Upregulated CCN1 from pleural mesothelial cells alters collagen I conformation and drives fibrosis via ITGB1/MAPK signaling.

BACKGROUND: Pleural mesothelial cells (PMCs) have been identified as key contributors to pleural fibrosis. Cellular communication network factor 1 (CCN1), a matricellular protein, regulates cell–matrix interactions and fibrotic signaling in multiple contexts. However, the specific role and mechanism of CCN1 in PMCs during pleural fibrosis remained unclear. METHODS: Expression of CCN1 was evaluated in human pleural fibrosis samples and bleomycin-induced mouse models. In vitro, PMCs were treated with recombinant CCN1 or fibrotic matrix. Mechanistic studies included gene knockdown, immunoprecipitation, mass spectrometry, and functional assays. RESULTS: CCN1 was significantly elevated in pleural fibrosis tissues. CCN1 expression was driven by YAP/TAZ activation and in turn promoted further YAP/TAZ activation, creating a feedback loop to produce more CCN1. Upregulated CCN1 directly altered conformation of type I collagen (collagen I) by binding vWC binding domain. Then, CCN1 with conformation-changed collagen I activated integrin β1 (ITGB1)/MAPK signaling, which induced remodeling of cytoskeleton as well as fibrosis. At last, it was confirmed that neutralization of CCN1 reduced pleural fibrosis in vitro and in vivo. CONCLUSIONS: Upregulated CCN1 contributes to pleural fibrosis via changing collagen I conformation and ITGB1/MAPK pathway activation. Targeting CCN1 is a potential therapeutic strategy.