Ontogenically distinct mouse alveolar macrophages modulate cigarette smoke-induced lung inflammation via Spp1

Abstract

Chronic obstructive pulmonary disease (COPD) is 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 cigarette smoke (CS)-induced COPD mouse model, we find that CS-triggered lung inflammation and emphysema-like tissue damage correlate with substantial changes in the lung myeloid compartment. Using fate-mapping, we show that, while most CS-induced alveolar macrophages (AM) are recruited bone marrow monocyte-derived AM (BM-AM), Em-AM persist and undergo similar inflammation- and emphysema-associated adaptations as BM-AM upon CS. Following co-culture with epithelial cells, CS-activated BM-AM and Em-AM both mediate inflammation and damage, and in vitro and in vivo studies identify osteopontin (Spp1) as a driver of CS-induced AM adaptations and damage. Therefore, our data support that the CS-exposed niche, rather than ontogeny, is the main determinant of AM fate in COPD-like pathology, and that Spp1 may be a potential therapeutic target to mitigate AM dysfunction in COPD. Fate-mapping of alveolar macrophages sheds light on the role of the cigarette smoke-exposed niche and osteopontin (Spp1) in driving cell dysfunction and tissue damage in the context of COPD.