GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis

Qian Mo; Mansoor Bolideei; Shan-Jie Rong; Jia-Hui Luo; Chun-Liang Yang; Wan-Ying Lu; Qi-Jie Chen; Jia-Wei Zhao; Fa-Xi Wang; Ting Wang; Yang Li; Xi Luo; Shu Zhang; Fei Xiong; Qi-Lin Yu; Zi-Yun Zhang; Shi-Wei Liu; Fei Sun; Ling-Li Dong; Cong-Yi Wang

doi:10.1016/j.isci.2024.109798

GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis

iScience. 2024 Apr 26;27(6):109798. doi: 10.1016/j.isci.2024.109798. eCollection 2024 Jun 21.

Authors

Qian Mo^{1

2

3}, Mansoor Bolideei¹, Shan-Jie Rong¹, Jia-Hui Luo¹, Chun-Liang Yang¹, Wan-Ying Lu¹, Qi-Jie Chen¹, Jia-Wei Zhao¹, Fa-Xi Wang¹, Ting Wang¹, Yang Li¹, Xi Luo¹, Shu Zhang¹, Fei Xiong¹, Qi-Lin Yu¹, Zi-Yun Zhang², Shi-Wei Liu⁴, Fei Sun¹, Ling-Li Dong², Cong-Yi Wang^{1

4}

Affiliations

¹ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
² Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
³ Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
⁴ Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China.

Abstract

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

Keywords: Biological sciences; Immunology; Natural sciences; Pharmacology; Physiology.