Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.
Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.
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DOI：
10.1038/nature11984
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发表时间：
2013-04-25
期刊：
影响因子：
64.8
通讯作者：
Kuchroo, Vijay K.
中科院分区：
文献类型：
--
作者：
Wu, Chuan;Yosef, Nir;Thalhamer, Theresa;Zhu, Chen;Xiao, Sheng;Kishi, Yasuhiro;Regev, Aviv;Kuchroo, Vijay K.
Th17细胞是高度促炎细胞，对清除细胞外病原体和诱导多种自身免疫性疾病至关重要。IL-23通过增加IL-23受体（IL-23R）的表达，赋予Th17细胞致病效应功能，在稳定和强化Th17表型中发挥关键作用。然而，IL-23维持Th17应答并诱导致病效应功能的确切分子机制尚不清楚。在这里，我们使用发育中的Th17细胞的转录谱来构建其信号网络模型，并指定调节Th17发育的主要节点。我们发现血清糖皮质激素激酶-1 （SGK1）是一种丝氨酸-苏氨酸激酶，是IL-23信号传导下游的重要节点。SGK1对于调节IL-23R表达和通过使fox01失活来稳定Th17细胞表型至关重要，fox01是IL-23R表达的直接抑制因子。SGK1已被证明在其他细胞中控制Na+运输和盐（NaCl）稳态。本研究表明，盐浓度适度升高可诱导SGK1表达，促进IL-23R表达，增强Th17细胞的体外和体内分化，加速自身免疫的发展。SGK1的缺失以依赖il -23的方式取消了Na+介导的Th17分化。这些数据表明，SGK1在诱导致病性Th17细胞中起着关键作用，并为高盐饮食等环境因素触发Th17发育并促进组织炎症的机制提供了分子视角。
Th17 cells are highly proinflammatory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases. IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing Th17 cells with pathogenic effector functions. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used transcriptional profiling of developing Th17 cells to construct a model of their signaling network and nominate major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase, as an essential node downstream of IL-23 signaling. SGK1 is critical for regulating IL-23R expression and stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells. We here show that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation.
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影响因子：
5.3
作者：
Brunet, A;Park, J;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.8
作者：
Aggarwal, S;Ghilardi, N;Gurney, AL
通讯作者：
Gurney, AL
DOI：
10.1073/pnas.0504609102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Storey, JD;Xiao, WZ;Davis, RW
通讯作者：
Davis, RW
DOI：
10.1073/pnas.0903602106
发表时间：
2009-09-01
影响因子：
11.1
作者：
Stegbauer, Johannes;Lee, De-Hyung;Linker, Ralf A.
通讯作者：
Linker, Ralf A.
影响因子：
82.9
作者：
Salker, Madhuri S.;Christian, Mark;Brosens, Jan J.
通讯作者：
Brosens, Jan J.