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Published on: August 2, 2021
Shp2 Deficiency Impairs the Inflammatory Response Against Haemophilus influenzae by Regulating Macrophage
Lifang Zhao1, Jingyan Xia2, Tiantian Li3
1Department of Infectious Diseases.
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.
Insights
Shp2 phosphatase regulates macrophage polarization during nontypeable Haemophilus influenzae (NTHi) lung infections. Inhibiting Shp2 promotes M2 macrophage polarization, reducing inflammation and improving bacterial clearance.
Area of Science:
- Immunology
- Molecular Biology
- Microbiology
Background:
- Macrophages play a critical role in regulating inflammation during pulmonary infections.
- The molecular mechanisms governing macrophage polarization in response to nontypeable Haemophilus influenzae (NTHi) are not fully understood.
Purpose of the Study:
- To investigate the role of Shp2 (Src homology 2 domain-containing phosphatase) in macrophage polarization and host defense against NTHi pulmonary infection.
Main Methods:
- Utilized mouse models of NTHi infection with selective Shp2 inhibition and genetic deletion (Shp2-/-).
- Assessed inflammatory responses, macrophage polarization (M1/M2 markers), and bacterial clearance.
- Performed in vitro studies to elucidate signaling pathways involved in Shp2-mediated macrophage regulation.
Main Results:
- Shp2 levels increased upon NTHi stimulation.
- Selective Shp2 inhibition in mice attenuated inflammation by promoting M2 macrophage polarization.
- Shp2-/- mice exhibited impaired inflammatory responses and reduced bacterial clearance.
- In vitro, Shp2 regulated M1 macrophage gene expression via p65-nuclear factor-κB signaling.
Conclusions:
- Shp2 is essential for orchestrating macrophage function during NTHi pulmonary infection.
- Shp2 plays a critical role in regulating host innate immunity against bacterial lung infections.
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