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PLoS Pathog . Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice

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  • PLoS Pathog . Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice


    PLoS Pathog


    . 2020 Aug 26;16(8):e1008823.
    doi: 10.1371/journal.ppat.1008823. Online ahead of print.
    Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice


    Junji Chida 1 , Hideyuki Hara 1 , Keiji Uchiyama 1 , Etsuhisa Takahashi 2 , Hironori Miyata 3 , Hidetaka Kosako 4 , Yukiko Tomioka 5 , Toshihiro Ito 6 , Hiroyuki Horiuchi 7 , Haruo Matsuda 8 , Hiroshi Kido 2 , Suehiro Sakaguchi 1



    AffiliationsFree article

    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.


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