Requirement of Gαi1 and Gαi3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response.
Requirement of Gαi1 and Gαi3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response.
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白介素 4 诱导的信号传导、巨噬细胞 M2 极化和过敏性哮喘反应中 G α i1 和 G α i3 的需要
作者：
Bai JY;Li Y;Xue GH;Li KR;Zheng YF;Zhang ZQ;Jiang Q;Liu YY;Zhou XZ;Cao C
IL-4诱导巨噬细胞中的Akt活化，这是完全M2（交替）极化所需的。我们使用多种遗传学方法研究了Gαi1和Gαi3在M2极化中的作用。方法和结果：在MEFs和原代鼠BMDM中，Gαi1/3 shRNA、敲除或显性失活突变减弱了IL-4诱导的IL 4 R α内吞作用、Gab 1募集以及Akt激活，而STAT 6信号不受影响。在IL-4刺激后，Gαi1/3蛋白与IL-4 R α的胞内结构域和APPL 1接头结合，介导BMDM中IL-4 R α内体运输和Gab 1-Akt活化。相比之下，用shRNA或敲除Gαi1/3的基因沉默导致BMDM对IL-4诱导的M2极化不敏感。相反，Gαi1/3过表达的BMDM在IL-4刺激下表现出优先的M2反应。在原代人巨噬细胞中，Gαi1/3沉默抑制IL-4诱导的Akt活化和Th 2基因表达，但Gαi1/3过表达增强。在Gαi1/3双敲除（DKO）小鼠中，注射IL-4复合物或几丁质可有效抑制M2极化。此外，在哮喘小鼠模型中，卵清蛋白诱导的气道炎症和高反应性在Gα i 1/3 DKO小鼠中大大受损。结论：这些发现强调了Gαi1/3在调节IL-4诱导的信号传导、巨噬细胞M2极化和过敏性哮喘反应中的新的和重要的作用。
IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of Gαi1 and Gαi3 in M2 polarization using multiple genetic methods. Methods and Results: In MEFs and primary murine BMDMs, Gαi1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4Rα endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Following IL-4 stimulation, Gαi1/3 proteins associated with the intracellular domain of IL-4Rα and the APPL1 adaptor, to mediate IL-4Rα endosomal traffic and Gab1-Akt activation in BMDMs. In contrast, gene silencing of Gαi1/3 with shRNA or knockout resulted in BMDMs that were refractory to IL-4-induced M2 polarization. Conversely, Gαi1/3-overexpressed BMDMs displayed preferred M2 response with IL-4 stimulation. In primary human macrophages IL-4-induced Akt activation and Th2 genes expression were inhibited with Gαi1/3 silencing, but augmented with Gαi1/3 overexpression. In Gαi1/3 double knockout (DKO) mice, M2 polarization, by injection of IL-4 complex or chitin, was potently inhibited. Moreover, in a murine model of asthma, ovalbumin-induced airway inflammation and hyperresponsiveness were largely impaired in Gαi1/3 DKO mice. Conclusion: These findings highlight novel and essential roles for Gαi1/3 in regulating IL-4-induced signaling, macrophage M2 polarization and allergic asthma response.
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影响因子：
3.9
作者：
Diggins NL;Webb DJ
通讯作者：
Webb DJ
DOI：
10.1016/j.bbrc.2015.01.160
发表时间：
2015-03-13
影响因子：
3.1
作者：
Du Shi-lin;Xue Yuan;Tong Chao-yang
通讯作者：
Tong Chao-yang
影响因子：
7.2
作者：
Gupta, Sahil;Jain, Arpit;Namgaladze, Dmitry
通讯作者：
Namgaladze, Dmitry
影响因子：
29
作者：
Bouhlel, M. Amine;Derudas, Bruno;Chinetti-Gbaguidi, Giulia
通讯作者：
Chinetti-Gbaguidi, Giulia
影响因子：
7.7
作者：
Gschweitl M;Ulbricht A;Barnes CA;Enchev RI;Stoffel-Studer I;Meyer-Schaller N;Huotari J;Yamauchi Y;Greber UF;Helenius A;Peter M
通讯作者：
Peter M