PDF(Pubmed)
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.
摘要：
高盐（HS）消耗是通过干扰免疫稳态的多种自身免疫性疾病的危险因素。然而，HS加重类风湿性关节炎(RA)发病机制的确切机制尚不明确.在这里，我们发现，在HS暴露后PDPK1和SGK1的磷酸化增强减弱了FoxO1的表达，从而增强了CD4T细胞的糖酵解能力，导致Th17增强但Treg程序受损。GSK2334470(GSK),PDPK1/SGK1双重抑制剂，有效减轻HS诱导的糖酵解能力增强和IL-17A的过度产生。因此,在胶原诱导的关节炎（CIA）模型中，GSK的给药明显减轻了HS加重的RA进展。总的来说，我们的数据表明，HS消费通过PDPK1-SGK1-FoxO1信号传导破坏Th17/Treg稳态，而GSK可能是临床上对抗RA进展的可行药物。
