C-type lectin-like receptor 2 in lung epithelium protects against acute lung injury.

C-type lectin-like receptor 2 (CLEC2) is a transmembrane receptor highly expressed on platelets, which regulates platelet aggregation and immune response. Yet, the function of CLEC2 in lung epithelium and its contribution to acute lung injury (ALI) is unclear. In this study, a lung epithelial-specific CLEC2 knockout mouse (Clec1bAT2-KO) was generated and performed for ALI models. In both LPS- and acid-induced lung injury models, the ALI signs of Clec1bAT2-KO mice were further exacerbated. The therapeutic application of epithelial-restricted CLEC2 overexpression using adeno-associated virus (AAV) or CLEC2 activation using its endogenous ligand podoplanin serves as a lung epithelial protective agent in the setting of ALI. Transcriptomic analyses reveal that CLEC2-regulated genes are highly enriched in chemotaxis, cytokine, and extracellular matrix (ECM) components. Lung injury was partially attenuated in Ccl5-/-, Csf3-/-, and Cxcl1-/- mice pretreated with AAV-si-CLEC2, followed by LPS challenge. Loss of CLEC2 leads to ECM degradation, which could be reversed by exogenous transforming growth factor beta (TGF-β). Furthermore, interferon regulatory factor 1 (IRF1) was identified as the key molecule that regulates CLEC2-related cytokine/chemokine production and ECM degradation. These findings suggest that epithelial CLEC2 protects against ALI by modulating spleen tyrosine kinase/IRF1-mediated cytokine/chemokine production and TGF-β-mediated ECM remodeling.