1
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Kabil A, Nayyar N, Xu C, Brassard J, Hill LA, Shin SB, Chopra S, Lo B, Li Y, Bal M, Theret M, Rossi FMV, Underhill TM, Hughes MR, McNagny KM. Functional targeting of ILC2s and ILC3s reveals selective roles in intestinal fibrosis and homeostasis. J Exp Med 2025; 222:e20241671. [PMID: 40434419 DOI: 10.1084/jem.20241671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 03/06/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Innate lymphoid cells (ILCs) are long-lived, tissue-resident cell analogs to T helper subsets that lack antigen-specific receptors. Understanding the roles of specific ILCs in chronic inflammation and fibrosis has been limited by inadequate tools for selective targeting. Here, we used Il17rb-CreERT2-eGFP and Rorc-Cre strains to selectively delete RORα in ILC2s and ILC3/Th17 cells, respectively. RORα deletion in ILC2s caused significant loss of gastrointestinal ILC2s, increased ILC3 abundance, elevated Th17-type responses, and heightened susceptibility to Crohn's disease-like fibrosis. Conversely, RORα deletion in ILC3/Th17 cells reduced IL-17 production, protecting against fibrosis. Using isolithocholic acid (isoLCA), a microbial secondary bile acid and RORγt inverse agonist, we confirmed the role of ILC3s/Th17 cells in fibrosis. In RORγt reporter and Th17-deficient Rag1-/- mice, isoLCA reduced IL-17 production by ILC3s and attenuated intestinal fibrosis by dampening RORγt-dependent ILC3/Th17 responses. These findings reveal a novel interplay between ILC2s and ILC3s in gut homeostasis and demonstrate the therapeutic potential of targeting RORγt in ILC3s as a strategy for preventing fibrosis.
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MESH Headings
- Animals
- Homeostasis/immunology
- Fibrosis
- Mice
- Immunity, Innate
- Lymphocytes/immunology
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Intestines/pathology
- Intestines/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 1/genetics
- Mice, Knockout
- Interleukin-17/metabolism
- Mice, Inbred C57BL
- Crohn Disease/immunology
- Crohn Disease/pathology
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Affiliation(s)
- Ahmed Kabil
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Natalia Nayyar
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Chengxi Xu
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Julyanne Brassard
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Lesley A Hill
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Samuel B Shin
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Sameeksha Chopra
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Bernard Lo
- Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Yicong Li
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Mya Bal
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Marine Theret
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Fabio M V Rossi
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
- The Department of Medical Genetics, University of British Columbia, Vancouver, Canada
| | - T Michael Underhill
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Michael R Hughes
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
| | - Kelly M McNagny
- School of Biomedical Engineering, University of British Columbia , Vancouver, Canada
- The Department of Medical Genetics, University of British Columbia, Vancouver, Canada
- The Center for Heart Lung Innovation, St Paul's Hospital , Vancouver, Canada
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2
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Gao Y, Liu X, Lv J, Gu C, Tao T, Zhang C, Huang D, Jia R, Yu X, Su W. Ifosfamide alleviates autoimmune toxicity and enhances antitumor efficacy in melanoma immunotherapy. Biochem Pharmacol 2025; 236:116851. [PMID: 40081767 DOI: 10.1016/j.bcp.2025.116851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/21/2025] [Accepted: 03/03/2025] [Indexed: 03/16/2025]
Abstract
Autoimmune toxicity affects up to 60 % of patients receiving immune checkpoint inhibitor (ICI) therapy for cancer, presenting a notable clinical obstacle that constrains its wider application. Hence, there is an imperative demand to develop novel strategies to manage immune-related adverse events (irAEs). Ifosfamide (IFO) shares structural and functional resemblances with cyclophosphamide (CPA). Despite the acknowledged dual anti-tumor and immunomodulatory effects of CPA, the specific effect of IFO on autoimmune conditions remains elusive. Here, we evaluated the efficacy of IFO on experimental autoimmune uveitis (EAU) mouse models and explored the cell-specific effects of IFO under autoimmune conditions using single-cell RNA sequencing. Our data indicated that IFO effectively alleviated inflammatory infiltration and reversed pathological alterations of EAU. Subsequent single-cell data analysis and in vivo experiments suggested IFO exerted broad suppressive effects on autoimmune responses, concurrently restoring the balance between Th17 and Treg populations. In addition, we observed that IFO enhanced CD8+ T cell activation and its cytotoxic immune responses, highlighting the cell-type-specific immunomodulatory effects of IFO. Moreover, we constructed EAU models on tumor-bearing mice under ICI treatment, and found that ICI exacerbated EAU symptoms. IFO not only possessed anti-tumor effects as monotherapy, but also augmented ICI efficacy by promoting CD8+ T cell-mediated immunity. Furthermore, we found that IFO alleviated EAU symptoms exacerbated by ICI treatment and effectively restored Th17/Treg balance. Our results elucidated the immunomodulatory effects of IFO treatment, providing evidence for the application of IFO in managing autoimmune conditions and irAEs.
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Affiliation(s)
- Yuehan Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiuxing Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jianjie Lv
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chenyang Gu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Tianyu Tao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chun Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Danping Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Xinping Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenru Su
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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3
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Rodrigues PF, Wu S, Trsan T, Panda SK, Fachi JL, Liu Y, Du S, de Oliveira S, Antonova AU, Khantakova D, Sudan R, Desai P, Diamond MS, Gilfillan S, Anderson SK, Cella M, Colonna M. Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens. Cell 2025; 188:2720-2737.e22. [PMID: 40185101 DOI: 10.1016/j.cell.2025.03.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 01/26/2025] [Accepted: 03/10/2025] [Indexed: 04/07/2025]
Abstract
The intestinal immune system maintains tolerance to harmless food proteins and gut microbiota through peripherally derived RORγt+ Tregs (pTregs), which prevent food intolerance and inflammatory bowel disease. Recent studies suggested that RORγt+ antigen-presenting cells (APCs), which encompass rare dendritic cell (DC) subsets and type 3 innate lymphoid cells (ILC3s), are key to pTreg induction. Here, we developed a mouse with reduced RORγt+ APCs by deleting a specific cis-regulatory element of Rorc encoding RORγt. Single-cell RNA sequencing and flow cytometry analyses confirmed the depletion of a RORγt+ DC subset and ILC3s. These mice showed a secondary reduction in pTregs, impaired tolerance to oral antigens, and an increase in T helper (Th)2 cells. Conversely, ILC3-deficient mice showed no pTregs or Th2 cell abnormalities. Lineage tracing revealed that RORγt+ DCs share a lymphoid origin with ILC3s, consistent with their similar phenotypic traits. These findings highlight the role of lymphoid RORγt+ DCs in maintaining intestinal immune balance and preventing conditions like food allergies.
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Affiliation(s)
- Patrick Fernandes Rodrigues
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Shitong Wu
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Tihana Trsan
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Santosh K Panda
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - José Luís Fachi
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Yizhou Liu
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Siling Du
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Sarah de Oliveira
- Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Alina Ulezko Antonova
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Darya Khantakova
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Raki Sudan
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Pritesh Desai
- Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Michael S Diamond
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA; Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Susan Gilfillan
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Stephen K Anderson
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Marina Cella
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA.
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4
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Accogli T, Hibos C, Milian L, Geindreau M, Richard C, Humblin E, Mary R, Chevrier S, Jacquin E, Bernard A, Chalmin F, Paul C, Ryffel B, Apetoh L, Boidot R, Bruchard M, Ghiringhelli F, Vegran F. The intrinsic expression of NLRP3 in Th17 cells promotes their protumor activity and conversion into Tregs. Cell Mol Immunol 2025; 22:541-556. [PMID: 40195474 PMCID: PMC12041534 DOI: 10.1038/s41423-025-01281-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025] Open
Abstract
Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.
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Affiliation(s)
- Théo Accogli
- INSERM, Dijon, France
- University of Burgundy, Dijon, France
| | | | - Lylou Milian
- INSERM, Dijon, France
- University of Burgundy, Dijon, France
- Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France
| | | | - Corentin Richard
- Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France
| | | | | | - Sandy Chevrier
- Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France
| | - Elise Jacquin
- INSERM, Dijon, France
- University of Burgundy, Dijon, France
| | | | - Fanny Chalmin
- Cancer Biology Transfer Platform, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France
| | - Catherine Paul
- LIIC, EA7269, Université de Bourgogne Franche Comté, Dijon, France
- Immunology and Immunotherapy of Cancer Laboratory, EPHE, PSL Research University, Paris, France
| | - Berhard Ryffel
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orléans, France
| | - Lionel Apetoh
- Brown Center for Immunotherapy, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Romain Boidot
- Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France
| | | | - François Ghiringhelli
- INSERM, Dijon, France
- University of Burgundy, Dijon, France
- Cancer Biology Transfer Platform, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France
- Genetic and Immunology Medical Institute, Dijon, France
- Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
| | - Frédérique Vegran
- INSERM, Dijon, France.
- University of Burgundy, Dijon, France.
- Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France.
- Cancer Biology Transfer Platform, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France.
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5
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Chen YF, Li JW, Li FF, Bo L, Xiao Y, Jin QX, Jin GH, Meng FP, Huang XZ, Jin D. Therapeutic potential of Inonotus obliquus polysaccharide-induced tolerogenic bone marrow-derived dendritic cells via regulation of CD4 + T cell differentiation in a colitis mouse model. Int J Biol Macromol 2025; 306:141505. [PMID: 40015397 DOI: 10.1016/j.ijbiomac.2025.141505] [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: 04/24/2024] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Over-proliferation, activation, or aberrant CD4+ T cell differentiation causes various immune-related diseases. DCs are significant professional APCs that regulate the differentiation of CD4+ T cells to participate in an inflammatory response. IOP is an edible fungal polysaccharide with immunoregulatory and anti-inflammatory bioactivities, however, the cellular mechanisms by which they regulate the immune system to exert their anti-inflammatory effects remain unclear. The present study aimed to investigate the effects of IOP on the regulation of CD4+ T cell differentiation and the correlative mechanisms related to DCs. IOP did not regulate the proliferation and activation of CD4+ T cells. However, it inhibited the differentiation of Th1 and Th17 cells and promoted the differentiation of Treg cells. IOP maintained the immature phenotype of BMDCs, which induces immune tolerance and promotes the differentiation of CD4+ T cells into Treg cells. Transfusion of IOPL-BMDC into colitis mice markedly alleviated colitis-associated inflammation and maintained the colon's integrity. IOPL-BMDCs inhibited the differentiation of CD4+ T cells into inflammatory effective Th1 cells in the spleen and MLN while promoting their differentiation into immune-tolerant, anti-inflammatory Treg cells. In conclusion, this research demonstrated that IOP strongly regulates the polarization of CD4+ T cells to Treg subsets with inflammatory suppressive effects by inducing immature tolerant DCs, which provides strategic evidence for the therapeutic application of IOP in colitis, and IOP-induced tolerant DCs provide a new therapeutic approach to the development of a DC vaccine for colitis.
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Affiliation(s)
- Yi-Fang Chen
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Jia-Wei Li
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Fang-Fang Li
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Lin Bo
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Yao Xiao
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Quan-Xin Jin
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Gui-Hua Jin
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Fan-Ping Meng
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Xue-Zhu Huang
- Department of Anaesthesiology, The Affiliated Hospital of Yanbian University, Yan Ji 133000, China.
| | - Dan Jin
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China.
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6
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Fan T, Tai C, Sleiman KC, Cutcliffe MP, Kim H, Liu Y, Li J, Xin G, Grashel M, Baert L, Ekeocha C, Vergenes P, Lima S, Lo WL, Lin J, Hanaoka B, Tankersley TN, Wang M, Zhang X, Tsokos GC, Jarjour W, Longman R, Wu HJJ. Aberrant T follicular helper cells generated by T H17 cell plasticity in the gut promote extraintestinal autoimmunity. Nat Immunol 2025; 26:790-804. [PMID: 40307450 DOI: 10.1038/s41590-025-02125-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 03/12/2025] [Indexed: 05/02/2025]
Abstract
Much remains unknown regarding T follicular helper 17 (TFH17) cells commonly found in autoimmune patients. We previously showed that (and here ask why) egress of gut segmented filamentous bacteria (SFB)-induced TFH cells from Peyer's patches (PP) to systemic sites promotes arthritis. We found splenic TFH17 cells are gut derived. Functional analyses using fate-mapping mice revealed a c-Maf-dependent and SFB-induced TH17-to-TFH cell reprogramming that dominantly occurs in PPs. Unlike conventional TFH cells, TH17-derived TFH cells are highly migratory and atypically concentrated in the dark zone of germinal centers (GCs). Compared to conventional TFH cells, TH17-derived TFH cells express higher levels of TFH-associated functional molecules and more robustly conjugate with B cells. Gain- and loss-of-function studies demonstrated their dominance in promoting GC B cells and arthritis. Notably, murine gut TH17-derived TFH signatures exist in rheumatoid arthritis patients. Thus, gut T cell plasticity generates atypical, potent TFH cells promoting systemic autoimmunity.
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Affiliation(s)
- Tingting Fan
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Chi Tai
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Kiah C Sleiman
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Madeline P Cutcliffe
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Haram Kim
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ye Liu
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jianying Li
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA
| | - Gang Xin
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology; The Ohio State Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Mollyanna Grashel
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Laurie Baert
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Chinwe Ekeocha
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Paige Vergenes
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Svetlana Lima
- Jill Roberts Center and Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Wan-Lin Lo
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Judith Lin
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Beatriz Hanaoka
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Trevor N Tankersley
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing, China
| | - George C Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Wael Jarjour
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Randy Longman
- Jill Roberts Center and Institute for Research in Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Hsin-Jung Joyce Wu
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, USA.
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA.
- Pelotonia Institute for Immuno-Oncology; The Ohio State Comprehensive Cancer Center, Columbus, Ohio, USA.
- Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, AZ, USA.
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7
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Zhu D, Ma X, Wang J, Chen T, Yang J, Liu Y, Lin Z, Wu M, Hu TY, Zhang Y. A Sequential Release Micro-nano System for Colitis Therapy via Gut Microbiota and Immune Regulation. Angew Chem Int Ed Engl 2025; 64:e202424409. [PMID: 39980315 DOI: 10.1002/anie.202424409] [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: 12/31/2024] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 02/22/2025]
Abstract
Commencing with the breakdown of the intestinal barrier, various pathogenic factors, such as dysbiosis of the gut microbiota, harmful inflammatory cytokines, and immune system imbalance, collectively contribute to the development of colitis. Numerous interventions focusing on single factors have been developed to provide short-term therapeutic benefits, but the continued existence of unresolved pathogenic factors can lead to disease exacerbation. Here we have designed a multicomponent system-inulin microspheres encapsulating selenium-containing nanomicelles, aiming to tackle the multiple factors associated with colitis. This micro-nano drug delivery platform achieves sequential release of drugs in the inflamed colon, with each component of the system functioning independently and jointly. The outer layer of inulin supplies nutrients for probiotics. The inner core comprises selenocystamine and 3-oxolithocholic acid, which polarize macrophages towards an anti-inflammatory phenotype and regulate adaptive immunity by inhibiting TH17-cell differentiation, respectively. In an acute colitis mouse model, this therapeutic system ameliorates colonic inflammation, enhances the abundance of gut microbiota, and modulates the mucosal immune system, showing potential in preventing colitis.
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Affiliation(s)
- Dongdong Zhu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaocao Ma
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jingguo Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Tiantian Chen
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jiahui Yang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yan Liu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhun Lin
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Minhao Wu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Tony Y Hu
- Center of Cellular and Molecular Diagnosis, Tulane University School of Medicine, New Orleans, Louisiana, 70112, United States
| | - Yuanqing Zhang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
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8
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Sarkar D, Pramanik A, Saha J, Das D, Mahanti K, Mahato M, Mondal P, Bhattacharyya S. Amelioration of imiquimod induced psoriasis through reduction in IL-17A and Th17 population by dihydromyricetin involves regulation of RORγt pathway. Int Immunopharmacol 2025; 153:114492. [PMID: 40112600 DOI: 10.1016/j.intimp.2025.114492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND AND PURPOSE Psoriasis is a chronic inflammatory skin disorder affecting approximately 125 million people. IL-17 A secreted from Th17 cells plays a major role in elucidating psoriasis. Dihydromyricetin (DHM) is plant derived flavonoid isolated from leaves and stems of Rattan tea (Ampelopsis grossedentata). Reports indicate anti-inflammatory property of DHM but no information is currently available on its mechanism of action or effect on IL17 producing Th17 cells and exact role in psoriasis. EXPERIMENTAL APPROACH DHM shows strong anti-inflammatory properties in vitro, DHM reduced LPS-induced ROS generation, and pro-inflammatory cytokines in macrophages. The efficacy of DHM against chronic inflammatory disorder in vivo was investigated in imiquimod-induced psoriasis established in male BALB/C mice as this model closely resembles human psoriasis. Immunophenotyping and cytokine production were observed by flow cytometry, the status of gene expression was determined by real-time PCR, and nuclear co-localization and immunofluorescence of skin tissue were studied using confocal microscopy. KEY RESULTS We observed increased inflammatory parameters in imiquimod treated diseased animals and the application of DHM topically and orally reduced the inflammatory parameters and improved indicators of cardiac damage prominent in psoriatic conditions. In our study, we found that the application of DHM dose-dependently reduced the percentage of IL-17 A-producing T cell population and reduced the nuclear co-translocation of RORγt in psoriatic T cells and possibly also influenced upstream IL-6 signaling. CONCLUSION AND IMPLICATIONS Our study suggests that DHM effectively alleviates psoriatic symptoms, and its mechanism of action involves the regulation of RORγt pathway in T cells.
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Affiliation(s)
- Debanjan Sarkar
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India
| | - Anik Pramanik
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India
| | - Jayasree Saha
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India; Currently, DST-SERB NPDF, School of Bioscience, IIT Kharagpur, Paschim Medinipur, West Bengal 721302, India
| | - Dona Das
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India
| | - Krishna Mahanti
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India
| | - Maniprabha Mahato
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India
| | - Pallabi Mondal
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India
| | - Sankar Bhattacharyya
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, India.
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9
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Wang H, Guo J, Chen X, Liu S, Li W, Yang L, Wang J, Han Y. Biphasic role of L-TGF-β2 in modulating lamprey inflammation: Insights into vertebrate immune evolution. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 167:105372. [PMID: 40252986 DOI: 10.1016/j.dci.2025.105372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 04/16/2025] [Accepted: 04/16/2025] [Indexed: 04/21/2025]
Abstract
The regulation of inflammatory balance is central to immune homeostasis, with disruptions contributing to autoimmune diseases. As representatives of early vertebrates, lampreys offer a valuable model for investigating the evolutionary foundations of immune regulation. This study examines the dual role of L-TGF-β2 in modulating inflammation in lampreys, providing insights into the evolutionary origins of immune homeostasis mechanisms. Using lipopolysaccharide (LPS)-induced inflammation models, recombinant L-TGF-β2 was found to enhance leukocyte chemotaxis in quiescent states while inhibiting excessive migration during activation. Quantitative PCR revealed that L-TGF-β2 stimulates pro-inflammatory cytokine expression during early inflammatory phases and attenuates it during resolution. Tissue-specific expression patterns of TGF-β receptors indicated their potential role in mediating the distinct regulatory effects of L-TGF-β2 across diverse immune environments. These findings align with the biphasic functions of TGF-β observed in higher vertebrates, underscoring the evolutionary conservation of this signaling pathway. This research enhances understanding the functional versatility of TGF-β signaling and its pivotal role in vertebrate immune evolution, providing insights into ancient mechanisms of immune homeostasis and their modern implications for inflammatory disease research.
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Affiliation(s)
- Hao Wang
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Junfu Guo
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Xuanyi Chen
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Siqi Liu
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Wenna Li
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Lu Yang
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Jianmiao Wang
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Yinglun Han
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China.
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10
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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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11
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Strutzenberg TS, Mann MD, Li X, Shin H, Kelsey J, Aiyer S, Yu J, Gray G, Zhang Z, Shan Z, Zhou B, Zheng Y, Griffin PR, Lyumkis D. Nucleosome Engagement Regulates RORγt Structure and Dynamics. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.10.642251. [PMID: 40161694 PMCID: PMC11952427 DOI: 10.1101/2025.03.10.642251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The retinoic acid-related orphan receptor gamma (RORγt) acts as the major transcriptional activator in Th17 cell development and function to mediate adaptive immune defenses against pathogenic infection. RORγt engages accessible DNA response elements in the genome and interplays with coactivator proteins and accessory transcription factors to drive gene expression. However, how the chromatin environment mediates RORγt structure, dynamics, and function remains unclear. Here, we profile how the nucleosome promotes or restricts access to the main RORγt DNA response elements found in native enhancers and promoters, revealing preferential binding in regions of free DNA and nucleosomal entry/exit sites, with single base-pair resolution. Solution phase measurements using hydrogen deuterium exchange coupled to mass spectrometry identify novel allosteric effects that influence RORγt binding and mediate chromatin dynamics. A high-resolution structure of RORγt bound to the nucleosome reveals how structured elements assemble to confer binding specificity and avidity to chromatin substrates. The observations suggest an activation model where RORγt binding to chromatinized DNA promotes coregulator recruitment and chromatin decompaction.
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Affiliation(s)
| | - Matthew D. Mann
- The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Xiandu Li
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Hyejeong Shin
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Jordan Kelsey
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Sriram Aiyer
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Jingting Yu
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Gennavieve Gray
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Zeyuan Zhang
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Zelin Shan
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Bo Zhou
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Ye Zheng
- The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Patrick R. Griffin
- The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Dmitry Lyumkis
- The Salk Institute for Biological Studies, La Jolla, CA, USA
- Graduate School for Biological Sciences, Section of Molecular Biology, University of California San Diego, La Jolla, California, USA
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12
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Mickael ME, Kubick N, Miftari K, Horbańczuk JO, Atanasov AG, Binçe K, Religa P, Kamińska A, Sacharczuk M, Ławiński M. The Role of Th17/Treg Axis in Retinal Pathology Associated with Diabetes and Treatment Options. BIOLOGY 2025; 14:275. [PMID: 40136531 PMCID: PMC11940215 DOI: 10.3390/biology14030275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/26/2025] [Accepted: 03/06/2025] [Indexed: 03/27/2025]
Abstract
Diabetic retinopathy (DR) is a major complication of diabetes, leading to vision impairment and blindness. The pathogenesis of DR involves multiple factors, including hyperglycemia-induced vascular damage, hypertension, obesity, anemia, immune dysregulation, and disruption of the blood-retinal barrier (BRB). Th17 and Treg cells, two types of CD4+ T cells, play opposing roles in inflammation. Th17 cells are pro-inflammatory, producing cytokines such as IL-17A, while Treg cells help suppress immune responses and promote anti-inflammatory effects. Recent studies highlight the importance of the Th17/Treg balance in retinal inflammation and disease progression in DR. Our literature review reveals an imbalance in DR, with increased Th17 activity and reduced Treg function. This shift creates a pro-inflammatory environment in the retina, worsening vascular leakage, neovascularization, and vision loss. The limited infiltration of Treg cells suggests that Th17 cells may uniquely infiltrate the retina by overwhelming or outnumbering Tregs or increasing the expression of recruiting chemokines, rather than only taking advantage of a damaged BRB. Therapeutic strategies, such as neutralizing IL-17A and enhancing Treg function with compounds like IL-35 or curcumin, may reduce inflammation and retinal damage. Restoring the balance between Th17 and Treg cells could provide new approaches for treating DR by controlling inflammation and preventing further retinal damage.
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Affiliation(s)
- Michel-Edwar Mickael
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Jastrzebiec, Poland; (J.O.H.); (A.G.A.); (M.S.)
| | - Norwin Kubick
- Department of Biology, Institute of Plant Science and Microbiology, University of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany;
| | - Kreshnik Miftari
- Faculty of Medicine, University of Prishtina, Str. “George Bush”, No. 31, 10 000 Prishtine, Kosovo; (K.M.); (K.B.)
| | - Jarosław Olav Horbańczuk
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Jastrzebiec, Poland; (J.O.H.); (A.G.A.); (M.S.)
| | - Atanas G. Atanasov
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Jastrzebiec, Poland; (J.O.H.); (A.G.A.); (M.S.)
- Ludwig Boltzmann Institute Digital Health and Patient Safety, Medical University of Vienna, 1090 Vienna, Austria
| | - Korona Binçe
- Faculty of Medicine, University of Prishtina, Str. “George Bush”, No. 31, 10 000 Prishtine, Kosovo; (K.M.); (K.B.)
| | - Piotr Religa
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institute, SE-141 86 Stockholm, Sweden;
| | - Agnieszka Kamińska
- Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszyński University in Warsaw, 01-938 Warsaw, Poland;
| | - Mariusz Sacharczuk
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Jastrzebiec, Poland; (J.O.H.); (A.G.A.); (M.S.)
- Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-091 Warsaw, Poland
| | - Michał Ławiński
- Department of General Surgery, Gastroenterology and Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland;
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13
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Yu Y, Xue B, Tong L, Bassuk AG, Johnson AK, Wei SG. RORγt Mediates Angiotensin II-Induced Pressor Responses, Microglia Activation, and Neuroinflammation by Disrupting the Blood-Brain Barrier in Rats. J Am Heart Assoc 2025; 14:e040461. [PMID: 40008506 DOI: 10.1161/jaha.124.040461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/15/2025] [Indexed: 02/27/2025]
Abstract
BACKGROUND The RORγt (nuclear receptor retinoid-related orphan receptor γt) has been identified as a master transcription factor critical for the differentiation of T helper 17 cells, the primary source of IL-17A (interleukin-17A). We previously demonstrated that IL-17A promotes neuroinflammation and sympathetic excitation, contributing to cardiac dysfunction in heart failure and angiotensin II (ANG II)-induced hypertension. The present study sought to determine whether inhibiting RORγt, thereby reducing IL-17A production, could attenuate microglial activation, neuroinflammation, and sympathetic excitation by preserving the integrity of the blood-brain barrier (BBB) in ANG II-induced hypertensive rats. METHODS Rats underwent a 2-week subcutaneous infusion of ANG II, with concurrent daily subcutaneous administration of the RORγt inhibitor digoxin or vehicle. RESULTS Compared with controls, ANG II-infused rats exhibited elevated IL-17A levels in both the periphery and brain, along with increased blood pressure and sympathetic tone-effects that were significantly attenuated by inhibiting RORγt with digoxin. ANG II-infused rats also displayed heightened BBB permeability, decreased expression of the BBB regulator Mfsd2a (major facilitator superfamily domain-containing protein 2a), increased caveolar transcytosis, and degradation of tight junction proteins in BBB endothelial cells within the hypothalamic paraventricular nucleus, a key autonomic regulatory brain center, all of which were alleviated by digoxin. Additionally, ANG II-infused rats showed marked microglial activation and elevated expression of proinflammatory cytokines within the paraventricular nucleus, both of which were mitigated by digoxin. CONCLUSIONS These findings suggest that RORγt inhibition reduces neuroinflammation and sympathetic activation to ameliorate ANG II-induced hypertension, likely by mitigating IL-17A-induced BBB disruption and microglial activation in the paraventricular nucleus.
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Affiliation(s)
- Yang Yu
- Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA USA
| | - Baojian Xue
- Stead Family Department of Pediatrics, Department of Neurology University of Iowa Carver College of Medicine Iowa City IA USA
| | - Lei Tong
- Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA USA
| | - Alexander G Bassuk
- Stead Family Department of Pediatrics, Department of Neurology University of Iowa Carver College of Medicine Iowa City IA USA
- The Iowa Neuroscience Institute University of Iowa Carver College of Medicine Iowa City IA USA
| | - Alan K Johnson
- Abboud Cardiovascular Research Center University of Iowa Carver College of Medicine Iowa City IA USA
- Department of Psychological and Brain Sciences University of Iowa Carver College of Medicine Iowa City IA USA
| | - Shun-Guang Wei
- Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA USA
- Abboud Cardiovascular Research Center University of Iowa Carver College of Medicine Iowa City IA USA
- The Iowa Neuroscience Institute University of Iowa Carver College of Medicine Iowa City IA USA
- Iowa City VA Medical Center Iowa City IA USA
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14
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Zeng Q, Guo H, Tang N, Renavikar PS, Karandikar NJ, Lovett-Racke AE, Racke MK, Yan C, Tang R, Sinha S, Ghosh K, Ryal JP, Ouyang S, Chen M, Amari F, Vincenzo C, Pope RM, Li Y, Yang H, Langdon WY, Zhang J. K27-linked RORγt ubiquitination by Nedd4 potentiates Th17-mediated autoimmunity. J Biomed Sci 2025; 32:26. [PMID: 39972304 PMCID: PMC11841259 DOI: 10.1186/s12929-025-01120-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 01/17/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The HECT E3 ubiquitin ligase Nedd4 has been shown to positively regulate T cell responses, but its role in T helper (Th) cell differentiation and autoimmunity is unknown. Th17 cells are believed to play a pivotal role in the development and pathogenesis of autoimmune diseases. Nevertheless, the regulation of RORγt activation during Th17 cell differentiation by TCR signaling is yet to be elucidated. These uncharted aspects inspire us to explore the potential role of Nedd4 in Th17-mediated autoimmunity. METHODS We evaluated the impact of Nedd4 deficiency on mouse T cell development and differentiation using flow cytometry and siRNA transfection, and subsequently validated these findings in T cells from patients with multiple sclerosis (MS). Furthermore, we investigated the influence of Nedd4 deficiency on Th17-mediated autoimmunity through experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Subsequently, we elucidated the molecular mechanism underlying the interaction between Nedd4 and RORgt through immunoprecipitation, mass spectrometry analysis, and lentiviral transduction. Additionally, we identified Nedd4 as an E3 ubiquitin ligase for RORγt. Moreover, we characterized the tyrosine residue sites and polyubiquitination patterns involved in RORγt ubiquitination. RESULTS In this study, we report that loss of Nedd4 in T cells specifically impairs pathogenic and non-pathogenic Th17 responses, and Th17-mediated EAE development. At the molecular level, Nedd4 binds to the PPLY motif within the ligand binding domain of RORγt, and targets RORγt at K112 for K27-linked polyubiquitination, thus augmenting its activity. CONCLUSION Nedd4 is a crucial E3 ubiquitin ligase for RORγt in the regulating Th17 cell development and offers potential therapeutic benefits for treating Th17-mediated autoimmune diseases.
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MESH Headings
- Nedd4 Ubiquitin Protein Ligases/genetics
- Nedd4 Ubiquitin Protein Ligases/metabolism
- Nedd4 Ubiquitin Protein Ligases/immunology
- Animals
- Th17 Cells/immunology
- Mice
- Ubiquitination
- Humans
- Autoimmunity/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Multiple Sclerosis/immunology
- Multiple Sclerosis/genetics
- Mice, Inbred C57BL
- Cell Differentiation
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Affiliation(s)
- Qiuming Zeng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA.
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA.
- Clinical Research Center for Neuroimmune and Neuromuscular Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
| | - Hui Guo
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA.
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA.
| | - Na Tang
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Pranav S Renavikar
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Nitin J Karandikar
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Amy E Lovett-Racke
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Michael K Racke
- Department of Neurology, The Ohio State University, Columbus, OH, 43210, USA
| | - Chengkai Yan
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Rong Tang
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Sushmita Sinha
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Krishnendu Ghosh
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Jeremy P Ryal
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Song Ouyang
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Min Chen
- Genetically Engineered Mouse Modeling Core, The Ohio State University, Columbus, OH, 43210, USA
| | - Foued Amari
- Genetically Engineered Mouse Modeling Core, The Ohio State University, Columbus, OH, 43210, USA
| | - Coppola Vincenzo
- Genetically Engineered Mouse Modeling Core, The Ohio State University, Columbus, OH, 43210, USA
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA
| | - R Marshall Pope
- Proteomics Facility, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
| | - Yalan Li
- Genetically Engineered Mouse Modeling Core, The Ohio State University, Columbus, OH, 43210, USA
| | - Huan Yang
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
- Clinical Research Center for Neuroimmune and Neuromuscular Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Wallace Y Langdon
- School of Biomedical Sciences, The University of Western Australia, Perth, Australia
| | - Jian Zhang
- Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA.
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA.
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15
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Nematullah M, Fatma M, Zhou G, Rashid F, Ayasolla K, Ahmed ME, She R, Mir S, Zahoor I, Hoda N, Rattan R, Giri S. Immune-responsive gene-1: The mitochondrial Key to Th17 Cell Pathogenicity in CNS Autoimmunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.12.24.573264. [PMID: 38234838 PMCID: PMC10793427 DOI: 10.1101/2023.12.24.573264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
Pathogenic Th17 cells play crucial roles in CNS autoimmune diseases such as multiple sclerosis (MS), but their regulation by endogenous mechanisms remains unknown. Through RNA-seq analysis of primary brain glial cells, we identified immuno-responsive gene 1 (Irg1) as one of the highly upregulated gene under inflammatory conditions. Validation in the spinal cord of animals with experimental autoimmune encephalomyelitis (EAE), an MS model, confirmed elevated Irg1 levels in myeloid, CD4, and B cells in the EAE group raising the concern if Irg1 is detrimental or protective. Irg1 knockout (KO) mice exhibited severe EAE disease, increased mononuclear cell infiltration, and increased levels of triple-positive CD4+ T cells expressing IL17a, GM-CSF, and IFNγ. A lack of Irg1 in macrophages elevates Class II expression, promoting the polarization of myelin-primed CD4+ T cells into pathogenic Th17 cells via the NLRP3/IL-1β axis. Adoptive transfer in Rag-1 KO and single-cell RNA sequencing highlighted the crucial role of Irg1 in shaping pathogenic Th17 cells. Moreover, bone marrow chimeras revealed that immune cells lacking Irg1 maintained pathogenic and inflammatory phenotypes, suggesting its protective role in autoimmune diseases, including MS.
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Affiliation(s)
| | - Mena Fatma
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Guoli Zhou
- Center for Statistical Training & Consulting (CSTAT), Michigan State University, 293 Farm Lane, East Lansing, MI
| | - Faraz Rashid
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Kameshwar Ayasolla
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
| | | | - Ruicong She
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Sajad Mir
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Insha Zahoor
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Nasrul Hoda
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Ramandeep Rattan
- Division of Gynecology Oncology, Department of Women's Health Services, Henry Ford Hospital, Detroit, MI, 48202, USA
| | - Shailendra Giri
- Department of Neurology, Henry Ford Health System, Detroit, MI, 48202, USA
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Prado DS, Cattley RT, Sonego AB, Sutariya P, Wu S, Lee M, Boggess WC, Shlomchik MJ, Hawse WF. The phospholipid kinase PIKFYVE is essential for Th17 differentiation. J Exp Med 2025; 222:e20240625. [PMID: 39738812 DOI: 10.1084/jem.20240625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/13/2024] [Accepted: 12/02/2024] [Indexed: 01/02/2025] Open
Abstract
T helper 17 (Th17) cells are effector cells that mediate inflammatory responses to bacterial and fungal pathogens. While the cytokine signaling inputs required to generate Th17s are established, less is known about intracellular pathways that drive Th17 differentiation. Our previously published phosphoproteomic screen identifies that PIKFYVE, a lipid kinase that generates the phosphatidylinositol PtdIns(3,5)P2, is activated during Th17 differentiation. Herein, we discovered that PIKFYVE regulates kinase and transcription factor networks to promote Th17 differentiation. As a specific example, PtdIns(3,5)P2 directly stimulates mTORC1 kinase activity to promote cell division and differentiation pathways. Furthermore, PIKFYVE promotes STAT3 phosphorylation, which is required for Th17 differentiation. Chemical inhibition or CD4-specific deletion of PIKFYVE reduces Th17 differentiation and autoimmune pathology in the experimental autoimmune encephalomyelitis murine model of multiple sclerosis. Our findings identify molecular mechanisms by which PIKFYVE promotes Th17 differentiation and suggest that PIKFYVE is a potential therapeutic target in Th17-driven autoimmune diseases.
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Affiliation(s)
- Douglas S Prado
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh , Pittsburgh, PA, USA
| | - Richard T Cattley
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh , Pittsburgh, PA, USA
| | - Andreza B Sonego
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh , Pittsburgh, PA, USA
| | - Parth Sutariya
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh , Pittsburgh, PA, USA
| | - Shuxian Wu
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mijoon Lee
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| | - William C Boggess
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
| | - Mark J Shlomchik
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - William F Hawse
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh , Pittsburgh, PA, USA
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Tang Y, Zhang L, Huang P, She Z, Luo S, Peng H, Chen Y, Luo J, Duan W, Xiao Y, Liu L, Liu L. Understanding the intricacies of cellular mechanisms in remyelination: The role of circadian rhythm. Neurochem Int 2025; 183:105929. [PMID: 39756585 DOI: 10.1016/j.neuint.2025.105929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/27/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025]
Abstract
The term "circadian rhythm" refers to the 24-h oscillations found in various physiological processes in organisms, responsible for maintaining bodily homeostasis. Many neurological diseases mainly involve the process of demyelination, and remyelination is crucial for the treatment of neurological diseases. Current research mainly focuses on the key role of circadian clocks in the pathophysiological mechanisms of multiple sclerosis. Various studies have shown that the circadian rhythm regulates various cellular molecular mechanisms and signaling pathways involved in remyelination. The process of remyelination is primarily mediated by oligodendrocyte precursor cells (OPCs), oligodendrocytes, microglia, and astrocytes. OPCs are activated, proliferate, migrate, and ultimately differentiate into oligodendrocytes after demyelination, involving many key signaling pathway and regulatory factors. Activated microglia secretes important cytokines and chemokines, promoting OPC proliferation and differentiation, and phagocytoses myelin debris that inhibits remyelination. Astrocytes play a crucial role in supporting remyelination by secreting signals that promote remyelination or facilitate the phagocytosis of myelin debris by microglia. Additionally, cell-to-cell communication via gap junctions allows for intimate contact between astrocytes and oligodendrocytes, providing metabolic support for oligodendrocytes. Therefore, gaining a deeper understanding of the mechanisms and molecular pathways of the circadian rhythm at various stages of remyelination can help elucidate the fundamental characteristics of remyelination and provide insights into treating demyelinating disorders.
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Affiliation(s)
- Yufen Tang
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Lu Zhang
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Peng Huang
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Zhou She
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Senlin Luo
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Hong Peng
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Yuqiong Chen
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Jinwen Luo
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Wangxin Duan
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Yangyang Xiao
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China
| | - Lingjuan Liu
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China.
| | - Liqun Liu
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Child Development and Behavior, Changsha, 410011, Hunan, China.
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18
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Gooderham MJ, Mrowietz U, Kadus W, Drda K, Gu H, Vangerow H, Flack M, Korell J, Sofen H, Papp KA. Phase II Randomized Trial of BI 730357, an Oral RORγt Inhibitor, for Moderate-to-Severe Plaque Psoriasis. J Invest Dermatol 2025:S0022-202X(25)00034-X. [PMID: 39848568 DOI: 10.1016/j.jid.2024.12.025] [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: 01/29/2024] [Revised: 12/11/2024] [Accepted: 12/13/2024] [Indexed: 01/25/2025]
Abstract
TRIAL DESIGN This 2-part, double-blinded trial assessed the RORγt inhibitor BI 730357 in plaque psoriasis. METHODS In part 1, patients were randomized 2:2:2:2:1 to 25, 50, 100, and 200 mg BI 730357 or placebo once daily (fasting conditions); nonresponders were switched to higher doses. In part 2, a separate patient set was randomized 4:4:1 to receive BI 730357 (400 mg once daily, 200 mg twice daily) or a placebo (fed conditions). Patients from parts 1 and 2 could enter a long-term extension trial. Coprimary endpoints included ≥75% reduction from baseline in PASI75 and static Physician's Global Assessment score of 0/1 (clear/almost clear) at week 12. RESULTS In total, 274 patients were treated (178 [part 1] and 96 [part 2]). In part 1, 12 (30.0%) patients achieved PASI75 (P = .0062), and 11 (27.5%) achieved static Physician's Global Assessment of 0/1 (P = .0095) with BI 730357 200 mg versus none receiving placebo. Exposure-response relationship plateaued at ≥200 mg once daily BI 730357. Drug-related adverse events occurred in ≤15.8% of patients. Of 165 patients who entered the long-term extension, 93 (56.4%) achieved PASI75 during treatment, and ≤18.5% experienced a drug-related adverse event. CONCLUSIONS BI 730357 was well tolerated, with moderate efficacy versus placebo in plaque reduction (clinicaltrials.gov: NCT03635099 and NCT03835481).
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Affiliation(s)
- Melinda J Gooderham
- Skin Centre for Dermatology, Peterborough, Canada; Probity Medical Research, Inc., Waterloo, Canada; Department of Medicine, Queen's University, Kingston, Canada.
| | - Ulrich Mrowietz
- Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Werner Kadus
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Kristin Drda
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
| | - Hui Gu
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
| | - Harald Vangerow
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Mary Flack
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
| | - Julia Korell
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
| | - Howard Sofen
- University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
| | - Kim A Papp
- Probity Medical Research, Inc., Waterloo, Canada; Alliance Clinical Trials, Waterloo, Canada; Division of Dermatology, University of Toronto School of Medicine, Toronto, Canada
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19
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Xu X, Zhang H, Meng K, Cai H, Liu W, Song L, Zhang Z, Zhu Q, Han X, Han Y, Yang P. Limosilactobacillus reuteri ZY15 Alleviates Intestinal Inflammation and Barrier Dysfunction via AKT/mTOR/HIF-1α/RORγt/IL-17 Signaling and the Gut Microbiota in ETEC K88-Challenged Mice. Antioxidants (Basel) 2025; 14:58. [PMID: 39857392 PMCID: PMC11763039 DOI: 10.3390/antiox14010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/27/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
Limosilactobacillus reuteri, a recognized probiotic, improves intestinal health in animals, but the mechanism remains unclear. This study investigates the mechanisms by which L. reuteri ZY15, isolated from healthy pig feces, mitigates intestinal barrier damage and inflammation caused by oxidative stress in Enterotoxigenic Escherichia coli (ETEC) K88-challenged mice. The results indicated that L. reuteri ZY15 increased antioxidant capacity by reducing serum reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. L. reuteri ZY15 enhanced the intestinal barrier by upregulating mucin 1, mucin 2, occludin, zonula occludens-1 (ZO-1), and claudin-1 expressions in protein and mRNA levels. It significantly alleviated intestinal inflammation by reducing the proinflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17 (IL-17) mRNA and protein levels. Notably, L. reuteri ZY15 suppressed intestinal inflammation by inhibiting AKT/mTOR/HIF-1α/RORγt/IL-17 pathway activation. Additionally, it significantly altered the structure of gut microorganisms by enriching Akkermansia and Clostridia_UCG.014, and thereby re-establishing colonization resistance and alleviating ETEC K88-induced intestinal barrier damage and inflammation in mice. Taken together, our findings reveal the protective mechanism of L. reuteri ZY15 in mice challenged with ETEC K88 by regulating AKT/mTOR/HIF-1α/RORγt/IL-17 signaling and microbial imbalance. Leveraging these properties, live L. reuteri ZY15 offers a promising alternative treatment for Escherichia coli-induced diarrhea in weaned piglets.
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Affiliation(s)
- Xin Xu
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Hongwei Zhang
- Chengde Academy of Agriculture and Forestry Sciences, Chengde 067000, China;
| | - Kun Meng
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Hongying Cai
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Weiwei Liu
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Liye Song
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Zihan Zhang
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Qijun Zhu
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Xiling Han
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Yunsheng Han
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Peilong Yang
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
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20
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Wang D, Liu R. The IL-12 family of cytokines: pathogenetic role in diabetic retinopathy and therapeutic approaches to correction. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:125-133. [PMID: 39120722 DOI: 10.1007/s00210-024-03360-9] [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: 06/20/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
One vision-threatening side effect of systematic diabetes mellitus is diabetic retinopathy (DR). Recent studies have revealed that the development and progression of DR depend critically on inflammation resulting from diabetes. By attracting leukocytes to endothelium, the higher production of the inflammatory mediators induces degeneration of retinal capillaries, hence increasing vascular permeability and thrombosis probability. The leukocytes that are recruited eventually generate additional proinflammatory and proangiogenic substances, resulting in the increased infiltration of leukocytes in the retina. This process also leads to changes in the blood retinal barrier and the formation of new blood vessels, which helps to counteract the damage caused by the blockage of blood flow. IL-12 family members, IL-12, IL-23, IL-27, and IL-35, play a crucial role in regulating the responses of T helper (Th)1 and Th17 cell populations. The collected data from studies investigating the levels of IL-12 family members in the blood and eye tissues suggest that IL-12 is linked to DR, indicating that it may have a role in the development of DR as a sequential component of the immune response. This review specifically examines the possibility of using IL-12 family cytokines as a therapeutic approach for diabetes, taking into consideration their involvement in the development of DR.
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Affiliation(s)
- Dan Wang
- The Fifth Department of Geriatrics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Ruixia Liu
- The Fifth Department of Geriatrics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
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21
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Han C, Qian X, Pei H, Zhang C, Wang J, Zhou X, Li W, Yang Y, Wu S. Double-Negative T Cells Promote Liver Fibrosis Progression by Regulating Treg/Th17. J Biochem Mol Toxicol 2024; 38:e70028. [PMID: 39575557 DOI: 10.1002/jbt.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/03/2024] [Accepted: 10/09/2024] [Indexed: 01/03/2025]
Abstract
We investigated the mechanism whereby double-negative T cells (DNTs) regulate Treg/Th17 balance to promote the progression of liver fibrosis. Liver fibrosis was induced with carbon tetrachloride (CCl4) in mice. Mouse DNTs were isolated, amplified and injected. The proportions of iTreg (CDF4+CD25+Foxp3+) and Th17 (CD4+IL-17A+) in peripheral mononuclear cells, spleen and liver were analyzed by flow cytometry, and the cytokine levels were determined through enzyme-linked immunosorbent assay (ELISA). DNTs could promote the Th17 differentiation and inhibit the iTreg differentiation. The role of DNTs in promoting liver fibrosis progression and tissue inflammation was exerted through activation of IκBa. The use of IL-17A monoclonal antibody enabled suppression of the DNTs effects, reduction of the Th17 proportion and alleviation of liver fibrosis. Hal could suppress the Th17 differentiation and the effect of DNTs. DNTs can promote the Th17 differentiation through IL-17A and inhibit iTreg differentiation, thereby facilitating the liver fibrosis progression and microenvironmental inflammation. DNTs are a kind of important immunocytes that promote the liver fibrosis progression.
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Affiliation(s)
- Chenyang Han
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoying Qian
- Department of Dermatological, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang, China
| | - Hongyan Pei
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, China
| | - Caiqun Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jin Wang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaohong Zhou
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Wenyan Li
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yi Yang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shasha Wu
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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22
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Nematisouldaragh D, Nguyen H, Rabinovich-Nikitin I. Agonists, inverse agonists, and antagonists as therapeutic approaches to manipulate retinoic acid-related orphan receptors. Can J Physiol Pharmacol 2024; 102:620-633. [PMID: 38728749 DOI: 10.1139/cjpp-2024-0099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
Retinoic acid-related orphan receptors (RORs) serve as transcription factors that play a pivotal role in a myriad of physiological processes within the body. Their involvement extends to critical biological processes that confer protective effects in the heart, immune system, and nervous system, as well as contributing to the mitigation of several aggressive cancer types. These protective functions are attributed to ROR's regulation of key proteins and the management of various cellular processes, including autophagy, mitophagy, inflammation, oxidative stress, and glucose metabolism, highlighting the emerging need for pharmacological approaches to modulate ROR expression. Thus, the modulation of RORs is a rapidly growing area of research aimed not only at comprehending these receptors, but also at manipulating them to attain the desired physiological response. Despite the presence of natural ROR ligands, the development of synthetic agonists with high selectivity for these receptors holds substantial therapeutic potential. The exploration and advancement of such compounds can effectively target diseases associated with ROR dysregulation, thereby providing avenues for therapeutic interventions. Herein, we provide a comprehensive examination of the multifaceted role of ROR in diverse physiological and pathophysiological conditions, accompanied by an in-depth exploration of a spectrum of ROR agonists, inverse agonists, and antagonists.
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Affiliation(s)
- Darya Nematisouldaragh
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Huong Nguyen
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Inna Rabinovich-Nikitin
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
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23
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Tyring S, Moore A, Morita A, Hong HCH, Song IH, Eccleston J, Levy G, Mohamed MEF, Qian Y, Wu T, Pan A, Hew K, Papp KA. Cedirogant in adults with psoriasis: a phase II, randomized, placebo-controlled clinical trial. Clin Exp Dermatol 2024; 49:1347-1355. [PMID: 38699939 DOI: 10.1093/ced/llae152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/28/2024] [Accepted: 04/18/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Dysregulated interleukin (IL)-17/IL-23 signalling contributes to psoriasis pathogenesis. Cedirogant is an inverse agonist of nuclear receptor ROR-gamma isoform 2 (RORyt), a key transcription factor responsible for IL-17 synthesis and a regulator of the T helper 17 cell lineage programme. OBJECTIVES To evaluate the efficacy and safety of cedirogant to treat moderate-to-severe psoriasis. METHODS In this phase IIb, multicentre, double-blind, 16-week study (NCT05044234), adults aged 18-65 years were randomized 1 : 1 : 1 : 1 to once-daily oral cedirogant 75 mg, 150 mg, 375 mg or placebo. Assessments included: ≥ 50%/75%/90%/100% improvement from baseline in Psoriasis Area and Severity Index (PASI 50/75/90/100), static Physician's Global Assessment 0/1, Psoriasis Symptoms Scale 0 and improvements in itch; adverse events (AEs); pharmacokinetics; and IL-17A/F biomarker levels. Efficacy results based on observed cases were summarized descriptively. RESULTS Of 156 enrolled patients, most were male (70.5%); 39 patients were randomized to each treatment. Only 47 patients completed the study; the study was terminated early owing to preclinical findings. At week 16, PASI 75 achievement rates (primary endpoint) were 29%, 8% and 42% in the cedirogant 75-mg, 150-mg and 375-mg groups, respectively, and 0% in the placebo group. AE rates were similar in the cedirogant 75-mg, 150-mg and placebo groups, and higher in the cedirogant 375-mg group; most AEs were mild or moderate. CONCLUSIONS Patients with psoriasis who received cedirogant showed PASI improvement, and cedirogant was generally well tolerated. The results should be interpreted in the context of early study termination. Cedirogant development has been discontinued.
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Affiliation(s)
- Stephen Tyring
- Center for Clinical Studies, Department of Dermatology, McGovern School of Medicine, University of Texas Health Science Center, Houston, TX, USA
| | - Angela Moore
- Arlington Research Center, Arlington, TX, USA
- Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA
| | - Akimchi Morita
- Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - H Chih-Ho Hong
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
- Probity Medical Research, Surrey, BC, Canada
| | | | | | | | | | | | | | - Anqi Pan
- AbbVie Inc., North Chicago, IL, USA
| | | | - Kim A Papp
- Alliance Clinical Research and Probity Medical Research, Waterloo, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
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Nematisouldaragh D, Kirshenbaum E, Uzonna M, Kirshenbaum L, Rabinovich-Nikitin I. The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis. Int J Mol Sci 2024; 25:11340. [PMID: 39518891 PMCID: PMC11545807 DOI: 10.3390/ijms252111340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/18/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
Retinoic-acid-related orphan receptors (RORs) are transcription factors belonging to the nuclear receptor subfamily consisting of RORα, RORβ, and RORγ. By binding to the ROR response elements (ROREs) on target gene promoters, RORs regulate a wide variety of cellular processes, including autophagy, mitophagy, oxidative stress, and inflammation. The regulatory roles of RORs are observed in cardiac cells, hepatocytes, pulmonary epithelial cells, renal cells, immune cells, and cancer cells. A growing body of clinical and experimental evidence suggests that ROR expression levels are markedly reduced under different pathological and stress conditions, suggesting that RORs may play a critical role in the pathogenesis of a variety of disease states, including myocardial infarction, immune disorders, cancer, and metabolic syndrome. Reductions in RORs are also associated with inhibition of autophagy, increased reactive oxygen species (ROS), and increased cell death, underscoring the importance of RORs in the regulation of these processes. Herein, we highlight the relationship between RORs and homeostatic processes that influence cell viability. Understanding how these intricate processes are governed at the cellular level is of high scientific and clinical importance to develop new therapeutic strategies that modulate ROR expression and disease progression.
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Affiliation(s)
- Darya Nematisouldaragh
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (D.N.); (E.K.); (M.U.); (L.K.)
- The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Eryn Kirshenbaum
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (D.N.); (E.K.); (M.U.); (L.K.)
- The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Michael Uzonna
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (D.N.); (E.K.); (M.U.); (L.K.)
- The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Lorrie Kirshenbaum
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (D.N.); (E.K.); (M.U.); (L.K.)
- The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Pharmacology and Therapeutics, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, MB R2H 2A6, Canada
| | - Inna Rabinovich-Nikitin
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada; (D.N.); (E.K.); (M.U.); (L.K.)
- The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
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Chou SP, Chuang YJ, Chen BS. Systems Biology Methods via Genome-Wide RNA Sequences to Investigate Pathogenic Mechanisms for Identifying Biomarkers and Constructing a DNN-Based Drug-Target Interaction Model to Predict Potential Molecular Drugs for Treating Atopic Dermatitis. Int J Mol Sci 2024; 25:10691. [PMID: 39409019 PMCID: PMC11477013 DOI: 10.3390/ijms251910691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/29/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
This study aimed to construct genome-wide genetic and epigenetic networks (GWGENs) of atopic dermatitis (AD) and healthy controls through systems biology methods based on genome-wide microarray data. Subsequently, the core GWGENs of AD and healthy controls were extracted from their real GWGENs by the principal network projection (PNP) method for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation. Then, we identified the abnormal signaling pathways by comparing the core signaling pathways of AD and healthy controls to investigate the pathogenesis of AD. Then, IL-1β, GATA3, Akt, and NF-κB were selected as biomarkers for their important roles in the abnormal regulation of downstream genes, leading to cellular dysfunctions in AD patients. Next, a deep neural network (DNN)-based drug-target interaction (DTI) model was pre-trained on DTI databases to predict molecular drugs that interact with these biomarkers. Finally, we screened the candidate molecular drugs based on drug toxicity, sensitivity, and regulatory ability as drug design specifications to select potential molecular drugs for these biomarkers to treat AD, including metformin, allantoin, and U-0126, which have shown potential for therapeutic treatment by regulating abnormal immune responses and restoring the pathogenic signaling pathways of AD.
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Affiliation(s)
- Sheng-Ping Chou
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Yung-Jen Chuang
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Bor-Sen Chen
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
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Biagioli M, Di Giorgio C, Morretta E, Bellini R, Massa C, Urbani G, Bordoni M, Marchianò S, Lachi G, Sepe V, Monti MC, Distrutti E, Zampella A, Fiorucci S. Development of dual GPBAR1 agonist and RORγt inverse agonist for the treatment of inflammatory bowel diseases. Pharmacol Res 2024; 208:107403. [PMID: 39265668 DOI: 10.1016/j.phrs.2024.107403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/14/2024]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
| | | | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy; Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Lachi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Maria Chiara Monti
- Department of Pharmacy, University of Salerno, Salerno, Italy; Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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27
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Lima RS, Belchior-Bezerra M, Silva de Oliveira D, Rocha RDS, Medeiros NI, Mattos RT, Dos Reis IC, Marques AS, Rosário PW, Calsolari MR, Correa-Oliveira R, Dutra WO, Moreira PR, Gomes JA. Obesity Influences T CD4 Lymphocytes Subsets Profiles in Children and Adolescent's Immune Response. J Nutr 2024; 154:3133-3143. [PMID: 39019165 DOI: 10.1016/j.tjnut.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/14/2024] [Accepted: 07/08/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Evidence shows that CD4+ T cells are altered in obesity and play a significant role in the systemic inflammation in adults with the disease. OBJECTIVES Because the profile of these cells is poorly understood in the pediatric population, this study aims to investigate the profile of CD4+ T lymphocytes and the plasma levels of cytokines in this population. METHODS Using flow cytometry, we compared the expression profile of lymphocyte markers, master transcription factors, cytokines, and molecules involved in the regulation of the immune response in CD4+ T cells from children and adolescents with obesity (OB group, n = 20) with those with eutrophy group (EU group, n = 16). Plasma levels of cytokines in both groups were determined by cytometric bead array (CBA). RESULTS The OB group presents a lower frequency of CD3+ T cells, as well as a decreased frequency of CD4+ T cells expressing CD28, IL-4, and FOXP3, but an increased frequency of CD4+IL-17A+ cells compared with the EU group. The frequency of CD28 is increased in Th2 and Treg cells in the OB group, whereas CTLA-4 is decreased in all subpopulations compared with the EU group. Furthermore, Th2, Th17, and Treg profiles can differentiate the EU and OB groups. IL-10 plasma levels are reduced in the OB group and negatively correlated with adiposity and inflammatory parameters. CONCLUSIONS CD4+ T cells have an altered pattern of expression in children and adolescents with obesity, contributing to the inflammatory state and clinical characteristics of these patients.
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Affiliation(s)
- Rafael Silva Lima
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mayara Belchior-Bezerra
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Daniela Silva de Oliveira
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Nayara I Medeiros
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Imunologia Celular e Molecular, Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil
| | - Rafael T Mattos
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Isabelle Camile Dos Reis
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Aiessa Santos Marques
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Pedro Ws Rosário
- Centro de Especialidades Médicas (CEM), Hospital Santa Casa, Belo Horizonte, Brazil
| | | | - Rodrigo Correa-Oliveira
- Imunologia Celular e Molecular, Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil
| | - Walderez O Dutra
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Paula Rocha Moreira
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Juliana As Gomes
- Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
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28
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da Costa AL, Prieto-Oliveira P, Duarte-Barbosa M, Andreata-Santos R, Peter CM, Prolo de Brito T, Antoneli F, Durães-Carvalho R, Briones MRS, Maricato JT, Zanotto PMA, Jacob Machado D, Janini LMR. The Relationship between HERV, Interleukin, and Transcription Factor Expression in ZIKV Infected versus Uninfected Trophoblastic Cells. Cells 2024; 13:1491. [PMID: 39273061 PMCID: PMC11394337 DOI: 10.3390/cells13171491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/21/2024] [Accepted: 08/31/2024] [Indexed: 09/15/2024] Open
Abstract
Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the placenta. This immune response counts with the participation of interleukins and transcription factors. Additionally, it has the potential involvement of human endogenous retroviruses (HERVS). Interleukins are immune response regulators that aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. HERVs are remnants of ancient viral infections that integrate into the genome and produce syncytin proteins crucial for placental development. Since ZIKV can infect trophoblast cells, we analyzed the relationship between ZIKV infection, HERV, interleukin, and transcription factor modulations in the placenta. To investigate the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asian-Brazilian) using Taqman and RT2 Profiler PCR Array assays. Our results indicate that early ZIKV infection (24-72 h) does not induce differential interleukins, transcription factors, and HERV expression. However, we show that the expression of a few of these host defense genes appears to be linked independently of ZIKV infection. Future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and transcription factors in the placenta.
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Affiliation(s)
- Anderson Luís da Costa
- Laboratory of Retrovirology, Discipline of Infectology, Department of Medicine, Federal University of São Paulo (EPM-UNIFESP), São Paulo 04039-032, Brazil; (A.L.d.C.); (M.D.-B.)
| | - Paula Prieto-Oliveira
- Department of Bioinformatics and Genomics, College of Computing and Informatics, University of North Carolina at Charlotte, 9331 Robert D. Snyder Rd., Charlotte, NC 28223, USA; (P.P.-O.); (D.J.M.)
- Computational Intelligence to Predict Health and Environmental Risks Center, University of North Carolina at Charlotte, 9201 University City BLVD, Charlotte, NC 28223, USA
| | - Márcia Duarte-Barbosa
- Laboratory of Retrovirology, Discipline of Infectology, Department of Medicine, Federal University of São Paulo (EPM-UNIFESP), São Paulo 04039-032, Brazil; (A.L.d.C.); (M.D.-B.)
| | - Robert Andreata-Santos
- Laboratory of Retrovirology, Discipline of Microbiology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04039-032, Brazil; (R.A.-S.); (C.M.P.); (T.P.d.B.); (R.D.-C.); (J.T.M.)
| | - Cristina M. Peter
- Laboratory of Retrovirology, Discipline of Microbiology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04039-032, Brazil; (R.A.-S.); (C.M.P.); (T.P.d.B.); (R.D.-C.); (J.T.M.)
- Center for Medical Bioinformatics, Federal University of São Paulo, São Paulo 04039-032, Brazil; (F.A.); (M.R.S.B.)
| | - Thamires Prolo de Brito
- Laboratory of Retrovirology, Discipline of Microbiology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04039-032, Brazil; (R.A.-S.); (C.M.P.); (T.P.d.B.); (R.D.-C.); (J.T.M.)
| | - Fernando Antoneli
- Center for Medical Bioinformatics, Federal University of São Paulo, São Paulo 04039-032, Brazil; (F.A.); (M.R.S.B.)
| | - Ricardo Durães-Carvalho
- Laboratory of Retrovirology, Discipline of Microbiology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04039-032, Brazil; (R.A.-S.); (C.M.P.); (T.P.d.B.); (R.D.-C.); (J.T.M.)
- Department of Morphology and Genetics, Federal University of São Paulo, São Paulo 04039-032, Brazil
| | - Marcelo R. S. Briones
- Center for Medical Bioinformatics, Federal University of São Paulo, São Paulo 04039-032, Brazil; (F.A.); (M.R.S.B.)
| | - Juliana T. Maricato
- Laboratory of Retrovirology, Discipline of Microbiology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04039-032, Brazil; (R.A.-S.); (C.M.P.); (T.P.d.B.); (R.D.-C.); (J.T.M.)
| | - Paolo M. A. Zanotto
- Laboratory of Molecular Evolution and Bioinformatics, Department of Microbiology, Institute of Biosciences, University of São Paulo, São Paulo 05508-000, Brazil;
| | - Denis Jacob Machado
- Department of Bioinformatics and Genomics, College of Computing and Informatics, University of North Carolina at Charlotte, 9331 Robert D. Snyder Rd., Charlotte, NC 28223, USA; (P.P.-O.); (D.J.M.)
- Computational Intelligence to Predict Health and Environmental Risks Center, University of North Carolina at Charlotte, 9201 University City BLVD, Charlotte, NC 28223, USA
| | - Luiz M. R. Janini
- Laboratory of Retrovirology, Discipline of Infectology, Department of Medicine, Federal University of São Paulo (EPM-UNIFESP), São Paulo 04039-032, Brazil; (A.L.d.C.); (M.D.-B.)
- Laboratory of Retrovirology, Discipline of Microbiology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo 04039-032, Brazil; (R.A.-S.); (C.M.P.); (T.P.d.B.); (R.D.-C.); (J.T.M.)
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29
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Kumagai Y. BootCellNet, a resampling-based procedure, promotes unsupervised identification of cell populations via robust inference of gene regulatory networks. PLoS Comput Biol 2024; 20:e1012480. [PMID: 39348410 PMCID: PMC11466406 DOI: 10.1371/journal.pcbi.1012480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 10/10/2024] [Accepted: 09/11/2024] [Indexed: 10/02/2024] Open
Abstract
Recent advances in measurement technologies, particularly single-cell RNA sequencing (scRNA-seq), have revolutionized our ability to acquire large amounts of omics-level data on cellular states. As measurement techniques evolve, there has been an increasing need for data analysis methodologies, especially those focused on cell-type identification and inference of gene regulatory networks (GRNs). We have developed a new method named BootCellNet, which employs smoothing and resampling to infer GRNs. Using the inferred GRNs, BootCellNet further infers the minimum dominating set (MDS), a set of genes that determines the dynamics of the entire network. We have demonstrated that BootCellNet robustly infers GRNs and their MDSs from scRNA-seq data and facilitates unsupervised identification of cell clusters using scRNA-seq datasets of peripheral blood mononuclear cells and hematopoiesis. It has also identified COVID-19 patient-specific cells and their potential regulatory transcription factors. BootCellNet not only identifies cell types in an unsupervised and explainable way but also provides insights into the characteristics of identified cell types through the inference of GRNs and MDS.
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Affiliation(s)
- Yutaro Kumagai
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Ibaraki, Japan
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30
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Liu SJ, Zhao Q, Liu XC, Gamble AB, Huang W, Yang QQ, Han B. Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery. Med Res Rev 2024; 44:1971-2014. [PMID: 38515232 DOI: 10.1002/med.22037] [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: 12/11/2023] [Revised: 03/04/2024] [Accepted: 03/10/2024] [Indexed: 03/23/2024]
Abstract
Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA-approved drugs and experimental molecules, display markedly different biological activities. The time-dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future.
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Affiliation(s)
- Shuai-Jiang Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Qian Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao-Chen Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Allan B Gamble
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian-Qian Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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31
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Nierath WF, Leitner E, Reimann S, Schwarz R, Hinz B, Bleich A, Vollmar B, Zechner D. GSK805 inhibits alpha-smooth muscle expression and modulates liver inflammation without impairing the well-being of mice. FASEB J 2024; 38:e23889. [PMID: 39157975 DOI: 10.1096/fj.202400733r] [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: 04/16/2024] [Revised: 06/21/2024] [Accepted: 08/05/2024] [Indexed: 08/20/2024]
Abstract
Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.
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Affiliation(s)
- Wiebke-Felicitas Nierath
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Emily Leitner
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Sabrina Reimann
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Rico Schwarz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Brigitte Vollmar
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Dietmar Zechner
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
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32
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Sun X, Gu R, Bai J. Differentiation and regulation of CD4 + T cell subsets in Parkinson's disease. Cell Mol Life Sci 2024; 81:352. [PMID: 39153043 PMCID: PMC11335276 DOI: 10.1007/s00018-024-05402-0] [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: 03/09/2024] [Revised: 08/06/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease, and its hallmark pathological features are the loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta (SNpc) and the accumulation of alpha-synuclein (α-syn). It has been shown that the integrity of the blood-brain barrier (BBB) is damaged in PD patients, and a large number of infiltrating T cells and inflammatory cytokines have been detected in the cerebrospinal fluid (CSF) and brain parenchyma of PD patients and PD animal models, including significant change in the number and proportion of different CD4+ T cell subsets. This suggests that the neuroinflammatory response caused by CD4+ T cells is an important risk factor for the development of PD. Here, we systematically review the differentiation of CD4+ T cell subsets, and focus on describing the functions and mechanisms of different CD4+ T cell subsets and their secreted cytokines in PD. We also summarize the current immunotherapy targeting CD4+ T cells with a view to providing assistance in the diagnosis and treatment of PD.
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Affiliation(s)
- Xiaowei Sun
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China
- Southwest United Graduate School, Kunming, 650500, China
| | - Rou Gu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Jie Bai
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China.
- Southwest United Graduate School, Kunming, 650500, China.
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Jin Y, Pan Z, Zhou J, Wang K, Zhu P, Wang Y, Xu X, Zhang J, Hao C. Hedgehog signaling pathway regulates Th17 cell differentiation in asthma via IL-6/STAT3 signaling. Int Immunopharmacol 2024; 139:112771. [PMID: 39074418 DOI: 10.1016/j.intimp.2024.112771] [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: 04/23/2024] [Revised: 07/10/2024] [Accepted: 07/22/2024] [Indexed: 07/31/2024]
Abstract
Asthma is the most prevalent chronic inflammatory disease of the airways in children. The most prevalent phenotype of asthma is eosinophilic asthma, which is driven by a Th2 immune response and can be effectively managed by inhaled corticosteroid therapy. However, there are phenotypes of asthma with Th17 immune response that are insensitive to corticosteroid therapy and manifest a more severe phenotype. The treatment of this corticosteroid-insensitive asthma is currently immature and requires further attention. The objective of this study is to elucidate the regulation of the Hedgehog signaling pathway in Th17 cell differentiation in asthma. The study demonstrated that both Smo and Gli3, key components of the Hedgehog signaling pathway, were upregulated in Th17 polarization in vitro and in a Th17-dominant asthma model in vivo. Inhibiting Smo with a small molecule inhibitor or genetically knocking down Gli3 was found to suppress Th17 polarization. Smo was found to increase in Th1, Th2, Th17 and Treg polarization, while Gli3 specifically increased in Th17 polarization. ChIP-qPCR analyses indicated that Gli3 can directly interact with IL-6 in T cells, inducing STAT3 phosphorylation and promoting Th17 cell differentiation. Furthermore, the study demonstrated a correlation between elevated Gli3 expression and IL-17A and IL-6 expression in children with asthma. In conclusion, the study demonstrated that the Hedgehog signaling pathway plays an important role in the pathogenesis of asthma, as it regulates the differentiation of Th17 cells through the IL-6/STAT3 signaling. This may provide a potential therapeutic target for corticosteroid-insensitive asthma driven by Th17 cells.
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Affiliation(s)
- Yuting Jin
- Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China; Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Zhenzhen Pan
- Department of Respiration, Wuxi Children's Hospital, Wuxi, China
| | - Ji Zhou
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Kai Wang
- Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Peijie Zhu
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Yufeng Wang
- Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China
| | - Xuena Xu
- Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China
| | - Jinping Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
| | - Chuangli Hao
- Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China.
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Kalim UU, Biradar R, Junttila S, Khan MM, Tripathi S, Khan MH, Smolander J, Kanduri K, Envall T, Laiho A, Marson A, Rasool O, Elo LL, Lahesmaa R. A proximal enhancer regulates RORA expression during early human Th17 cell differentiation. Clin Immunol 2024; 264:110261. [PMID: 38788884 DOI: 10.1016/j.clim.2024.110261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/19/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.
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Affiliation(s)
- Ubaid Ullah Kalim
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
| | - Rahul Biradar
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Sini Junttila
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Mohd Moin Khan
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Subhash Tripathi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Meraj Hasan Khan
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Johannes Smolander
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Kartiek Kanduri
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Tapio Envall
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Asta Laiho
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Alexander Marson
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Omid Rasool
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Laura L Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland; Institute of Biomedicine, University of Turku, Turku, Finland
| | - Riitta Lahesmaa
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland; Institute of Biomedicine, University of Turku, Turku, Finland.
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Mohamed MEF, Qian Y, D'Cunha R, Hao S, Carcereri De Prati R, Levy GF, Hew K, Liu W. Pharmacokinetics, Safety, and Tolerability of Cedirogant in Healthy Japanese and Chinese Adults. Clin Pharmacol Drug Dev 2024; 13:801-809. [PMID: 38410874 DOI: 10.1002/cpdd.1386] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/23/2024] [Indexed: 02/28/2024]
Abstract
Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma, thymus (RORγt) developed for treatment of psoriasis. This study aimed to characterize pharmacokinetics, pharmacodynamics, safety, and tolerability of cedirogant following a single oral dose in Japanese participants and multiple oral doses in Japanese and Chinese participants. The single doses evaluated in healthy Japanese participants were 75, 225, and 395 mg. The multiple doses evaluated in both healthy Japanese and Chinese participants was 375 mg once daily for 14 days. Cedirogant plasma exposure increased dose proportionally with administration of single doses. Maximum cedirogant plasma concentration was reached within a median time of 4-5 hours after dosing. The harmonic mean elimination half-life ranged from 19 to 25 hours. Cedirogant pharmacokinetics were similar between Japanese and Chinese participants. Compared with healthy Western participants in a cross-study analysis, steady-state cedirogant plasma exposure was 38%-73% higher in Japanese or Chinese participants. Ex vivo interleukin-17 inhibition increased in a dose-dependent manner and was maximized by 375 mg once-daily doses. The cedirogant regimens tested were generally well tolerated, and no new safety issues were identified. The results supported enrollment of Japanese and Chinese subjects in subsequent clinical trials for cedirogant.
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Affiliation(s)
| | - Yuli Qian
- Clinical Pharmacology, AbbVie, North Chicago, IL, USA
| | | | - Shuai Hao
- Discovery and Exploratory Statistics, AbbVie, North Chicago, IL, USA
| | | | - Gweneth F Levy
- Pharmacovigilance and Patient Safety, AbbVie, North Chicago, IL, USA
| | - Kinjal Hew
- Precision Medicine Immunology, AbbVie, North Chicago, IL, USA
| | - Wei Liu
- Clinical Pharmacology, AbbVie, North Chicago, IL, USA
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Li X, Fu S, Cheng H, Ma M, Song Z, Li J, Wu S, Zhang C, Wang X, Tang M, Pu X, Ji Q, Liang J, Zhao Z, Körner H, Li B, Shao M, Wang H. Differentiation of Type 17 Mucosal-Associated Invariant T Cells in Circulation Contributes to the Severity of Sepsis. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1248-1261. [PMID: 38599461 DOI: 10.1016/j.ajpath.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/05/2024] [Accepted: 03/15/2024] [Indexed: 04/12/2024]
Abstract
Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and retinoic acid receptor-related orphan receptor γt in patients with sepsis. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA-sequencing analysis revealed an enhanced expression of lactate dehydrogenase A (LDHA) in MAIT17 in patients with sepsis. Cell-culture experiments demonstrated that phosphoinositide 3-kinase-LDHA signaling was required for retinoic acid receptor-related orphan receptor γt expression in MAIT17. Finally, the elevated levels of plasma IL-18 promoted the differentiation of circulating MAIT17 cells in sepsis. In summary, this study reveals a new role of circulating MAIT17 in promoting sepsis severity and suggests the phosphoinositide 3-kinase-LDHA signaling as a driving force in MAIT17 responses.
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Affiliation(s)
- Xinying Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; School of Life Sciences, Anhui Medical University, Hefei, China
| | - Sicheng Fu
- School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China
| | - Hao Cheng
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Min Ma
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zijian Song
- School of Pharmacy, Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Jun Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shuang Wu
- School of Pharmacy, Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Chong Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoxia Wang
- School of Public Health, Anhui Medical University, Hefei, China
| | - Maoyu Tang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China
| | - Xuexue Pu
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiang Ji
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jinquan Liang
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhibin Zhao
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Heinrich Körner
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Bin Li
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Departments of Respiratory and Critical Care Medicine and Thoracic Surgery, Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Shao
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
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Sato K, Hara-Chikuma M, Yasui M, Inoue J, Kim YG. Sufficient water intake maintains the gut microbiota and immune homeostasis and promotes pathogen elimination. iScience 2024; 27:109903. [PMID: 38799550 PMCID: PMC11126815 DOI: 10.1016/j.isci.2024.109903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/16/2024] [Accepted: 05/01/2024] [Indexed: 05/29/2024] Open
Abstract
Water is the most abundant substance in the human body and plays a pivotal role in various bodily functions. While underhydration is associated with the incidence of certain diseases, the specific role of water in gut function remains largely unexplored. Here, we show that water restriction disrupts gut homeostasis, which is accompanied by a bloom of gut microbes and decreased numbers of immune cells, especially Th17 cells, within the colon. These microbial and immunological changes in the gut are associated with an impaired ability to eliminate the enteric pathogen Citrobacter rodentium. Moreover, aquaporin 3, a water channel protein, is required for the maintenance of Th17 cell function and differentiation. Taken together, adequate water intake is critical for maintaining bacterial and immunological homeostasis in the gut, thereby enhancing host defenses against enteric pathogens.
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Affiliation(s)
- Kensuke Sato
- Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa 252-0882, Japan
| | - Mariko Hara-Chikuma
- Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masato Yasui
- Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Joe Inoue
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan
| | - Yun-Gi Kim
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
- Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan
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Banks LB, Sklarz T, Gohil M, O'Leary C, Behrens EM, Sun H, Chen YH, Koretzky GA, Jordan MS. Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.07.598023. [PMID: 38915532 PMCID: PMC11195075 DOI: 10.1101/2024.06.07.598023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2 -/- T cells exhibited enhanced IL-4 production in vitro under Th2 polarizing conditions. In vivo , Akt2 -/- mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.
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Qin L, Chen C, Gui Z, Jiang Y. IRX5's influence on macrophage polarization and outcome in papillary thyroid cancer. Front Oncol 2024; 14:1399484. [PMID: 38868535 PMCID: PMC11167072 DOI: 10.3389/fonc.2024.1399484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 05/10/2024] [Indexed: 06/14/2024] Open
Abstract
Background With a rise in recent years, thyroid cancer (TC) is the most prevalent hormonal cancer worldwide. It is essential to investigate the inherent variability at the molecular level and the immune environment within tumors of various thyroid cancer subtypes in order to identify potential targets for therapy and provide precise treatment for patients with thyroid adenocarcinoma. Methods First, we analyzed the expression of IRX5 in pan-cancer and papillary thyroid carcinoma by bioinformatics methods and collected paired samples from our center for validation. Subsequently, we analyzed the significance of IRX5 on the prognosis and diagnosis of PTC. Next, we explored the possible mechanisms by which IRX5 affects the prognosis of thyroid cancer patients by GO/KEGG enrichment analysis, and further investigated the effect of IRX5 on immune infiltration of thyroid cancer. Ultimately, by conducting experiments on cells and animals, we were able to show how IRX5 impacts the aggressive characteristics of thyroid cancer cells and its influence on macrophages within the immune system of thyroid cancer. Results In 11 malignant tumors, including PTC, IRX5 is overexpressed and associated with a poor prognosis. IRX5 may affect the prognosis of PTC through embryonic organ development, ossification, mesenchyme development, etc. Increased IRX5 expression decreases the presence of cytotoxic and Th17 cells in papillary thyroid cancer. IRX5 was highly expressed in different PTC cell lines, such as K-1 and TPC-1. Silencing IRX5 effectively halted the growth and movement of PTC cells while also decreasing M2 polarization and enhancing M1 polarization in tumor-associated macrophages. Conclusion IRX5 could impact the outlook of individuals with PTC by stimulating the shift of macrophages to M2 in the immune surroundings of thyroid cancer growths, suggesting a potential new focus for treating thyroid cancer, particularly through immunotherapy.
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Affiliation(s)
- Lu Qin
- Department of Thyroid Vascular Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, ;China
| | - Cheng Chen
- Department of Nuclear Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, ;China
| | - Zhengwei Gui
- Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Thyroid and Breast Surgery, Wuhan, ;China
| | - Yun Jiang
- Department of Ultrasound, Hubei Hospital of Integrated Traditional Chinese and Western Medicines, Wuhan, ;China
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Wu Z, Liu X, Huang W, Chen J, Li S, Chao J, Xie J, Liu L, Yang Y, Wu X, Qiu H. CIRP increases Foxp3 + regulatory T cells and inhibits development of Th17 cells by enhancing TLR4-IL-2 signaling in the late phase of sepsis. Int Immunopharmacol 2024; 132:111924. [PMID: 38531201 DOI: 10.1016/j.intimp.2024.111924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 03/14/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND T helper (Th) cell imbalances have been associated with the pathophysiology of sepsis, including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Cold-inducible RNA-binding protein (CIRP), a novel damage-associated molecular pattern (DAMP) was reported that could induce T cell activation, and skew CD4+ T cells towards a Th1 profile. However, the effect and underlying mechanisms of CIRP on Th17/Treg differentiation in sepsis still remains unknown. METHODS A prospective exploratory study including patients with sepsis was conducted. Blood samples were collected from patients on days 0, 3 and 7 on admission. The serum CIRP and peripheral blood Treg/Th17 percentage was determined by ELISA and flow cytometry. CD4+ T cells from the spleen and lymph nodes of mice with experimental sepsis were collected after treatment with normal saline (NS), recombinant murine CIRP (rmCIRP) and C23 (an antagonist for CIRP-TLR4) at late stage of sepsis. RNA-seq was conducted to reveal the pivotal molecular mechanism of CIRP on Treg/Th17 differentiation. Naïve CD4+ T cell was isolated from the Tlr4 null and wildtype mice in the presence or absence rmCIRP and C23 to confirmed above findings. RESULTS A total of 19 patients with sepsis finally completed the study. Serum CIRP levels remained high in the majority of patients up to 1 week after admittance was closely associated with high Treg/Th17 ratio of peripheral blood and poor outcome. A univariate logistic analysis demonstrated that higher CIRP concentration at Day 7 is an independent risk factor for Treg/Th17 ratio increasing. CIRP promotes Treg development and suppresses Th17 differentiation was found both in vivo and in vitro. Pretreated with C23 not only alleviated the majority of negative effect of CIRP on Th17 differentiation, but also inhibited Treg differentiation, to some extent. Tlr4 deficiency could abolish almost all downstream effects of rmCIRP. Furthermore, IL-2 is proved a key downstream molecules of the effect CIRP, which also could amplify the activated CD4+ T lymphocytes. CONCLUSIONS Persistent high circulating CIRP level may lead to Treg/Th17 ratio elevated through TLR4 and subsequent active IL-2 signaling which contribute to immunosuppression during late phases of sepsis.
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Affiliation(s)
- Zongsheng Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xu Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Wei Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jing Chen
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Songli Li
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jie Chao
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Ling Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xiaojing Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
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Rani A. RAR-related orphan receptor alpha and the staggerer mice: a fine molecular story. Front Endocrinol (Lausanne) 2024; 14:1300729. [PMID: 38766309 PMCID: PMC11099308 DOI: 10.3389/fendo.2023.1300729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/15/2023] [Indexed: 05/22/2024] Open
Abstract
The retinoic acid-related orphan receptor alpha (RORα) protein first came into the limelight due to a set of staggerer mice, discovered at the Jackson Laboratories in the United States of America by Sidman, Lane, and Dickie (1962) and genetically deciphered by Hamilton et al. in 1996. These staggerer mice exhibited cerebellar defects, an ataxic gait, a stagger along with several other developmental abnormalities, compensatory mechanisms, and, most importantly, a deletion of 160 kilobases (kb), encompassing the RORα ligand binding domain (LBD). The discovery of the staggerer mice and the subsequent discovery of a loss of the LBD within the RORα gene of these mice at the genetic level clearly indicated that RORα's LBD played a crucial role in patterning during embryogenesis. Moreover, a chance study by Roffler-Tarlov and Sidman (1978) noted reduced concentrations of glutamic acid levels in the staggerer mice, indicating a possible role for the essence of a nutritionally balanced diet. The sequential organisation of the building blocks of intact genes, requires the nucleotide bases of deoxyribonucleic acid (DNA): purines and pyrimidines, both of which are synthesized, upon a constant supply of glutamine, an amino acid fortified in a balanced diet and a byproduct of the carbohydrate and lipid metabolic pathways. A nutritionally balanced diet, along with a metabolic "enzymatic machinery" devoid of mutations/aberrations, was essential in the uninterrupted transcription of RORα during embryogenesis. In addition to the above, following translation, a ligand-responsive RORα acts as a "molecular circadian regulator" during embryogenesis and not only is expressed selectively and differentially, but also promotes differential activity depending on the anatomical and pathological site of its expression. RORα is highly expressed in the central nervous system (CNS) and the endocrine organs. Additionally, RORα and the clock genes are core components of the circadian rhythmicity, with the expression of RORα fluctuating in a night-day-night sigmoidal pattern and undoubtedly serves as an endocrine-like, albeit "molecular-circadian regulator". Melatonin, a circadian hormone, along with tri-iodothyronine and some steroid hormones are known to regulate RORα-mediated molecular activity, with each of these hormones themselves being regulated rhythmically by the hypothalamic-pituitary axis (HPA). The HPA regulates the circadian rhythm and cyclical release of hormones, in a self-regulatory feedback loop. Irregular sleep-wake patterns affect circadian rhythmicity and the ability of the immune system to withstand infections. The staggerer mice with their thinner bones, an altered skeletal musculature, an aberrant metabolic profile, the ataxic gait and an underdeveloped cerebellar cortex; exhibited compensatory mechanisms, that not only allowed the survival of the staggerer mice, but also enhanced protection from microbial invasions and resistance to high-fat-diet induced obesity. This review has been compiled in its present form, more than 14 years later after a chromatin immunoprecipitation (ChIP) cloning and sequencing methodology helped me identify signal transducer and activator of transcription 5 (STAT5) target sequences, one of which was mapped to the first intron of the RORα gene. The 599-base-long sequence containing one consensus TTCNNNGAA (TTCN3GAA) gamma-activated sequence (GAS) and five other non-consensus TTN5AA sequences had been identified from the clones isolated from the STAT5 target sites (fragments) in human phytohemagglutinin-activated CD8+ T lymphocytes, during my doctoral studies between 2006 and 2009. Most importantly, preliminary studies noted a unique RORα expression profile, during a time-course study on the ribonucleic acid (RNA), extracted from human phytohemagglutinin (PHA) activated CD8+ T lymphocytes stimulated with interleukin-2 (IL-2). This review mainly focuses on the "staggerer mice" with one of its first roles materialising during embryogenesis, a molecular-endocrine mediated circadian-like regulatory process.
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Affiliation(s)
- Aradhana Rani
- Medical Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India
- Human Resource Development and Management, Indian Institute of Technology (IIT) Kharagpur, West Bengal, India
- Immunology, King’s College London, London, United Kingdom
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Liu Y, Wang F, Cheng B, Zhou G. Melatonin improves salivary gland damage and hypofunction in pSS by inhibiting IL-6/STAT3 signaling through its receptor-dependent manner. Mol Immunol 2024; 169:10-27. [PMID: 38460474 DOI: 10.1016/j.molimm.2024.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/31/2024] [Accepted: 02/15/2024] [Indexed: 03/11/2024]
Abstract
OBJECTIVE Primary Sjogren's syndrome (pSS) is an autoimmune disease of the exocrine glands with no specific or efficient treatments. Melatonin, a natural hormone, is revealed to show multiple biological functions, both receptor-dependent and independent effects, including anti-apoptotic, antioxidant, and anti-inflammatory activities. However, the potential mechanism by which melatonin protects salivary glands (SGs) of pSS from damage needs to be clarified. The purpose of current study was to explore the role and receptor-related mechanisms of melatonin in pSS-induced glandular damage. METHODS AND RESULTS NOD/Ltj mice were used to spontaneously mimic pSS-induced glandular hypofunction in vivo and primary human salivary gland epithelial (HSGE) cells were stimulated by interferon-γ (IFN-γ) to mimic pSS-induced inflammation in SGs cells in vitro. Melatonin-treated mice exhibited a significant reduction in SG injury of NOD/Ltj mice, which was accompanied by an increase in salivary flow rate, a decrease in inflammatory infiltration within the gland, and a suppression of oxidative stress indicators as well as cell apoptosis. Notably, both melatonin membrane receptors and nuclear receptors played an important role in the anti-apoptotic effects of melatonin on the SGs of NOD/Ltj mice. Furthermore, melatonin blocked the IL-6/STAT3 pathway through receptor-dependent manners in IFN-γ-stimulated HSGE cells. However, it was evident that the anti-oxidative and anti-apoptotic properties of melatonin on IFN-γ-stimulated HSGE cells were diminished by IL-6 treatment. CONCLUSION Melatonin had the potential to mitigate inflammation, oxidative stress, and apoptosis in SGs of pSS by inhibiting the IL-6/STAT3 pathway through receptor-dependent mechanisms. This intervention effectively prevented glandular damage and preserved functional integrity.
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Affiliation(s)
- Yi Liu
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China
| | - Fang Wang
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China; Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University, China
| | - Bo Cheng
- Department of Stomatology, Zhongnan Hospital of Wuhan University, China.
| | - Gang Zhou
- The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China; Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University, China.
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43
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Kiperman T, Ma K. Circadian Clock in Muscle Disease Etiology and Therapeutic Potential for Duchenne Muscular Dystrophy. Int J Mol Sci 2024; 25:4767. [PMID: 38731986 PMCID: PMC11083552 DOI: 10.3390/ijms25094767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/20/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Circadian clock and clock-controlled output pathways exert temporal control in diverse aspects of skeletal muscle physiology, including the maintenance of muscle mass, structure, function, and metabolism. They have emerged as significant players in understanding muscle disease etiology and potential therapeutic avenues, particularly in Duchenne muscular dystrophy (DMD). This review examines the intricate interplay between circadian rhythms and muscle physiology, highlighting how disruptions of circadian regulation may contribute to muscle pathophysiology and the specific mechanisms linking circadian clock dysregulation with DMD. Moreover, we discuss recent advancements in chronobiological research that have shed light on the circadian control of muscle function and its relevance to DMD. Understanding clock output pathways involved in muscle mass and function offers novel insights into the pathogenesis of DMD and unveils promising avenues for therapeutic interventions. We further explore potential chronotherapeutic strategies targeting the circadian clock to ameliorate muscle degeneration which may inform drug development efforts for muscular dystrophy.
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Affiliation(s)
| | - Ke Ma
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA;
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Gilad Y, Shimon O, Han SJ, Lonard DM, O’Malley BW. Steroid receptor coactivators in Treg and Th17 cell biology and function. Front Immunol 2024; 15:1389041. [PMID: 38698860 PMCID: PMC11063348 DOI: 10.3389/fimmu.2024.1389041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 03/29/2024] [Indexed: 05/05/2024] Open
Abstract
Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in governing numerous aspects of CD4+ T cell biology. Here we review findings that establish the SRCs as essential regulators of regulatory T cells (Tregs) and T helper 17 (Th17) cells, with a focus on their crucial roles in Treg immunity in cancer and Treg-Th17 cell phenotypic plasticity.
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Affiliation(s)
- Yosi Gilad
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- CoRegen, Inc., Baylor College of Medicine, Houston, TX, United States
| | - Ortal Shimon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- CoRegen, Inc., Baylor College of Medicine, Houston, TX, United States
| | - Sang Jun Han
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- CoRegen, Inc., Baylor College of Medicine, Houston, TX, United States
- Nuclear Receptor, Transcription and Chromatin Biology Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
| | - David M. Lonard
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- CoRegen, Inc., Baylor College of Medicine, Houston, TX, United States
- Nuclear Receptor, Transcription and Chromatin Biology Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
| | - Bert W. O’Malley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- CoRegen, Inc., Baylor College of Medicine, Houston, TX, United States
- Nuclear Receptor, Transcription and Chromatin Biology Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
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45
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Alvarez F, Liu Z, Bay A, Piccirillo CA. Deciphering the developmental trajectory of tissue-resident Foxp3 + regulatory T cells. Front Immunol 2024; 15:1331846. [PMID: 38605970 PMCID: PMC11007185 DOI: 10.3389/fimmu.2024.1331846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 02/14/2024] [Indexed: 04/13/2024] Open
Abstract
Foxp3+ TREG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, TREG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading TREG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires TREG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident TREG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident TREG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.
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Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Zhiyang Liu
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Alexandre Bay
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Ciriaco A. Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
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Liu Q, Wang J, Sun H, Zhang Z, Wang H, Ma S, Zhang C, Wang Q, Cai G, Zheng J, Nie Y, Liu P, Wang J. Targeting RORγ inhibits the growth and metastasis of hepatocellular carcinoma. Mol Ther 2024; 32:749-765. [PMID: 38310356 PMCID: PMC10928303 DOI: 10.1016/j.ymthe.2024.01.032] [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: 07/08/2023] [Revised: 11/04/2023] [Accepted: 01/30/2024] [Indexed: 02/05/2024] Open
Abstract
Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.
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Affiliation(s)
- Qianqian Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Junhua Wang
- Clinical Research Institute, The First People's Hospital of Foshan, Foshan 528000, China
| | - Huizi Sun
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Zhenhua Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Hong Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Shuai Ma
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
| | - Chenxi Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Qianqian Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Guodi Cai
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Jianwei Zheng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Yichu Nie
- Clinical Research Institute, The First People's Hospital of Foshan, Foshan 528000, China.
| | - Peiqing Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China; National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China.
| | - Junjian Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China; National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China.
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Zhang T, Huo H, Zhang Y, Tao J, Yang J, Rong X, Yang Y. Th17 cells: A new target in kidney disease research. Int Rev Immunol 2024; 43:263-279. [PMID: 38439681 DOI: 10.1080/08830185.2024.2321901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/26/2023] [Accepted: 01/09/2024] [Indexed: 03/06/2024]
Abstract
Type 17 T helper (Th17) cells, which are a subtype of CD4+ T helper cells, secrete pro-inflammatory cytokines such as IL-17A, IL-17F, IL-21, IL-22, and GM-CSF, which play crucial roles in immune defence and protection against fungal and extracellular pathogen invasion. However, dysfunction of Th17 cell immunity mediates inflammatory responses and exacerbates tissue damage. This pathological process initiated by Th17 cells is common in kidney diseases associated with renal injury, such as glomerulonephritis, lupus nephritis, IgA nephropathy, hypertensive nephropathy, diabetic kidney disease and acute kidney injury. Therefore, targeting Th17 cells to treat kidney diseases has been a hot topic in recent years. This article reviews the mechanisms of Th17 cell-mediated inflammation and autoimmune responses in kidney diseases and discusses the related clinical drugs that modulate Th17 cell fate in kidney disease treatment.
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Affiliation(s)
- Tao Zhang
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Ministry of Education, Guangzhou, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Hongyan Huo
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Ministry of Education, Guangzhou, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yinghui Zhang
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Ministry of Education, Guangzhou, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jie Tao
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Ministry of Education, Guangzhou, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Junzheng Yang
- Guangdong Nephrotic Drug Engineering Technology Research Center, The R&D Center of Drug for Renal Diseases, Consun Pharmaceutical Group, Guangzhou, Guangdong, China
| | - Xianglu Rong
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Ministry of Education, Guangzhou, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yiqi Yang
- Key Laboratory of Glucolipid Metabolic Disorder, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Ministry of Education, Guangzhou, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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48
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Wen Y, Wang H, Tian D, Wang G. TH17 cell: a double-edged sword in the development of inflammatory bowel disease. Therap Adv Gastroenterol 2024; 17:17562848241230896. [PMID: 38390028 PMCID: PMC10883129 DOI: 10.1177/17562848241230896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the gastrointestinal tract, and its pathogenesis has not been fully understood. Extensive dysregulation of the intestinal mucosal immune system is critical in the development and progression of IBD. T helper (Th) 17 cells have the characteristics of plasticity. They can transdifferentiate into subpopulations with different functions in response to different factors in the surrounding environment, thus taking on different roles in regulating the intestinal immune responses. In this review, we will focus on the plasticity of Th17 cells as well as the function of Th17 cells and their related cytokines in IBD. We will summarize their pathogenic and protective roles in IBD under different conditions, respectively, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatment.
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Affiliation(s)
- Yue Wen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ge Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
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Mok H, Ostendorf E, Ganninger A, Adler AJ, Hazan G, Haspel JA. Circadian immunity from bench to bedside: a practical guide. J Clin Invest 2024; 134:e175706. [PMID: 38299593 PMCID: PMC10836804 DOI: 10.1172/jci175706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2024] Open
Abstract
The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We then consider the evidence linking circadian rhythms to vaccination, an important clinical realization of immune function. Finally, we discuss practical steps to translate circadian immunity to the patient's bedside.
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Affiliation(s)
- Huram Mok
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Elaine Ostendorf
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Alex Ganninger
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Avi J. Adler
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Guy Hazan
- Department of Pediatrics, Soroka University Medical Center, Beer-Sheva, Israel
- Research and Innovation Center, Saban Children’s Hospital, Beer-Sheva, Israel
| | - Jeffrey A. Haspel
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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Lantz BJ, Moriwaki M, Oyebamiji OM, Guo Y, Gonzalez Bosc L. Chronic hypoxia disrupts T regulatory cell phenotype contributing to the emergence of exTreg-T H17 cells. Front Physiol 2024; 14:1304732. [PMID: 38347920 PMCID: PMC10859758 DOI: 10.3389/fphys.2023.1304732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 12/28/2023] [Indexed: 02/15/2024] Open
Abstract
The imbalance between pro-inflammatory T helper 17 (TH17) cells and anti-inflammatory regulatory T cells (Tregs) has been implicated in multiple inflammatory and autoimmune conditions, but the effects of chronic hypoxia (CH) on this balance have yet to be explored. CH-exposed mice have an increased prevalence of TH17 cells in the lungs with no change in Tregs. This imbalance is significant because it precedes the development of pulmonary hypertension (PH), and TH17 cells are a major contributor to CH-induced PH. While Tregs have been shown to attenuate or prevent the development of certain types of PH through activation and adoptive transfer experiments, why Tregs remain unable to prevent disease progression naturally, specifically in CH-induced PH, remains unclear. Our study aimed to test the hypothesis that increased TH17 cells observed following CH are caused by decreased circulating levels of Tregs and switching of Tregs to exTreg-TH17 cells, following CH. We compared gene expression profiles of Tregs from normoxia or 5-day CH splenocytes harvested from Foxp3tm9(EGFP/cre/ERT2)Ayr/J x Ai14-tdTomato mice, which allowed for Treg lineage tracing through the presence or absence of EGFP and/or tdTomato expression. We found Tregs in CH exposed mice contained gene profiles consistent with decreased suppressive ability. We determined cell prevalence and expression of CD25 and OX40, proteins critical for Treg function, in splenocytes from Foxp3tm9(EGFP/cre/ERT2)Ayr/J x Ai14-tdTomato mice under the same conditions. We found TH17 cells to be increased and Tregs to be decreased, following CH, with protein expression of CD25 and OX40 in Tregs matching the gene expression data. Finally, using the lineage tracing ability of this mouse model, we were able to demonstrate the emergence of exTreg-TH17 cells, following CH. These findings suggest that CH causes a decrease in Treg suppressive capacity, and exTregs respond to CH by transitioning to TH17 cells, both of which tilt the Treg-TH17 cell balance toward TH17 cells, creating a pro-inflammatory environment.
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Affiliation(s)
- Benjamin J. Lantz
- Gonzalez Bosc Laboratory, Health Sciences Center, Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, United States
| | - Mika Moriwaki
- Gonzalez Bosc Laboratory, Health Sciences Center, Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, United States
| | - Olufunmilola M. Oyebamiji
- Division of Molecular Medicine, Health Sciences Center, Internal Medicine, University of New Mexico, Albuquerque, NM, United States
| | - Yan Guo
- Department of Public Health and Sciences, University of Miami, Miami, FL, United States
| | - Laura Gonzalez Bosc
- Gonzalez Bosc Laboratory, Health Sciences Center, Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, United States
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