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

Abstract

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 IM^pi (pro-inflammatory) and IM^ai (anti-inflammatory), from recruited Mono^pi. A subset of recruited Mono^pi could get the proliferating phenotype (namely pMono^pi), and meanwhile pMono^pi served as the intermediate of Mono^pi-to-IM^ai transition. The presence of growth differentiation factor 15 (GDF15) facilitated Mono^pi-to-pMono^pi-to-IM^ai transition, whereas GDF15 deficiency exerted the negative feedback effect of enhancing Mono^pi-to-IM^pi 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.

Graphical abstract

Keywords

diffuse alveolar damage / immunology / interstitial macrophage / monocyte / GDF15 / single-cell transcriptomics

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© The Author(s) 2025. Published by Oxford University Press on behalf of Higher Education Press.