Siglec-F Protects Against Elastase-induced Lung Inflammation and Emphysema in Mice

ABSTRACT: Respiratory surfaces are exposed daily to billions of inhaled particles that could cause injury to thin alveolar surfaces where gas exchange occurs. Accordingly, robust defense is essential, but it must involve minimal tissue damage or physiologic disruption. Airspace macrophages (AMs) defend this delicate surface through non-inflammatory, homeostatic responses. Such protective responses fail in COPD, where AMs instead mediate alveolar destruction, causing emphysema. We hypothesized that emphysematous damage reflects a loss of AM restraint. We found reduced expression of inhibitory molecules, Siglec-7 and Siglec-9, on human AMs from COPD versus healthy lungs. This prompted us to deploy a model of elastase-induced emphysema to investigate the significance of Siglec-F, the murine paralog of human Siglec-7 and -9, on AM programming and alveolar destruction. Siglecf−/− mice showed significantly worse emphysematous alveolar damage. Unexpectedly, damage was predominantly driven by tissue resident AMs (RAMs), a population canonically considered protective. Bulk-RNAseq of Siglecf-/- RAMs revealed dysregulated pathways associated with extracellular matrix degradation, including overproduction of matrix metalloproteinase-8 (Mmp8). Altogether, our results uncover previously unrecognized roles for RAMs and Siglec-F in preserving alveolar integrity, and these findings implicate RAMs and Siglecs as potential therapeutic targets for limiting alveolar damage in human COPD.

ORGANISM(S): Mus musculus

PROVIDER: GSE307353 | GEO | 2026/02/24

REPOSITORIES: GEO