Selective ROCK2 inhibitor ameliorates established dermal and pulmonary fibrosis in murine systemic sclerosis by shifting the balance between Th17 and Treg cells 2134

Abstract Description Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by excessive fibrosis in skin and visceral organs leading to irreversible scarring and organ failure. Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) regulates key pro-fibrotic pathways implicated in both pro-inflammatory reactions and altered extracellular matrix remodeling. By using the bleomycin-induced SSc model we found that therapeutic administration of GV101, a novel selective ROCK2 inhibitor, attenuated dermal thickness and lung fibrosis induced by repeated subcutaneous injections of bleomycin in mice. GV101 treatment significantly reduced collagen levels in skin and lungs demonstrated by Hydroxyproline and SirCol assessment, respectively. In vivo target engagement was shown by diminished pCofilin and pSTAT3 in spleen. Furthermore, ROCK2 targeting reduced leukocytes infiltrates in bronchoalveolar lavage fluids of treated mice, which was associated with significant decrease in levels of pro-inflammatory cytokines including IL-17, TNF-a, IL-1b and CXCL1, while the levels of IL-2 were increased. These changes in cytokines were consistent with a shift in the balance between Th17 and Treg subsets observed in the lungs of GV101-treated mice with SSc. All together, these data unveil the therapeutic potential of highly selective ROCK2 inhibitors in SSc, and further characterize the ROCK2-specific molecular mechanism of action simultaneously targeting both fibrotic and inflammatory pathways. Funding Sources The study was sponsored by Graviton Bioscience Topic Categories Therapeutic Approaches to Autoimmunity (THER)