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Updated: Dec 10, 2025
Evaluation of T Follicular Helper Cells and Germinal Center Response During Influenza A Virus Infection in Mice
Published on: June 27, 2020
Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice
Junji Chida1, Hideyuki Hara1, Keiji Uchiyama1
1Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, Tokushima, Japan.
Abstract:
The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection.
Insights
Stimulating the cellular prion protein (PrPC) with antibodies protected mice against lethal influenza A virus (IAV) infection by promoting anti-inflammatory M2 macrophages. This suggests PrPC is a potential therapeutic target for influenza.
Area of Science:
- Immunology
- Virology
- Cellular Biology
Background:
- The cellular prion protein (PrPC) is a membrane glycoprotein with largely unknown functions, especially in non-neuronal cells.
- PrPC's conversion to an amyloidogenic isoform is central to prion diseases.
- Understanding PrPC's role in non-neuronal cells could reveal novel therapeutic targets.
Purpose of the Study:
- To investigate the function of PrPC in non-neuronal cells, specifically its role in immune response to influenza A virus (IAV) infection.
- To determine if stimulating PrPC can confer protection against lethal influenza infection.
- To elucidate the mechanism by which PrPC stimulation affects macrophage polarization and immune response.
Main Methods:
- Mice were infected with influenza A viruses (IAVs) and treated with anti-PrP monoclonal antibodies (mAbs).
- Lung tissues were analyzed for macrophage accumulation and activation of Src family kinases (SFKs).
- Peritoneal macrophages were stimulated with anti-PrP mAbs in vitro and in vivo to assess M2 polarization via SFK activation.
Main Results:
- Anti-PrP mAb treatment protected mice from lethal IAV infection, correlating with increased anti-inflammatory M2 macrophages in lungs.
- Activation of SFKs was observed in M2 macrophages in IAV-infected lungs after anti-PrP mAb treatment.
- Inhibition of SFKs with dasatinib blocked M2 macrophage accumulation and abolished the protective effect of anti-PrP mAbs.
Conclusions:
- PrPC stimulation activates SFKs in macrophages, inducing polarization towards an anti-inflammatory M2 phenotype.
- This PrPC-mediated M2 polarization confers protective activity against lethal influenza A virus infection in mice.
- PrPC represents a novel therapeutic target for managing influenza A virus infections.
