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

Ye Chen; Rongzhen Liang; Xiaoyi Shi; Rong Shen; Liu Liu; Yan Liu; Youqiu Xue; Xinghua Guo; Junlong Dang; Donglan Zeng; Feng Huang; Jianbo Sun; Jingwen Zhang; Julie Wang; Nancy Olsen; Avery August; Weishan Huang; Yunfeng Pan; Song Guo Zheng

Biomedicine & Pharmacotherapy (Dec 2023)

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

Ye Chen,
Rongzhen Liang,
Xiaoyi Shi,
Rong Shen,
Liu Liu,
Yan Liu,
Youqiu Xue,
Xinghua Guo,
Junlong Dang,
Donglan Zeng,
Feng Huang,
Jianbo Sun,
Jingwen Zhang,
Julie Wang,
Nancy Olsen,
Avery August,
Weishan Huang,
Yunfeng Pan,
Song Guo Zheng

Affiliations

Ye Chen: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China; 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
Rongzhen Liang: 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
Xiaoyi Shi: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Rong Shen: Department of Geriatrics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
Liu Liu: Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, PR China
Yan Liu: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Youqiu Xue: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Xinghua Guo: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Junlong Dang: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Donglan Zeng: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Feng Huang: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
Jianbo Sun: The first Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China
Jingwen Zhang: Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
Julie Wang: 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
Nancy Olsen: Division of Rheumatology, Department of Medicine at the Penn State University Hershey Medical Center, Hershey, PA, USA
Avery August: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Weishan Huang: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA; Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
Yunfeng Pan: Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China; Correspondence to: Guangzhou 510630, China.
Song Guo Zheng: 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; Correspondence to: Shanghai 201600, China.

Journal volume & issue: Vol. 169
p. 115886

Abstract

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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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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