Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.
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Bulk RNA-seq data and epigenetic data have been deposited in the ArrayExpress Archive of Functional Genomics Data (accession code GSE147450). Clinical data and data sets generated for the study are stored on the secured server of the University of Nantes and are available from the corresponding authors upon reasonable request.
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We thank the Biological Resource Centre for biobanking (CHU Nantes, Hôtel Dieu, Centre de Ressources Biologiques (CRB), Nantes, France (BRIF: BB-0033-00040)), the Cytometry Facilty ‘Cytocell’, University of Nantes, and the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest) for its technical support. OSE Immunotherapeutics provided Sirpa−/− mice and anti-Sirpa antibody but had no role in data analyses or revision of the manuscript. A.R. and J.P. received funding from the Region Pays de la Loire. This work was funded with grants from the National Health and Medical Research Council of Australia (NHMRC) to J.V., the Sylvia and Charles Viertel Foundation (Senior Medical Research Fellowship to A.K.), the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.
The authors declare no competing interests.
Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Roquilly, A., Jacqueline, C., Davieau, M. et al. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis. Nat Immunol 21, 636–648 (2020). https://doi.org/10.1038/s41590-020-0673-x
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