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

Airspace macrophages (AMs) are essential for maintaining lung homeostasis. Their activity must be tightly controlled to prevent excessive immune responses and tissue damage, such as emphysematous alveolar destruction. Siglec-F is a canonical marker of AMs, but its functional role in lung disease remains unclear. Here, we investigated the role of Siglec-F in a murine model of elastase-induced emphysema. We found that Siglec-F-deficient mice exhibited worsened emphysematous phenotypes, along with accumulation and transcriptional reprogramming of resident AMs (RAMs). Transcriptomic profiling of Siglec-F-deficient RAMs revealed dysregulation of key pathways involved in tissue repair, including extracellular matrix degradation, TGF-β signaling, and phagocytosis. These findings demonstrate that Siglec-F is critical for restraining RAM activity and preserving alveolar integrity during injury. Our study provides new insight into the immunoregulatory function of Siglec-F in a tissue-destructive context and highlights the potential protective roles of Siglec signaling in chronic lung disease.