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

Lung inflammation, caused by acute exposure to ozone (O) - 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 exposure. However, the role of AMØs in promoting or limiting O-induced lung inflammation has not been clearly defined. Here, we used a mouse model of acute O exposure, lineage tracing, genetic knockouts, and data from O-exposed human volunteers to define the role and ontogeny of AMØs during acute O exposure. Lineage tracing experiments showed that 12, 24, and 72 h after exposure to O (2 ppm) for 3h all AMØs were tissue-resident origin. Similarly, in humans exposed to FA and O (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 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 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O-induced inflammation via MerTK-mediated efferocytosis.