2. Academic Validation
  3. GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis

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.
Qian Mo 1 2 3,  Mansoor Bolideei 1,  Shan-Jie Rong 1,  Jia-Hui Luo 1,  Chun-Liang Yang 1,  Wan-Ying Lu 1,  Qi-Jie Chen 1,  Jia-Wei Zhao 1,  Fa-Xi Wang 1,  Ting Wang 1,  Yang Li 1,  Xi Luo 1,  Shu Zhang 1,  Fei Xiong 1,  Qi-Lin Yu 1,  Zi-Yun Zhang 2,  Shi-Wei Liu 4,  Fei Sun 1,  Ling-Li Dong 2,  Cong-Yi Wang 1 4
Affiliations

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.
PMID: 38947509 DOI: 10.1016/j.isci.2024.109798
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.

Figures
Products