The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation.
The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation.
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DOI：
10.1038/ncomms8216
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发表时间：
2015-06-02
影响因子：
16.6
通讯作者：
Montminy M
中科院分区：
文献类型：
--
作者：
Hernandez JB;Chang C;LeBlanc M;Grimm D;Le Lay J;Kaestner KH;Zheng Y;Montminy M
先天免疫细胞响应炎症信号激活后，分泌T细胞极化细胞因子，促进naïve CD4 T细胞分化为辅助性T细胞亚群。其中，Th17细胞在许多自身免疫性疾病的发展中起着突出的作用。虽然主要被认为是一种免疫抑制信号，但已发现cAMP介导巨噬细胞源性前列腺素E2 （PGE2）对Th17细胞的促炎作用。在这里，我们发现PGE2通过激活CREB共激活因子CRTC2来增强Th17细胞分化。在去磷酸化之后，CRTC2通过与CREB结合从而刺激细胞因子IL-17A和IL-17F的表达。CRTC2突变小鼠Th17细胞数量减少，它们可以免受实验性自身免疫性脑炎（多发性硬化症的一种模型）的侵害。我们的研究结果表明，CRTC2的小分子抑制剂可能为自身免疫性疾病患者提供治疗益处。
Following their activation in response to inflammatory signals, innate immune cells secrete T cell polarizing cytokines that promote the differentiation of naïve CD4 T cells into T helper (Th) cell subsets. Amongst these, Th17 cells play a prominent role in the development of a number of autoimmune diseases. Although regarded primarily as an immunosuppressant signal, cAMP has been found to mediate pro-inflammatory effects of macrophage-derived prostaglandin E2 (PGE2) on Th17 cells. Here we show that PGE2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2. Following its dephosphorylation, CRTC2 stimulates the expression of the cytokines IL-17A and IL-17F by binding to CREB over both promoters. CRTC2 mutant mice have decreased Th17 cell numbers, and they are protected from experimental autoimmune encephalitis, a model for multiple sclerosis. Our results suggest that small molecule inhibitors of CRTC2 may provide therapeutic benefit to individuals with autoimmune disease.