulators in directing the development and differentiation of CD4+ and CD8+ T-cells.
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Affiliation(s)
- Luis O Correa
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI
| | - Martha S Jordan
- Department of Pathology and Laboratory Medicine; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Shannon A Carty
- Department of Internal Medicine, Division of Hematology and Oncology; Rogel Cancer Center, University of Michigan, Ann Arbor, MI
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15
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Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation. Cells 2021; 10:cells10040868. [PMID: 33921194 PMCID: PMC8069756 DOI: 10.3390/cells10040868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/29/2021] [Accepted: 04/06/2021] [Indexed: 12/14/2022] Open
Abstract
Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.
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16
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Chen XJ, Zhang H, Yang F, Liu Y, Chen G. DNA Methylation Sustains "Inflamed" Memory of Peripheral Immune Cells Aggravating Kidney Inflammatory Response in Chronic Kidney Disease. Front Physiol 2021; 12:637480. [PMID: 33737884 PMCID: PMC7962671 DOI: 10.3389/fphys.2021.637480] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/04/2021] [Indexed: 01/19/2023] Open
Abstract
The incidence of chronic kidney disease (CKD) has rapidly increased in the past decades. A progressive loss of kidney function characterizes a part of CKD even with intensive supportive treatment. Irrespective of its etiology, CKD progression is generally accompanied with the development of chronic kidney inflammation that is pathologically featured by the low-grade but chronic activation of recruited immune cells. Cumulative evidence support that aberrant DNA methylation pattern of diverse peripheral immune cells, including T cells and monocytes, is closely associated with CKD development in many chronic disease settings. The change of DNA methylation profile can sustain for a long time and affect the future genes expression in the circulating immune cells even after they migrate from the circulation into the involved kidney. It is of clinical interest to reveal the underlying mechanism of how altered DNA methylation regulates the intensity and the time length of the inflammatory response in the recruited effector cells. We and others recently demonstrated that altered DNA methylation occurs in peripheral immune cells and profoundly contributes to CKD development in systemic chronic diseases, such as diabetes and hypertension. This review will summarize the current findings about the influence of aberrant DNA methylation on circulating immune cells and how it potentially determines the outcome of CKD.
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Affiliation(s)
- Xiao-Jun Chen
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Hong Zhang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fei Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Yu Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Guochun Chen
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
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17
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The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment. Int J Mol Sci 2020; 21:ijms21051673. [PMID: 32121394 PMCID: PMC7084267 DOI: 10.3390/ijms21051673] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/26/2020] [Accepted: 02/27/2020] [Indexed: 12/11/2022] Open
Abstract
Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment.
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18
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Chen BL, Chen YQ, Ma BH, Yu SF, Li LY, Zeng QX, Zhou YT, Wu YF, Liu WL, Wan JB, Yang Y, Li CW. Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice. Clin Exp Allergy 2018; 48:1494-1508. [PMID: 30137697 DOI: 10.1111/cea.13258] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 07/03/2018] [Accepted: 07/05/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND Curcumin (Cur), derived from Curcuma species, exhibits anti-inflammatory, antioxidant, and anticancer effects. Although Cur has some beneficial effects on asthma, its clinical application is limited by its low bioavailability. Tetrahydrocurcumin (THC), the major active metabolite of Cur, has multiple biological functions, similarly to Cur, and importantly, it showed enhanced bioavailability in tissues and plasma. However, the effect of THC on asthma has not been reported. OBJECTIVE The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model. METHODS The anti-inflammatory effects of Cur and THC were evaluated in an ovalbumin-induced asthmatic mouse model. The nasal symptoms, pathological alterations of the lung tissues, oxidants and antioxidants, cytokine production, T cell subsets, and Th2-related signalling pathway activity were assessed. RESULTS Both THC and Cur had beneficial effects on asthmatic mice with regard to nasal symptoms, pathological changes (eosinophils and mucus hyper-production), oxidative stress (malondialdehyde), cytokine production (IL-13), Th17 and cytotoxic T cell subsets, and Th2 signalling pathway (IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2-Notch1/Notch2 axis) activity. THC was more effective than Cur in suppressing tissue eosinophilia, mucus production, and IL-4Rα/Jak1/STAT6 pathway activity. Furthermore, only THC inhibited peripheral eosinophil levels, Th2 cytokines (IL-4 and IL-5), and Th2 cell subsets and enhanced an antioxidant enzyme (glutathione). CONCLUSION AND CLINICAL RELEVANCE The above results demonstrated for the first time that THC was superior to Cur in modulating allergic asthmatic phenotypes, especially attenuating the Th2 response. THC might be a potentially effective agent for asthma treatment.
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Affiliation(s)
- Bin Lin Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Guangzhou Campus), Guangzhou, China
| | - Yan Qiu Chen
- Department of Otolaryngology, Guangzhou Women and Children Medical Centre, Guangzhou, China
| | - Bai Hui Ma
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Guangzhou Campus), Guangzhou, China
| | - Si Fei Yu
- Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Li Yue Li
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangzhou Key Laboratory of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing Xiang Zeng
- Department of Otolaryngology, Guangzhou Women and Children Medical Centre, Guangzhou, China
| | - Yu Tao Zhou
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangzhou Key Laboratory of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yin Fan Wu
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Guangzhou Campus), Guangzhou, China
| | - Wen Long Liu
- Department of Otolaryngology, Guangzhou Women and Children Medical Centre, Guangzhou, China
| | - Jian Bo Wan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Yan Yang
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Guangzhou Campus), Guangzhou, China
| | - Chun Wei Li
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangzhou Key Laboratory of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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19
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Russell‐Hallinan A, Watson CJ, Baugh JA. Epigenetics of Aberrant Cardiac Wound Healing. Compr Physiol 2018; 8:451-491. [DOI: 10.1002/cphy.c170029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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20
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A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J Autoimmun 2017; 87:1-15. [PMID: 29275836 DOI: 10.1016/j.jaut.2017.12.007] [Citation(s) in RCA: 208] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/06/2017] [Indexed: 02/08/2023]
Abstract
Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). Unlike the 'master regulators' T-bet and GATA3 that orchestrate Th1 and Th2 differentiation, respectively, RORγ controls transcription at relatively few loci in Th17 cells. Moreover, its expression is not stabilized by positive feedback loops but rather influenced by environmental cues, allowing for substantial functional plasticity. Importantly, a subset of IL-17/IFNγ double-producing Th17 cells was identified in both human and mouse models. Evidence is accumulating that these IL-17/IFNγ double-producing cells are pathogenic drivers in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, IL-17/IFNγ double-producing cells have been identified in disorders in which the role of autoimmunity remains unclear, such as sarcoidosis. The observed plasticity of Th17 cells towards the Th1 phenotype can be explained by extensive epigenetic priming of the IFNG locus in Th17 cells. In fact, Th17 cells display an IFNG chromatin landscape that is remarkably similar to that of Th1 cells. On the other hand, pathogenic capabilities of Th17 cells can be restrained by stimulating IL-10 production and transdifferentiation into IL-10 producing T regulatory type 1 (Tr1) cells. In this review, we discuss recent advances in our knowledge on the cellular and molecular mechanisms involved in Th17 differentiation, heterogeneity and plasticity. We focus on transcriptional regulation of the Th17 expression program, the epigenetic dynamics involved, and how genetic variants associated with autoimmunity may affect immune responses through distal gene regulatory elements. Finally, the implications of Th17 cell plasticity for the pathogenesis and treatment of human autoimmune diseases will be discussed.
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21
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Nanjappa SG, McDermott AJ, Fites JS, Galles K, Wüthrich M, Deepe GS, Klein BS. Antifungal Tc17 cells are durable and stable, persisting as long-lasting vaccine memory without plasticity towards IFNγ cells. PLoS Pathog 2017; 13:e1006356. [PMID: 28542595 PMCID: PMC5456400 DOI: 10.1371/journal.ppat.1006356] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 06/02/2017] [Accepted: 04/14/2017] [Indexed: 01/01/2023] Open
Abstract
Our understanding of persistence and plasticity of IL-17A+ memory T cells is clouded by conflicting results in models analyzing T helper 17 cells. We studied memory IL-17A+ CD8+ T-cell (Tc17) homeostasis, persistence and plasticity during fungal vaccine immunity. We report that vaccine-induced memory Tc17 cells persist with high fidelity to the type 17 phenotype. Tc17 cells persisted durably for a year as functional IL-17A+ memory cells without converting to IFNγ+ (Tc1) cells, although they produced multiple type I cytokines in the absence of residual vaccine antigen. Memory Tc17 cells were canonical CD8+ T cells with phenotypic features distinct from Tc1 cells, and were Ror(γ)thi, TCF-1hi, T-betlo and EOMESlo. In investigating the bases of Tc17 persistence, we observed that memory Tc17 cells had much higher levels of basal homeostatic proliferation than did Tc1 cells. Conversely, memory Tc17 cells displayed lower levels of anti-apoptotic molecules Bcl-2 and Bcl-xL than Tc1 cells, yet were resistant to apoptosis. Tc1 cells required Bcl-2 for their survival, but Bcl-2 was dispensable for the maintenance of Tc17 cells. Tc17 and Tc1 cells displayed different requirements for HIF-1α during effector differentiation and sustenance and memory persistence. Thus, antifungal vaccination induces durable and stable memory Tc17 cells with distinct requirements for long-term persistence that distinguish them from memory Tc1 cells. CD4+ T-cell deficient patients such as those with AIDS and idiopathic CD4+ T-cell lymphopenia are vulnerable to systemic fungal infections. We previously showed that CD8+ T cells can be exploited in CD4+ T cell deficient hosts for vaccine immunity against lethal fungal pneumonia in mice and that IL-17A production by these cells (Tc17) is essential. Existing dogma holds that IL-17A producing CD4+ T cells (Th17) are highly plastic, unstable, and convert into IFNγ producing cells, losing the capacity to produce IL-17A, which is the signature feature of Tc17 cells. Here, we show that vaccine-elicited antifungal Tc17 cells are maintained as stable and long-lasting memory cells that resist conversion into IFNγ cells (Tc1) and protect CD4+ T cell deficient hosts against lethal pulmonary fungal infection. Antifungal Tc17 cells displayed features that define classical memory cells. However, memory Tc17 exhibited different requirements than Tc1 cells in the factors that promote T cell survival, including anti-apoptotic molecules Bcl-2 and Bcl-xl, and HIF-1α, which aids survival of cells in lower oxygen conditions found during inflammation. Thus, our study reveals that fungal vaccination elicits a durable, stable population of Tc17 cells with distinct features of survival needed for preventing infection in immunocompromised hosts.
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Affiliation(s)
- Som Gowda Nanjappa
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
- * E-mail: (SGN); (BSK)
| | - Andrew J. McDermott
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
| | - J. Scott Fites
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
| | - Kevin Galles
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
| | - Marcel Wüthrich
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
| | - George S. Deepe
- Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
| | - Bruce S. Klein
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
- Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
- * E-mail: (SGN); (BSK)
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22
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Luo A, Leach ST, Barres R, Hesson LB, Grimm MC, Simar D. The Microbiota and Epigenetic Regulation of T Helper 17/Regulatory T Cells: In Search of a Balanced Immune System. Front Immunol 2017; 8:417. [PMID: 28443096 PMCID: PMC5385369 DOI: 10.3389/fimmu.2017.00417] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/23/2017] [Indexed: 12/14/2022] Open
Abstract
Immune cells not only affect tissue homeostasis at the site of inflammation but also exert systemic effects contributing to multiple chronic conditions. Recent evidence clearly supports an altered T helper 17/regulatory T cell (Th17/Treg) balance leading to the development and progression of inflammatory diseases that not only affect the gastrointestinal tract but also have whole-body manifestations, including insulin resistance. Epigenetic mechanisms are amenable to both environmental and circulating factors and contribute to determining the T cell landscape. The recently identified participation of the gut microbiota in the remodeling of the epigenome of immune cells has triggered a paradigm shift in our understanding of the etiology of various inflammatory diseases and opened new paths toward therapeutic strategies. In this review, we provide an overview of the contribution of the Th17/Treg balance in the development and progression of inflammatory bowel diseases and metabolic diseases. We discuss the involvement of epigenetic mechanisms in the regulation of T cell function in the particular context of dysbiosis. Finally, we examine the potential for nutritional interventions affecting the gut microbiota to reshape the T cell epigenome and address the inflammatory component of various diseases.
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Affiliation(s)
- Annie Luo
- St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Steven T Leach
- School of Women and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Romain Barres
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Luke B Hesson
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Michael C Grimm
- St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - David Simar
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Mechanisms of Disease and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
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23
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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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24
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Song MH, Nair VS, Oh KI. Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner. BMB Rep 2017; 50:49-54. [PMID: 27931518 PMCID: PMC5319665 DOI: 10.5483/bmbrep.2017.50.1.193] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Indexed: 01/09/2023] Open
Abstract
Previously, we reported that vitamin C facilitates the CpG demethylation of Foxp3 enhancer in CD4+Foxp3+ regulatory T cells (Tregs) by enhancing the activity of a DNA demethylase ten-eleven-translocation (Tet). However, it is not clear whether vitamin C affects other helper T cell lineages like T helper type 17 (Th17) cells which are related with Tregs. Here, we show that the expression of interleukin-17A (IL17) increases with the treatment of vitamin C but not with other antioxidants. Interestingly, the upregulation of IL17 was not accompanied by DNA demethylation in Il17 promoter and was independent of Tet enzymes. Rather, vitamin C reduced the trimethylation of histone H3 lysine 9 (H3K9me3) in the regulatory elements of the Il17 locus, and the effects of vitamin C were abrogated by knockdown of jumonji-C domain-containing protein 2 (jmjd2). These results suggest that vitamin C can affect the expression of IL17 by modulating the histone demethylase activity. [BMB Reports 2017; 50(1): 49-54].
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Affiliation(s)
- Mi Hye Song
- Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Varun Sasidharan Nair
- Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Kwon Ik Oh
- Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea
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Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis . Proc Natl Acad Sci U S A 2017; 114:E1678-E1687. [PMID: 28196884 DOI: 10.1073/pnas.1615783114] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS.
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TGF-β1 along with other platelet contents augments Treg cells to suppress anti-FVIII immune responses in hemophilia A mice. Blood Adv 2016; 1:139-151. [PMID: 28164173 DOI: 10.1182/bloodadvances.2016001453] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Platelets are a rich source of many cytokines and chemokines including transforming growth factor β 1 (TGF-β1). TGF-β1 is required to convert conventional CD4+ T (Tconv) cells into induced regulatory T (iTreg) cells that express the transcription factor Foxp3. Whether platelet contents will affect Treg cell properties has not been explored. In this study, we show that unfractionated platelet lysates (pltLys) containing TGF-β1 efficiently induced Foxp3 expression in Tconv cells. The common Treg cell surface phenotype and in vitro suppressive activity of unfractionated pltLys-iTreg cells were similar to those of iTreg cells generated using purified TGF-β1 (purTGFβ-iTreg) cells. However, there were substantial differences in gene expression between pltLys-iTreg and purTGFβ-iTreg cells, especially in granzyme B, interferon γ, and interleukin-2 (a 30.99-, 29.18-, and 17.94-fold difference, respectively) as determined by gene microarray analysis. In line with these gene signatures, we found that pltLys-iTreg cells improved cell recovery after transfer and immune suppressive function compared with purTGFβ-iTreg cells in factor VIII (FVIII)-deficient (F8null, hemophilia A model) mice after recombinant human FVIII (rhF8) infusion. Acute antibody-mediated platelet destruction in F8null mice followed by rhF8 infusion increased the number of Treg cells and suppressed the antibody response to rhF8. Consistent with these data, ex vivo proliferation of F8-specific Treg cells from platelet-depleted animals increased when restimulated with rhF8. Together, our data suggest that pltLys-iTreg cells may have advantages in emerging clinical applications and that platelet contents impact the properties of iTreg cells induced by TGF-β1.
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Ji H, Biagini Myers JM, Brandt EB, Brokamp C, Ryan PH, Khurana Hershey GK. Air pollution, epigenetics, and asthma. Allergy Asthma Clin Immunol 2016; 12:51. [PMID: 27777592 PMCID: PMC5069789 DOI: 10.1186/s13223-016-0159-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 10/04/2016] [Indexed: 12/13/2022] Open
Abstract
Exposure to traffic-related air pollution (TRAP) has been implicated in asthma development, persistence, and exacerbation. This exposure is highly significant as large segments of the global population resides in zones that are most impacted by TRAP and schools are often located in high TRAP exposure areas. Recent findings shed new light on the epigenetic mechanisms by which exposure to traffic pollution may contribute to the development and persistence of asthma. In order to delineate TRAP induced effects on the epigenome, utilization of newly available innovative methods to assess and quantify traffic pollution will be needed to accurately quantify exposure. This review will summarize the most recent findings in each of these areas. Although there is considerable evidence that TRAP plays a role in asthma, heterogeneity in both the definitions of TRAP exposure and asthma outcomes has led to confusion in the field. Novel information regarding molecular characterization of asthma phenotypes, TRAP exposure assessment methods, and epigenetics are revolutionizing the field. Application of these new findings will accelerate the field and the development of new strategies for interventions to combat TRAP-induced asthma.
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Affiliation(s)
- Hong Ji
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave. MLC 7037, Cincinnati, OH 45229 USA ; Pyrosequencing lab for Genomic and Epigenomic research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 USA
| | - Jocelyn M Biagini Myers
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave. MLC 7037, Cincinnati, OH 45229 USA
| | - Eric B Brandt
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave. MLC 7037, Cincinnati, OH 45229 USA
| | - Cole Brokamp
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 USA
| | - Patrick H Ryan
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 USA
| | - Gurjit K Khurana Hershey
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave. MLC 7037, Cincinnati, OH 45229 USA
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Hurtgen BJ, Castro-Lopez N, Jiménez-Alzate MDP, Cole GT, Hung CY. Preclinical identification of vaccine induced protective correlates in human leukocyte antigen expressing transgenic mice infected with Coccidioides posadasii. Vaccine 2016; 34:5336-5343. [PMID: 27622300 DOI: 10.1016/j.vaccine.2016.08.078] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/19/2016] [Accepted: 08/29/2016] [Indexed: 01/19/2023]
Abstract
There is an emerging interest to develop human vaccines against medically-important fungal pathogens and a need for a preclinical animal model to assess vaccine efficacies and protective correlates. HLA-DR4 (DRB1∗0401 allele) transgenic mice express a human major histocompatibility complex class II (MHC II) receptor in such a way that CD4+ T-cell response is solely restricted by this human molecule. In this study HLA-DR4 transgenic mice were immunized with a live-attenuated vaccine (ΔT) and challenged by the intranasal route with 50-70 Coccidioides posadasii spores, a potentially lethal dose. The same vaccination regimen offers 100% survival for C57BL/6 mice. Conversely, ΔT-vaccinated HLA-DR4 mice displayed 3 distinct manifestations of Coccidioides infection including 40% fatal acute (FAD), 30% disseminated (DD) and 30% pulmonary disease (PD). The latter 2 groups of mice had reduced loss of body weight and survived to at least 50days postchallenge (dpc). These results suggest that ΔT vaccinated HLA-DR4 mice activated heterogeneous immunity against pulmonary Coccidioides infection. Vaccinated HLA-DR4 mice displayed early expansion of Th1 and Th17 cells and recruitment of inflammatory innate cells into Coccidioides-infected lungs during the first 9dpc. While contraction rates of Th cells and the inflammatory response during 14-35dpc significantly differed among the 3 groups of vaccinated HLA-DR4 mice. The FAD group displayed a sharply reduced Th1 and Th17 response, while overwhelmingly recruiting neutrophils into lungs during 9-14days. The FAD group approached moribund by 14dpc. In contrast, vaccinated HLA-DR4 survivors gradually contracted Th cells and inflammatory response with the greatest rate in the PD group. While vaccinated HLA-DR4 mice are susceptible to Coccidioides infection, they are useful for evaluation of vaccine efficacy and identification of immunological correlates against this mycosis.
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Affiliation(s)
- Brady J Hurtgen
- Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, TX, USA
| | - Natalia Castro-Lopez
- Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA
| | - Maria Del Pilar Jiménez-Alzate
- Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Grupo de Micología Médica, Department of Microbiology and Parasitology, School of Medicine, Universidad de Antioquia, Medellín, Colombia
| | - Garry T Cole
- Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, TX, USA
| | - Chiung-Yu Hung
- Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Immune Defense Core, University of Texas, San Antonio, TX, USA.
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De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation. Proc Natl Acad Sci U S A 2016; 113:10631-6. [PMID: 27582468 DOI: 10.1073/pnas.1524490113] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
DNMT3a is a de novo DNA methyltransferase expressed robustly after T-cell activation that regulates plasticity of CD4(+) T-cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8(+) T-cell effector and memory fate decisions. Whereas effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T-cell intrinsic manner compared with wild-type animals. Rather than increasing plasticity of differentiated effector CD8(+) T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8(+) T cells. These data identify DNMT3a as a crucial regulator of CD8(+) early effector cell differentiation and effector versus memory fate decisions.
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Balancing Inflammation: The Link between Th17 and Regulatory T Cells. Mediators Inflamm 2016; 2016:6309219. [PMID: 27413254 PMCID: PMC4930807 DOI: 10.1155/2016/6309219] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Accepted: 02/29/2016] [Indexed: 12/22/2022] Open
Abstract
CD4+ T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+ T cells (Th17 cells) represent a distinct subset of the CD4+ T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+ T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells (TREG). The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 and TREG plasticity and discuss the biologic consequences of their unique relationship.
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Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 2016; 9:444-57. [PMID: 26307665 DOI: 10.1038/mi.2015.74] [Citation(s) in RCA: 319] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 07/07/2015] [Indexed: 02/04/2023]
Abstract
Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3(+)CD4(+) T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3(+)RORγt(+) T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3(+)RORγt(-) Tregs than to Foxp3(-)RORγt(+) T cells. Importantly, Foxp3(+)RORγt(+) T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3(+)RORγt(+) T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3(+)RORγt(-) Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3(+)RORγt(+) T cells as an important effector Treg subset in the intestinal system.
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Sasidharan Nair V, Song MH, Oh KI. Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner. THE JOURNAL OF IMMUNOLOGY 2016; 196:2119-31. [DOI: 10.4049/jimmunol.1502352] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/28/2015] [Indexed: 12/17/2022]
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Mehrotra P, Patel JB, Ivancic CM, Collett JA, Basile DP. Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism. Kidney Int 2015; 88:776-84. [PMID: 26200947 PMCID: PMC4589446 DOI: 10.1038/ki.2015.200] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 04/14/2015] [Accepted: 05/07/2015] [Indexed: 12/22/2022]
Abstract
Exposure of rats to elevated dietary salt following recovery from acute kidney injury (AKI) accelerates the transition to chronic kidney disease (CKD), and is dependent on lymphocyte activity. Here we tested whether high salt diet triggers lymphocyte activation in postischemic kidneys to worsen renal inflammation and fibrosis. Male Sprague-Dawley rats on a 0.4% salt diet were subjected to left unilateral ischemia-reperfusion and allowed to recover for 5 weeks. This resulted in a mild elevation of CD4(+) T cells relative to sham animals. Contralateral unilateral nephrectomy and elevated dietary salt (4%) for 4 extra weeks hastened CKD and interstitial fibrosis. Activated T cells were increased in the kidney threefold after 4 weeks of elevated dietary salt exposure relative to post-AKI rats before salt feeding. The T cell subset was largely positive for IL-17, indicative of Th-17 cells. Because angiotensin II activity may influence lymphocyte activation, injured rats were given the AT1R antagonist, losartan, along with high salt diet. This significantly reduced the number of renal Th-17 cells to levels of sham rats, and significantly reduced the salt-induced increase in fibrosis to about half. In vitro studies in AKI-primed CD4(+) T cells indicated that angiotensin II and extracellular sodium enhanced, and losartan inhibited, IL-17 expression. Thus, dietary salt modulates immune cell activity in postischemic recovering kidneys because of the activity of local RAS, suggesting the participation of these cells in CKD progression post-AKI.
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Affiliation(s)
- Purvi Mehrotra
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jaymin B Patel
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Carlie M Ivancic
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jason A Collett
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - David P Basile
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Dantec CL, Brooks WH, Renaudineau Y. Epigenomic revolution in autoimmune diseases. World J Immunol 2015; 5:62-67. [DOI: 10.5411/wji.v5.i2.62] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/01/2015] [Accepted: 05/06/2015] [Indexed: 02/05/2023] Open
Abstract
Autoimmunity is believed to develop when genetically predisposed individuals undergo epigenetic modifications in response to environmental factors. Recent advances in the understanding of epigenetic mechanisms suggest, in autoimmune diseases, a multi-step process involving environmental factors (e.g., drugs, stress) and endogenous factors (e.g., cytokines, gender), both leading to the deregulation of the epigenetic machinery (DNA methylation, histone modifications, miRNA), that in turn specifically affects the immune system and/or the target organ(s). Such effect is reinforced in those patients with risk variants mapping to epigenetically-controlled regulators of immune cells. As a consequence, autoreactive lymphocytes and autoantibodies are produced leading to the development of the autoimmune disease. Potential new therapeutic strategies and biomarkers are also addressed.
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