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Targeting kinase ITK treats autoimmune arthritis via orchestrating T cell differentiation and function

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机构: [1]Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China [2]Department of Geriatrics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China [3]Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, PR China [4]The first Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China [5]Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China [6]Division of Rheumatology, Department of Medicine at the Penn State University Hershey Medical Center, Hershey, PA, USA [7]Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA [8]Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA [9]Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201600, China
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关键词: ITK Collagen-Induced Arthritis RA Treg/Th17 Tfh Foxo1 MTOR Dihydroartemisinin

摘要:
IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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出版当年[2022]版:
大类 | 2 区 医学
小类 | 1 区 药学 2 区 医学:研究与实验
最新[2025]版:
大类 | 2 区 医学
小类 | 2 区 医学:研究与实验 2 区 药学
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出版当年[2021]版:
Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q1 PHARMACOLOGY & PHARMACY
最新[2023]版:
Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q1 PHARMACOLOGY & PHARMACY

影响因子: 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

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第一作者机构: [1]Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China [9]Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201600, China
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通讯机构: [1]Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China [9]Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201600, China [*1]Guangzhou 510630, China. [*2]Shanghai 201600, China
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