SHP2 deficiency promotes Staphylococcus aureus pneumonia following influenza infection
SHP2 deficiency promotes Staphylococcus aureus pneumonia following influenza infection
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SHP2缺陷促进流感感染后金黄色葡萄球菌肺炎
DOI：
10.1111/cpr.12721
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发表时间：
2019-11-29
影响因子：
8.5
通讯作者：
Xu, Feng
中科院分区：
文献类型：
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作者：
Ouyang, Wei;Liu, Chao;Xu, Feng
目的流感感染后继发性细菌性肺炎较为常见。然而，其潜在的分子机制仍不清楚。材料与方法采用条件性Shp2基因敲除小鼠(LysM(Cre/+)：Shp2(FLOX/FLOX))建立S金黄色葡萄球菌流感后肺炎小鼠模型。检测SHP2缺失小鼠和对照小鼠(Shp2(FLOX/FLOX))的存活率、细菌清除率、肺组织学、巨噬细胞表型以及I型干扰素和趋化因子的表达。我们注入额外的KC和MIP-2来检测LysM(Cre/+)：Shp2(FLOX/FLOX)小鼠的抗菌免疫反应的重建。进一步检测SHP2对MAPKs(JNK、p38和ERK1/2)、核因子-kappaBp65和IRF3等信号分子的影响。结果LysM(Cre/+)：Shp2(FLOX/FLOX)组小鼠在S金黄色葡萄球菌肺炎模型中表现出抗菌免疫功能低下和高死亡率。抗菌能力的减弱与I型干扰素的诱导和化学诱导剂KC和MIP-2的抑制有关，KC和MIP-2减少了中性粒细胞在继发性细菌入侵时向肺内的渗透。此外，Shp2基因敲除小鼠表现出对交替激活的巨噬细胞(M2表型)的极化增强。进一步的体外分析一致地证明，SHP2缺陷的巨噬细胞偏向于M2表型，并且具有降低的抗菌能力。此外，SHP2通过干扰巨噬细胞中的核因子-kappaB和IRF3信号来调节继发性细菌感染的炎症反应。结论流感后S金黄色葡萄球菌肺炎中SHP2的表达增强了宿主的免疫应答，促进了细菌的清除。
Objectives Secondary bacterial pneumonia is common following influenza infection. However, it remains unclear about the underlying molecular mechanisms. Materials and methods We established a mouse model of post-influenza S aureus pneumonia using conditional Shp2 knockout mice (LysM(Cre/+):Shp2(flox/flox)). The survival, bacterial clearance, pulmonary histology, phenotype of macrophages, and expression of type I interferons and chemokines were assessed between SHP2 deletion and control mice (Shp2(flox/flox)). We infused additional KC and MIP-2 to examine the reconstitution of antibacterial immune response in LysM(Cre/+):Shp2(flox/flox) mice. The effect of SHP2 on signal molecules including MAPKs (JNK, p38 and Erk1/2), NF-kappa B p65 and IRF3 was further detected. Results LysM(Cre/+):Shp2(flox/flox) mice displayed impaired antibacterial immunity and high mortality compared with control mice in post-influenza S aureus pneumonia. The attenuated antibacterial ability was associated with the induction of type I interferon and suppression of chemo-attractants KC and MIP-2, which reduced the infiltration of neutrophils into the lung upon secondary bacterial invasion. In additional, Shp2 knockout mice displayed enhanced polarization to alternatively activated macrophages (M2 phenotype). Further in vitro analyses consistently demonstrated that SHP2-deficient macrophages were skewed towards an M2 phenotype and had a decreased antibacterial capacity. Moreover, SHP2 modulated the inflammatory response to secondary bacterial infection via interfering with NF-kappa B and IRF3 signalling in macrophages. Conclusions Our findings reveal that the SHP2 expression enhances the host immune response and prompts bacterial clearance in post-influenza S aureus pneumonia.