Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
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DOI：
10.1038/nature11868
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发表时间：
2013-04-25
期刊：
影响因子：
64.8
通讯作者：
Hafler, David A.
中科院分区：
文献类型：
--
作者：
Kleinewietfeld, Markus;Manzel, Arndt;Titze, Jens;Kvakan, Heda;Yosef, Nir;Linker, Ralf A.;Muller, Dominik N.;Hafler, David A.
在过去的半个世纪中，自身免疫性疾病的发病率显著增加。虽然这类疾病的潜在遗传基础最近已被阐明，主要涉及免疫反应基因，但环境因素的变化必须最终推动这种增加。新鉴定的产生白细胞介素（IL）-17的CD 4+辅助性T细胞（Th 17细胞）群体在自身免疫性疾病中起关键作用。致病性IL-23依赖性Th 17细胞已被证明对于多发性硬化症（MS）动物模型实验性自身免疫性脑脊髓炎（EAE）的发生至关重要，而与MS相关的遗传风险因素与IL-23/Th 17途径相关。然而，关于直接影响Th 17细胞的环境因素知之甚少。在这里，我们表明，增加盐（氯化钠; NaCl）浓度发现局部生理条件下，在体内显着提高诱导小鼠和人的Th 17细胞。高盐条件激活p38/MAPK途径，涉及张力响应增强子结合蛋白（TonEBP/NFAT 5）和血清/糖皮质激素调节激酶1（SGK 1）在奎宁诱导的Th 17极化。基因沉默或p38/MAPK、NFAT 5或SGK 1的化学抑制消除了高盐诱导的Th 17细胞发育。在高盐条件下产生的Th 17细胞表现出高致病性和稳定的表型，其特征在于促炎细胞因子GM-CSF、TNFα和IL-2的上调。此外，用高盐饮食喂养的小鼠发展出更严重形式的EAE，与增强的中枢神经系统浸润和外周诱导的抗原特异性Th 17细胞一致。因此，增加饮食中的盐摄入量可能是通过诱导致病性Th 17细胞而发展自身免疫性疾病的环境风险因素。
There has been a marked increase in the incidence of autoimmune diseases in the last half-century. While the underlying genetic basis of this class of diseases has recently been elucidated implicating predominantly immune response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17 producing CD4+ helper T cells (Th17 cells) plays a pivotal role in autoimmune diseases. Pathogenic IL-23 dependent Th17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), and genetic risk factors associated with MS are related to the IL23/Th17 pathway. However, little is known regarding the environmental factors that directly influence Th17 cells. Here we show that increased salt (sodium chloride; NaCl) concentrations found locally under physiological conditions in vivo dramatically boost the induction of murine and human Th17 cells. High-salt conditions activate the p38/MAPK pathway involving the tonicity-responsive enhancer binding protein (TonEBP/NFAT5) and the serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced Th17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt induced Th17 cell development. The Th17 cells generated under high-salt display a highly pathogenic and stable phenotype characterized by the up-regulation of the pro-inflammatory cytokines GM-CSF, TNFα and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen specific Th17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic Th17 cells.
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影响因子：
11.2
作者：
Sherk AB;Frigo DE;Schnackenberg CG;Bray JD;Laping NJ;Trizna W;Hammond M;Patterson JR;Thompson SK;Kazmin D;Norris JD;McDonnell DP
通讯作者：
McDonnell DP
影响因子：
32.4
作者：
O'Connell RM;Kahn D;Gibson WS;Round JL;Scholz RL;Chaudhuri AA;Kahn ME;Rao DS;Baltimore D
通讯作者：
Baltimore D
影响因子：
14.9
作者：
Ortells MC;Morancho B;Drews-Elger K;Viollet B;Laderoute KR;López-Rodríguez C;Aramburu J
通讯作者：
Aramburu J
影响因子：
30.5
作者：
Reboldi, Andrea;Coisne, Caroline;Sallusto, Federica
通讯作者：
Sallusto, Federica
DOI：
10.1073/pnas.92.26.12230
发表时间：
1995-12-19
影响因子：
11.1
作者：
Shapiro, L;Dinarello, CA
通讯作者：
Dinarello, CA