國家衛生研究院 NHRI:Item 3990099045/15614
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    题名: Excess salt intake activates IL-21-dominant autoimmune diabetogenesis via a saltregulated ste20-related proline/alanine-rich kinase in CD4 T cells
    作者: Ciou, JJ;Chien, MW;Hsu, CY;Liu, YW;Dong, JL;Tsai, SY;Yang, SS;Lin, SH;Yen, BL;Fu, SH;Sytwu, HK
    贡献者: National Institute of Infectious Diseases and Vaccinology;Institute of Molecular and Genomic Medicine;Institute of Cellular and Systems Medicine
    摘要: 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.
    日期: 2024-04
    關聯: Diabetes. 2024 Apr;73(4):592-603.
    Link to: http://dx.doi.org/10.2337/db23-0599
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0012-1797&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001297097700002
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85188705622
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