LAUSR

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is a major cause of disability. Interestingly, the histone methyltransferase mixed-lineage leukemia 1 (MLL1) has been linked to many inflammation-related diseases. Moreover, toll-like receptor 4 (TLR4) has been reported to induce migration and invasion in RA-fibroblast-like synoviocytes (FLSs). This study intended to delineate the functional relevance of MLL1 in RA progression, which implicates the regulation of TLR4. First, clinical synovial tissues were collected from RA patients and patients with severe joint trauma to isolate FLSs. We identified highly expressed MLL1 and TLR4 in synovial tissues of RA patients, and the expression of them was positively correlated in RA-FLSs. More importantly, silencing of MLL1 and TLR4 resulted in suppressed migration and invasion of RA-FLSs, accompanied by reduced inflammation. Additionally, mechanistic investigations showed that MLL1 upregulated TLR4 expression by inducing H3K4me3 in the promoter region of TLR4. Functional assays revealed that overexpression of MLL1 activated the TRIF/NF-κB signaling pathway, resulting in accelerated migration and invasion, and inflammation of RA-FLSs in vitro. TLR4 knockdown could compromise the effects of MLL1 overexpression. The in vivo assays in a collagen-induced arthritis rat model validated the in vitro findings. Taken together, histone methyltransferase MLL1 induces TLR4 expression by mediating H3K4me3 in the TLR4 promoter, thus activating the TRIF/NF-κB signaling pathway, which thereby promotes the migration and invasion of RA-FLSs and ultimately exacerbates the progression of RA.