Neutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control

Resolution of lung injuries is vital to maintain gas exchange. Concurrently, there is an increased risk of secondary bacterial infections. Alveolar macrophages (AMs) are crucial for clearance of bacterial pathogens and inflammation, but environmental cues that switch these functional phenotypes of AMs remain elusive. Here, we discovered an incapacity of AMs to mount an effective immune response to bacteria during resolution of inflammation. Mechanistically, AM efferocytosis of neutrophils (PMNs), a hallmark of resolution, abrogated mitochondrial ROS (mtROS) production upon bacterial encounter. PMN-derived myeloperoxidase (MPO) fueled canonical glutaminolysis via uncoupling protein 2 (UCP2), which resulted in decreased mtROS dependent killing of bacteria and secretion of pro-inflammatory cytokines. Instead, MPO-enhanced UCP2 expression stabilized the mitochondrial membrane potential and boosted efferocytosis irrespective of the presence of bacterial pathogens. Overall, uptake of apoptotic PMNs primes AMs to prioritize resolution of inflammation over antibacterial responses, and similarly affects other murine macrophages and human AMs. ### Competing Interest Statement The authors have declared no competing interest.