SHP2 deficiency promotes Staphylococcus aureus pneumonia following influenza infection. (29th November 2019)

• Record Type: Journal Article
• Authors: Ouyang, Wei; Liu, Chao; Pan, Ying; Han, Yu; Yang, Liping; Xia, Jingyan; Xu, Feng
• Is Part Of: Cell proliferation. Volume 53:Number 1(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-11-29
• Subjects: chemo‐attractants -- inflammatory response -- macrophage polarization -- protein‐tyrosine phosphatase SHP2 -- secondary bacterial pneumonia -- type I interferon; Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.12721
• Languages: English
• ISSNs: 0960-7722

Abstract

Abstract: 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‐κB 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‐κB 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.