Shp2 Deficiency Impairs the Inflammatory Response AgainstHaemophilus influenzaeby 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.

Development and Characterization of an Endotoxemia Model in Zebra Fish

“…We also determined the effect of a previously published protein tyrosine phosphatase inhibitor, the Shp2 (Ptpn11a) inhibitor 11a-1 ( 28 ), in our endotoxemia model. Shp2 is required for pro-inflammatory cytokine production, ROS production, and macrophage M1 polarization ( 72 , 73 ), but has not been tested as a drug target in endotoxemia. As expected, significant decreases in the NF-ĸB levels (Figures 7 A,B) and mortality (Figure 7 C) in LPS-injected larvae treated with either the Shp2 inhibitor or corticosteroid were noted.…”

Absence of DCIR1 reduces the mortality rate of endotoxemic hepatitis in mice

“…Indeed, in the case of the GalN and LPS hepatitis model, NF‐κB activity appears to be controlled by both the TLR4 and DCIR1‐SHP‐2 pathways. Lack of SHP‐2 decreases p65‐NF‐κB signaling in Mϕ . Therefore, NF‐κB signaling though DCIR1‐SHP‐2 pathway may decrease in Dcir1 −/− mice, leading to low expression of CXCL1/KC in hepatitis.…”

Engineered proteins with sensing and activating modules for automated reprogramming of cellular functions

“…As our i SNAPs can rewire the anti-phagocytic CD47-SIRPα signaling toward pro-phagocytic actions, CD47 on tumor cells actually promotes phagocytosis of engineered macrophages. This rewiring of CD47 signaling to Shp2 or Syk activation can also lead to the macrophage conversion toward active M1 polarization via NF-κB activation 30 . Antibody-mediated phagocytosis of cancer cells by macrophages could further initiate an antitumor T-cell immune response via antigen-presenting function of macrophages 31 .…”