Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization

The molecular clock REV-ERB alpha regulates lung injury during fibrosis, but the role of REV-ERB alpha in fibrogenesis remains unknown. Here, the authors show that REV-ERB alpha interacts with the lysyl oxidase-collagen axis during fibrogenesis and demonstrate the therapeutic potential of Rev-erb alpha agonist against lung fibrosis. Molecular clock REV-ERB alpha is central to regulating lung injuries, and decreased REV-ERB alpha abundance mediates sensitivity to pro-fibrotic insults and exacerbates fibrotic progression. In this study, we determine the role of REV-ERB alpha in fibrogenesis induced by bleomycin and Influenza A virus (IAV). Bleomycin exposure decreases the abundance of REV-ERB alpha, and mice dosed with bleomycin at night display exacerbated lung fibrogenesis. Rev-erb alpha agonist (SR9009) treatment prevents bleomycin induced collagen overexpression in mice. Rev-erb alpha global heterozygous (Rev-erb alpha Het) mice infected with IAV showed augmented levels of collagens and lysyl oxidases compared with WT-infected mice. Furthermore, Rev-erb alpha agonist (GSK4112) prevents collagen and lysyl oxidase overexpression induced by TGF beta in human lung fibroblasts, whereas the Rev-erb alpha antagonist exacerbates it. Overall, these results indicate that loss of REV-ERB alpha exacerbates the fibrotic responses by promoting collagen and lysyl oxidase expression, whereas Rev-erb alpha agonist prevents it. This study provides the potential of Rev-erb alpha agonists in the treatment of pulmonary fibrosis.