Analysis of how melatonin-upregulated clock genes PER2 and CRY2 alleviate rheumatoid arthritis-associated interstitial lung disease

Abstract

Melatonin (Mel) serves as the central regulator for maintaining circadian rhythms and plays a crucial role not only in controlling the rhythmic clock, but also in several functional domains such as immunomodulation and anti-inflammation. In this study, we explored the clinical relevance of Mel and rheumatoid arthritis comorbid with interstitial lung disease (RA-ILD), and its potential therapeutic effects on arthropathy and pulmonary fibrosis (PF) in mice with collagen-induced arthritis (CIA). The results demonstrated that low serum levels of Mel were correlated with disease activity and severity of PF in RA-ILD patients. In addition, Mel was potentially efficacious in alleviating arthritis, bone destruction, and PF in a mouse model of CIA. Meanwhile, we observed that in lung tissues, the circadian-clock genes (CCGs) period circadian regulator 2 (PER2) and cryptochrome circadian regulator 2 (CRY2) were predominantly expressed in epithelial cells (ECs), and the regulation of their expression in ECs was closely correlated with Mel-mediated suppression of inflammatory responses and a significant reduction in macrophagic inflammatory activity. These results implied that Mel and its associated CCGs might play important regulatory roles in RA-ILD and its associated pathological processes.