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Excess Salt Intake Activates IL-21-dominant Autoimmune Diabetogenesis via A Salt-regulated Ste20-related Proline/alanine-rich Kinase in CD4 T Cells

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posted on 2024-01-18, 20:48 authored by Jing-Jie Ciou, Ming-Wei Chien, Chao-Yuan Hsu, Yu-Wen Liu, Jia-Ling Dong, Shin-Ying Tsai, Sung-Sen Yang, Shih-Hua Lin, B. Lin-Ju Yen, Shin-Huei Fu, Huey-Kang Sytwu

The fundamental mechanisms whereby a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Despite excess dietary salt intake acts as a risk factor for autoimmune diseases, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high-salt intake on autoimmune diabetes, non-obese diabetic (NOD) mice were fed with a high-salt diet (HSD) or a normal-salt diet from 6 to 12 weeks of age and monitored for diabetes development. Our results revealed that HSD accelerated diabetes progression with more severe insulitis in NOD mice in a CD4+ T cell-autonomous manner when compared to NSD group. Moreover, expression of IL-21 and SPAK in splenic CD4+ T cells from HSD-fed mice was significantly upregulated. Accordingly, we generated T cell-specific SPAK knockout (CKO) NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK CKO mice when compared to HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T cell pathogenicity. Finally, pharmacological inhibition of SPAK activity using a specific SPAK inhibitor (closantel) in NOD mice ameliorated diabetogenesis, further illuminating the potential of a SPAK-targeting immunotherapeutic approach for autoimmune diabetes. Here, we illustrate that a substantial association between salt sensitivity and the functional impact of SPAK on T cell pathogenicity serves as a central player linking high-salt intake influences to immune-pathophysiology of diabetogenesis in NOD mice.

Funding

This work was funded by Ministry of Science and Technology grants (MOST109-2320-B-400-018-MY3 and MOST110-2320-B-400-011-MY3), a National Science and Technology Council grant (NSTC112-2320-B-400-026-MY3), and Tri-Service General Hospital grants (TSGH-C02-112029 and VTA112-T-1-1).

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