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Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis

Nature Immunology volume 21, pages 636–648 (2020)Cite this article

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Abstract

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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Fig. 1: Recovery from infection or trauma is followed by a reduction of phagocytosis of extracellular bacteria by monocytes in humans.
Fig. 2: Recovery from infection is followed by susceptibility to secondary pneumonia and reduction in phagocytosis by alveolar macrophages in mice.
Fig. 3: Phagocytosis function of newly formed resident lung alveolar macrophages is altered locally by secondary inflammatory mediators released during infection.
Fig. 4: Treg cells and TGF-β are not major contributors to the paralysis program of alveolar macrophages.
Fig. 5: Phenotypic analysis origin of paralyzed alveolar macrophages.
Fig. 6: Sirpa is required for the priming, but not the maintenance, of the paralysis program of alveolar macrophages after infection.
Fig. 7: Potential of SIRPα as a biomarker and therapeutic target in hospitalized patients at risk of secondary pneumonia.

Data availability

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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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: Antoine Roquilly, Cedric Jacqueline.

  2. These authors jointly supervised this work: Antoine Roquilly, Jeremie Poschmann, Jose A. Villadangos and Karim Asehnoune.

Authors and Affiliations

  1. Université de Nantes, EA3826 Thérapeutiques Anti-Infectieuses, Institut de Recherche en Santé 2 Nantes Biotech, Nantes, France

    Antoine Roquilly, Cedric Jacqueline, Marion Davieau, Paul Rooze, Alexis Broquet, Barbara Misme-Aucouturier, Tanguy Chaumette, Mickael Vourc’h & Karim Asehnoune

  2. Université de Nantes, CHU Nantes, Pôle Anesthésie-Réanimation, Service d’Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, France

    Antoine Roquilly, Paul Rooze, Mickael Vourc’h, Raphael Cinotti & Karim Asehnoune

  3. Department of Microbiology and Immunology, Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia

    Antoine Roquilly, Hamish E. G. McWilliam & Jose A. Villadangos

  4. Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR1064, ITUN, Nantes, France

    Alice Mollé, Abderrahmane Sadek, Cynthia Fourgeux, Vanessa Gauttier & Jeremie Poschmann

  5. Department of Biology, Faculty of Science, Moulay Ismail University, Zitoune, Meknes, Morocco

    Abderrahmane Sadek

  6. Plateforme Cytocell, SFR François Bonamy, Nantes, France

    Nadege Marec

  7. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia

    Hamish E. G. McWilliam & Jose A. Villadangos

  8. CRCINA, INSERM, Université de Nantes, CHU de Nantes, Nantes, France

    Frederic Altare

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Contributions

C.J. performed experiments and contributed to the study design, data analyses, interpretation of results and writing and revision of the manuscript. M.D. and P.R. performed experiments and contributed to interpretation of results and revision of the manuscript. C.F. generated ChIP–seq and RNA-seq data. A.M., A.S. and J.P. performed bioinformatics analysis. A.B., B.M.-A., T.C., M.V., R.C., N.M., V.G., H.E.G.M. and F.A. contributed to interpretation of results and revision of the manuscript. A.R., C.J., J.P., J.A.V. and K.A. contributed to the study design, data analyses, interpretation of results and revision of the manuscript. All authors have approved the final manuscript for publication.

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Correspondence to Antoine Roquilly, Jeremie Poschmann, Jose A. Villadangos or Karim Asehnoune.

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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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