Tissue-resident alveolar macrophages reduce O 3 -induced inflammation via MerTK mediated efferocytosis.

Lung inflammation, caused by acute exposure to ozone (O ₃ ) - one of the six criteria air pollutants - is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung and their number increases following O ₃ exposure. However, the role of AMØs in promoting or limiting O ₃ -induced lung inflammation has not been clearly defined. Here, we used a mouse model of acute O ₃ exposure, lineage tracing, genetic knockouts, and data from O ₃ -exposed human volunteers to define the role and ontogeny of AMØs during acute O ₃ exposure. Lineage tracing experiments showed that 12, 24, and 72 h after exposure to O ₃ (2 ppm) for 3h all AMØs were tissue-resident origin. Similarly, in humans exposed to FA and O ₃ (200 ppb) for 135 minutes, we did not observe ~21h post-exposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O ₃ exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØ demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK - a key receptor involved in efferocytosis - also resulted in impaired clearance of apoptotic neutrophils followed O ₃ exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O ₃ -induced inflammation via MerTK-mediated efferocytosis.