Ghrelin/GHSR system attenuates collagen-induced arthritis in mice and ameliorates inflammation in human rheumatoid arthritis fibroblast-like synoviocytes

Ghrelin, an acylated peptide hormone, acts through its sole known receptor, the growth hormone secretagogue receptor (GHSR). Previous research indicated that ghrelin may be involved in rheumatoid arthritis (RA), yet the specific mechanisms remain unclear. This study aimed to explore the mechanism of ghrelin in RA synovial inflammation. Serum and synovial tissue from RA patients were collected for ghrelin expression analysis. We conducted our study using a collagen-induced arthritis (CIA) mouse model and an in vitro model using fibroblast-like synoviocytes (FLSs) induced by tumor necrosis factor-alpha (TNF-α). RNA-sequencing was performed to identify the potential signaling pathways involved in RA. Ghsr shRNA interference was used to assess whether the ghrelin receptor was involved. Ghrelin expression was decreased in synovial tissue of RA patients, and was negatively associated with TNF-α in the synovial fluid. In vivo experiments, acyl-ghrelin effectively suppressed CIA development, and Ghsr^−/− mice exhibited the significantly aggravated arthritis symptoms of CIA mice. RNA sequence analyses of synovial tissue in Ghsr^−/− and wild type mice indicated that ghrelin/GHSR system may inhibit inflammation through the PI3K/AKT pathway. In RA-FLSs, we found that acyl-ghrelin significantly suppressed the TNF-α induced increase in p-PI3K, p-AKT, p-NF-κB p65, IL-6 and IL-1β in RA FLSs. The effects of acyl-ghrelin on inflammatory factors were attenuated by the PI3K/AKT agonists. Ghsr shRNA reversed the anti-inflammatory effects of acyl-ghrelin. These results indicated that ghrelin/GHSR system has an important role in RA and could be a suitable candidate for RA therapy.