title: Shp2 Deficiency Impairs the Inflammatory Response Against Haemophilus influenzae by Regulating Macrophage Polarization.
abstract: Macrophages can polarize and differentiate to regulate initiation, development, and cessation of inflammation during pulmonary infection with nontypeable Haemophilus 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.
authors.affiliation: Department of Infectious Diseases.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Oncology Radiation, Second Affiliated Hospital.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Xia
authors.affiliation: Clinical Medical Class 1209.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases Experimental Medical Class 1102, Chu Kochen Honor College, Zhejiang University.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Infectious Diseases.
authors.forename: Wei
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Department of Infectious Diseases College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: Zhuping
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Pathology and Pathophysiology Program in Molecular Cell Biology, Zhejiang University School of Medicine.
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Infectious Diseases.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D006192:Haemophilus Infections / Q000276:immunology* / Q000473:pathology*; D006193:Haemophilus influenzae / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: Haemophilus influenzae; inflammatory response; macrophage polarization; protein-tyrosine phosphatase Shp2