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

doi:10.1016/j.biopha.2023.115886

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

Biomed Pharmacother. 2023 Dec 31:169:115886. doi: 10.1016/j.biopha.2023.115886. Epub 2023 Nov 22.

Authors

Ye Chen¹, Rongzhen Liang², Xiaoyi Shi³, Rong Shen⁴, Liu Liu⁵, Yan Liu³, Youqiu Xue³, Xinghua Guo³, Junlong Dang³, Donglan Zeng³, Feng Huang³, Jianbo Sun⁶, Jingwen Zhang⁷, Julie Wang², Nancy Olsen⁸, Avery August⁹, Weishan Huang¹⁰, Yunfeng Pan¹¹, Song Guo Zheng¹²

Affiliations

¹ 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.
² 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.
³ Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China.
⁴ Department of Geriatrics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China.
⁵ Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, PR China.
⁶ The first Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
⁷ Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
⁸ Division of Rheumatology, Department of Medicine at the Penn State University Hershey Medical Center, Hershey, PA, USA.
⁹ Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
¹⁰ 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.
¹¹ Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China. Electronic address: panyunf@mail.sysu.edu.cn.
¹² 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. Electronic address: Song.Zheng@shsmu.edu.cn.

PMID: 37992572
DOI: 10.1016/j.biopha.2023.115886

Abstract

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.

Keywords: Collagen-Induced Arthritis; Dihydroartemisinin; Foxo1; ITK; MTOR; RA; Tfh; Treg/Th17.

MeSH terms

Animals
Arthritis, Experimental* / drug therapy
Arthritis, Rheumatoid* / drug therapy
Autoimmune Diseases*
Cell Differentiation
Humans
T-Lymphocytes, Regulatory
Th17 Cells

Substances

emt protein-tyrosine kinase