Reduced Expression of m6A Demethylases FTO and ALKBH5 in Monocytes from the Site of Inflammation in Patients with Juvenile Idiopathic Arthritis

Abstract

N 6-methyladenosine (m 6A) has recently emerged as a post-transcriptional modulator governing cell-specific gene expression in innate immune cells, particularly in monocytes. Disruptions in m 6A homeostasis, manifested as the altered expression of m 6A-related proteins and m 6A levels, have been implicated in autoimmune disorders. Perturbations in m 6A dynamics within total Peripheral blood mononuclear cells (PBMCs) have shown strong correlations with disease severity in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It remains unclear in which specific cell type(s) m 6A homeostasis is disturbed, and also whether other rheumatic diseases such as juvenile idiopathic arthritis (JIA) show similar features. Here, we assess the involvement of m 6A and m 6A-regulatory proteins in JIA monocytes. Notably, the diminished expression of m 6A-eraser proteins FTO and ALKBH5 was observed in JIA monocytes extracted from the inflamed joint. This resulted in increased m 6A-methylated transcripts in monocytes from these patients. Correspondingly, we observed that culturing monocytes in the presence of synovial fluid from JIA inflamed joints reduced the expression of both FTO and ALKBH5. The knock-out of FTO in human monocytes of healthy controls increased monocyte activation, indicating the relevance of FTO and m 6A in the context of JIA. These findings underscore the potential of ALKBH5 and FTO expression as a biomarker in JIA and identify the m 6A machinery as a potential therapeutic target for the treatment of JIA and possibly other autoimmune diseases in the future.