Cell-type-specific efferocytosis restricts the functional plasticity of alveolar macrophages to prioritize resolution of inflammation over antibacterial defense

Resolution of lung injuries is vital to maintain gas exchange and restore homeostasis. Concurrently, there is an increased risk of secondary bacterial pneumonia. Alveolar macrophages (AMs) are crucial to not only initiate inflammation and clear bacteria but also promote resolution. However, environmental cues that switch these seemingly opposing functional phenotypes of AMs remain elusive. Resolution of lung inflammation requires efferocytosis of alveolar epithelial cells (AECs) and neutrophils (PMNs). Here, we discovered an incapacity of AMs to mount an effective immune response to bacteria during resolution of inflammation. Efferocytosis of both cell types led to an anti-inflammatory phenotype in AMs. Intriguingly though, only efferocytosis of PMNs reprogrammed mitochondrial metabolism of AMs to restrict functional plasticity during resolution of inflammation. PMN-derived Myeloperoxidase (MPO) fueled canonical glutaminolysis through Uncoupling protein 2 (UCP2) resulting in decreased mitochondrial reactive oxygen species (mtROS)-dependent killing of bacteria and secretion of pro-inflammatory cytokines. Instead, MPO-mediated stabilization of UCP2 inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. In contrast, efferocytosis of AECs resulted in a distinct anti-inflammatory phenotype in AMs maintaining phenotypic plasticity towards bacteria. Overall, uptake of apoptotic neutrophils switches AMs to prioritize resolution of inflammation over antibacterial responses and likewise affects human AMs. Key message: MPO activates an immunometabolic rheostat to restrict functional plasticity of macrophages to enhance resolution of inflammation at the expense of bacterial control.

Collections

Dissertationen/Habilitationen

Full item page

Cell-type-specific efferocytosis restricts the functional plasticity of alveolar macrophages to prioritize resolution of inflammation over antibacterial defense

Files

Date

Authors

Advisors/Reviewers

Further Contributors

Contributing Institutions

Publisher

Journal Title

Journal ISSN

Volume Title

Publisher

License

Quotable link

Abstract

Link to publications or other datasets

Description

Notes

Original publication in

Original publication in

Anthology

Collections

URI of original publication

Forschungsdaten

Series

Citation