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The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model

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  • The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model

    FASEB J. 2019 Aug 9:fj201901265R. doi: 10.1096/fj.201901265R. [Epub ahead of print]
    The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model.

    Schloer S#1,2, Hübel N#1,2, Masemann D2,3, Pajonczyk D1,2, Brunotte L2,3, Ehrhardt C2,3,4, Brandenburg LO5,6, Ludwig S2,3, Gerke V1,2, Rescher U1,2.
    Author information

    1 Center for Molecular Biology of Inflammation, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany. 2 Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany. 3 Center for Molecular Biology of Inflammation, Institute of Virology, University of Muenster, Muenster, Germany. 4 Section for Experimental Virology, Institute of Medical Microbiology, Jena University Hospital, Jena, Germany. 5 Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany. 6 Institute of Anatomy, Rostock University Medical Center, Rostock, Germany. # Contributed equally

    Abstract

    Pattern recognition receptors (PRRs) are key elements in the innate immune response. Formyl peptide receptor (FPR) 2 is a PRR that, in addition to proinflammatory, pathogen-derived compounds, also recognizes the anti-inflammatory endogenous ligand annexin A1 (AnxA1). Because the contribution of this signaling axis in viral infections is undefined, we investigated AnxA1-mediated FPR2 activation on influenza A virus (IAV) infection in the murine model. AnxA1-treated mice displayed significantly attenuated pathology upon a subsequent IAV infection with significantly improved survival, impaired viral replication in the respiratory tract, and less severe lung damage. The AnxA1-mediated protection against IAV infection was not caused by priming of the type I IFN response but was associated with an increase in the number of alveolar macrophages (AMs) and enhanced pulmonary expression of the AM-regulating cytokine granulocyte-M-CSF (GM-CSF). Both AnxA1-mediated increase in AM levels and GM-CSF production were abrogated when mouse (m)FPR2 signaling was antagonized but remained up-regulated in mice genetically deleted for mFPR1, an mFPR2 isoform also serving as AnxA1 receptor. Our results indicate a novel protective function of the AnxA1-FPR2 signaling axis in IAV pathology via GM-CSF-associated maintenance of AMs, expanding knowledge on the potential use of proresolving mediators in host defense against pathogens.-Schloer, S., Hübel, N., Masemann, D., Pajonczyk, D., Brunotte, L., Ehrhardt, C., Brandenburg, L.-O., Ludwig, S., Gerke, V., Rescher, U. The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model.


    KEYWORDS:

    innate immune system; mucosal immunity; pattern recognition receptors

    PMID: 31398292 DOI: 10.1096/fj.201901265R
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