4.7 Article

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

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NATURE IMMUNOLOGY
卷 21, 期 6, 页码 636-+

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DOI: 10.1038/s41590-020-0673-x

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  1. Region Pays de la Loire
  2. National Health and Medical Research Council of Australia (NHMRC)
  3. Sylvia and Charles Viertel Foundation
  4. Victorian State Government Operational Infrastructure Support
  5. Australian Government NHMRC Independent Research Institute Infrastructure Support scheme

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Sepsis and physical trauma can increase the susceptibility of patients to pneumonia. Roquilly and colleagues demonstrate that sepsis results in durable impairment of alveolar phagocytic function that is dependent on the localized expression of the inhibitory receptor SIRP alpha. 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 alpha (SIRP alpha) 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 SIRP alpha restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.

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