A cell differentiation landscape for monocyte and interstitial macrophage in the lung with diffuse alveolar damage

Diffuse alveolar damage (DAD) is recognized as a deadly type of acute inflammatory lung injury caused by toxic inhalants, but its cellular and molecular pathogenesis remains largely unclear. In this study, by using a mouse model of ricin-induced DAD, we explored the heterogeneity of recruited monocyte (Mono) and Mono-derived interstitial macrophage (IM) in the DAD lung. There was the development of 2 distinct IM subsets, namely IMpi (pro-inflammatory) and IMai (anti-inflammatory), from recruited Monopi. A subset of recruited Monopi could get the proliferating phenotype (namely pMonopi), and meanwhile pMonopi served as the intermediate of Monopi-to-IMai transition. The presence of growth differentiation factor 15 (GDF15) facilitated Monopi-to-pMonopi-to-IMai transition, whereas GDF15 deficiency exerted the negative feedback effect of enhancing Monopi-to-IMpi shift. These findings provided a cell differentiation landscape for Mono and IM in the DAD lung, which would promote a deeper understanding of cellular immunology of DAD and offer a theoretical basis for developing novel therapeutic strategies against acute lung injury.