Cell type–specific efferocytosis determines functional plasticity of alveolar macrophages
Resolution of lung injuries is vital to maintain gas exchange, but there is an increased risk of secondary bacterial infections during this stage. Alveolar macrophages (AMs) are crucial to clear bacteria and control the resolution of inflammation, but environmental cues that switch functional phenotypes of AMs remain incompletely understood. Here, we found that AMs lack the capacity to mount an effective immune response against bacteria during resolution of inflammation. Neutrophil (PMN)-derived myeloperoxidase (MPO) fueled canonical glutaminolysis via the mitochondrial membrane transporter uncoupling protein-2 (UCP2), resulting in decreased mtROS-dependent killing of bacteria and secretion of pro-inflammatory cytokines. MPO-enhanced UCP2 expression inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. Conversely, efferocytosis of other cell types resulted in a distinct anti-inflammatory AM phenotype while maintaining antibacterial phenotypic plasticity. Overall, our findings indicate that the uptake of apoptotic PMNs or MPO switches AMs to prioritize resolution of inflammation over antibacterial responses, a feature that is conserved in murine extrapulmonary macrophages and human AMs.
Authors
- Maximiliano Ruben Ferrero (ORCID: https://orcid.org/0000-0001-7934-0240)
- Susanne Herold (ORCID: https://orcid.org/0000-0001-6343-0911)
- Michael Wetstein (ORCID: https://orcid.org/0009-0002-0202-6848)
- Jochen Wilhelm (ORCID: https://orcid.org/0000-0001-5544-9647)
- Ioannis Alexopoulos (ORCID: https://orcid.org/0000-0002-5601-2831)
- U. Matt
- Victoria K. Ogungbemi-Alt (ORCID: https://orcid.org/0000-0002-8730-4749)
- Ana Ivonne Vazquez‐Armendariz (ORCID: https://orcid.org/0000-0001-8498-6492)
- Rajkumar Savai (ORCID: https://orcid.org/0000-0003-1538-2091)
- Natascha Sommer (ORCID: https://orcid.org/0000-0002-8915-7762)
- Irina Kuznetsova
- Learta Pervizaj-Oruqaj (ORCID: https://orcid.org/0000-0002-6839-1656)
- Martin Langelage (ORCID: https://orcid.org/0009-0004-4565-3897)
- Lucas Kimmig (ORCID: https://orcid.org/0000-0001-8297-0278)
- Christina Malainou (ORCID: https://orcid.org/0000-0003-4413-023X)
- Julian Better (ORCID: https://orcid.org/0000-0003-0324-7781)
- Siavash Mansouri (ORCID: https://orcid.org/0000-0003-0493-5084)
- Oleg Pak (ORCID: https://orcid.org/0000-0002-9733-3690)
- Mohammad Estiri
Institutions
- University of Chicago (US)
- Max Planck Institute for Heart and Lung Research (DE)
- Universities of Giessen and Marburg Lung Center (DE)
- Biomedicine Research Institute of Buenos Aires - CONICET - Partner Institute of the Max Planck Society (AR)
- Cardio-Pulmonary Institute (DE)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1126/sciimmunol.adl3852
- Citations
- 12
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 9.57