Shp2 Deficiency Impairs the Inflammatory Response Against Haemophilus influenzae by Regulating Macrophage Polarization
Shp2 Deficiency Impairs the Inflammatory Response Against Haemophilus influenzae by Regulating Macrophage Polarization
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Shp2 缺陷通过调节巨噬细胞极化损害针对流感嗜血杆菌的炎症反应
DOI：
10.1093/infdis/jiw205
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发表时间：
2016
影响因子：
6.4
通讯作者：
Xu F
中科院分区：
文献类型：
--
作者：
Zhao L;Xia J;Li T;Zhou H;Ouyang W;Hong Z;Ke Y;Qian J;Xu F
巨噬细胞可以极化和分化，以调节非分型流感嗜血杆菌（NTHi）肺部感染期间炎症的发生、发展和停止。然而，驱动巨噬细胞表型分化的潜在分子机制在很大程度上尚不清楚。我们的研究调查了Shp2（一种Src同源2结构域的磷酸酶）在肺部炎症和细菌清除中的调节作用。NTHi刺激后Shp2水平升高。在小鼠中选择性抑制Shp2通过使巨噬细胞偏向于选择性激活的巨噬细胞（M2）极化导致炎症反应减弱。肺部NTHi感染后，与野生型对照相比，单核/巨噬细胞中编码Shp2基因缺失的Shp2 - / -小鼠表现出炎症反应受损和抗菌能力下降。体外数据表明，Shp2通过激活p65 -核因子-κB信号通路调节活化的巨噬细胞（M1）基因表达，而不依赖于p38和细胞外调节的激酶-丝裂原活化蛋白激酶信号通路。综上所述，我们的研究表明，Shp2在协调巨噬细胞功能和调节宿主抗肺部细菌感染的先天免疫中是必需的。
Macrophages can polarize and differentiate to regulate initiation, development, and cessation of inflammation during pulmonary infection with nontypeableHaemophilus influenzae(NTHi). However, the underlying molecular mechanisms driving macrophage phenotypic differentiation are largely unclear. Our study investigated the role of Shp2, a Src homology 2 domain–containing phosphatase, in the regulation of pulmonary inflammation and bacterial clearance. Shp2 levels were increased upon NTHi stimulation. Selective inhibition of Shp2 in mice led to an attenuated inflammatory response by skewing macrophages toward alternatively activated macrophage (M2) polarization. Upon pulmonary NTHi infection,Shp2−/−mice, in which the gene encoding Shp2 in monocytes/macrophages was deleted, showed an impaired inflammatory response and decreased antibacterial ability, compared with wild-type controls. In vitro data demonstrated that Shp2 regulated activated macrophage (M1) gene expression via activation of p65–nuclear factor-κB signaling, independent of p38 and extracellular regulated kinase–mitogen-activated proteins kinase signaling pathways. Taken together, our study indicates that Shp2 is required to orchestrate macrophage function and regulate host innate immunity against pulmonary bacterial infection.