Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis
- 18 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (6), 636-648
- https://doi.org/10.1038/s41590-020-0673-x
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.Keywords
This publication has 63 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Disease Tolerance as a Defense StrategyScience, 2012
- Attributable Mortality of Ventilator-Associated PneumoniaAmerican Journal of Respiratory and Critical Care Medicine, 2011
- Fas Determines Differential Fates of Resident and Recruited Macrophages during Resolution of Acute Lung InjuryAmerican Journal of Respiratory and Critical Care Medicine, 2011
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Fluorescent reporters for Staphylococcus aureusJournal of Microbiological Methods, 2009
- The biology and future prospects of antivirulence therapiesNature Reviews Microbiology, 2008
- Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleenThe Journal of Experimental Medicine, 2007
- Translational control and target recognition by Escherichia coli small RNAs in vivoNucleic Acids Research, 2007
- Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like diseaseThe Journal of Experimental Medicine, 2007