Discoidin domain receptor 2 signaling through PIK3C2 in fibroblasts promotes lung fibrosis

Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), portends significant morbidity and mortality, and current therapeutic options are suboptimal. We have previously shown that type I collagen signaling through discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase expressed by fibroblasts, is critical for the regulation of fibroblast apoptosis and progressive fibrosis. However, the downstream signaling pathways for DDR2 remain poorly defined and could also be attractive potential targets for therapy. A recent phosphoproteomic approach indicated that PIK3C2 alpha, a poorly studied member of the PI3 kinase family, could be a downstream mediator of DDR2 signaling. We hypothesized that collagen I/DDR2 signaling through PIK3C2 alpha regulates fibroblast activity during progressive fibrosis. To test this hypothesis, we found that primary murine fibroblasts and IPF-derived fibroblasts stimulated with endogenous or exogenous type I collagen led to the formation of a DDR2/PIK3C2 alpha complex, resulting in phosphorylation of PIK3C2 alpha. Fibroblasts treated with an inhibitor of PIK3C2 alpha or with deletion of PIK3C2 alpha had fewer markers of activation after stimulation with TGF beta and more apoptosis after stimulation with a Fas-activating antibody. Finally, mice with fibroblast-specific deletion of PIK3C2 alpha had less fibrosis after bleomycin treatment than did littermate control mice with intact expression of PIK3C alpha. Collectively, these data support the notion that collagen/DDR2/PIK3C2 alpha signaling is critical for fibroblast function during progressive fibrosis, making this pathway a potential target for antifibrotic therapy. (c) 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.