Significance

Pulmonary fibrosis is a common final outcome of many lung diseases, and its occurrence may be closely associated with the disturbance of lung homeostasis and with alterations in pulmonary function. In this study, we identified leucine-rich repeat kinase 2 (LRRK2) as a pivotal molecule in alveolar type II epithelial (AT2)–coordinated pulmonary responses in the context of bleomycin-induced pulmonary fibrosis. Our results demonstrated that LRRK2 restrained progressive pulmonary fibrosis by preventing AT2 cell dysfunction and the subsequent CCL2/CCR2 axis–dependent macrophage-mediated profibrotic responses. Our study highlights the important biological functions of LRRK2 in the maintenance of lung homeostasis and the prevention of fibrotic lung disease, thereby providing a potential target for developing clinical therapeutic strategies.

Link: https://doi.org/10.1073/pnas.2106685118