Abstract
Platelets are a major reservoir of bioactive mediators, including growth factors such as transforming growth factor β1 (TGF-β1), that regulate vascular repair and tissue remodeling. Beyond these classical functions, platelets also participate in inflammatory hemostasis through activation pathways that differ from those engaged during hemostatic thrombus formation. However, the platelet mechanisms linking inflammatory vascular activation to chronic fibrotic remodeling remain poorly defined. Here, we identify the immunoreceptor tyrosine-based activation motif (ITAM)-coupled platelet receptor glycoprotein VI (GPVI) as a critical driver of fibrotic lung remodeling. We observed that platelets accumulated within fibrotic regions of lungs from patients with idiopathic pulmonary fibrosis and from mice with bleomycin-induced lung injury and displayed a preactivated phenotype characterized by P-selectin exposure and integrin αIIbβ3 activation. Using genetic mouse models, we demonstrate that platelet aggregation mediated by integrin β3 is dispensable for the development of lung fibrosis. Similarly, signaling through the ADP receptor P2Y12 was also dispensable. In contrast both genetic deletion and pharmacological inhibition of GPVI protected mice from bleomycin-induced mortality and markedly reduced lung fibrosis. Mechanistically, both GPVI deficiency and pharmacological GPVI inhibition reduced the early release of the platelet chemokine PF4 into bronchoalveolar lavage fluid, whereas TGF-β1 levels were unaffected. Consistently, PF4-deficient mice were protected from bleomycin-induced fibrosis, and PF4 directly promoted fibroblast differentiation and collagen gene expression in vitro. Together, these findings identify GPVI as a critical upstream regulator of platelet-driven fibrotic lung remodeling and support a model in which GPVI-dependent PF4 release contributes to pulmonary fibrosis independently of platelet aggregation