Abstract
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.