Ontogenically distinct alveolar macrophages mediate cigarette smoke-induced inflammation and damage

We employed single-cell RNA sequencing (scRNA seq) using the 10x Genomics platform to investigate how varying durations of cigarette smoke (CS) exposure affect myeloid cells of different ontogenies in mice. Chronic obstructive pulmonary disease (COPD) is often associated with CS and the third leading cause of death. While airway-recruited macrophages contribute to COPD pathogenesis, the role of embryonic alveolar macrophages (Em-AM) remains unclear. Using a CS-induced COPD mouse model, we found that CS-triggered lung inflammation and emphysema-like tissue damage correlated with substantial changes in the lung myeloid compartment. Using fate-mapping, we showed that, while most CS-induced AM were recruited bone marrow monocyte-derived AM (BM-AM), Em-AM persisted and underwent similar inflammation- and emphysema-associated adaptations as BM-AM upon CS. Therefore, our data support that the CS-exposed niche, rather than ontogeny, is the main determinant of AM fate in COPD, and that CS-induced AM changes may be potential therapeutic targets to mitigate AM dysfunction in COPD.