Toll‐Like Receptor 8 is a Therapeutic Target in Rheumatoid Arthritis

OBJECTIVE: This study aimed to explore the pathogenic role of Toll-like receptor 8 (TLR8) in rheumatoid arthritis (RA) and evaluate its potential as a therapeutic target. Using a combination of in vitro and in vivo models, we explored the functional involvement of TLR8 in RA pathogenesis and assessed the efficacy of TLR8 inhibition. METHODS: Gene expression profiles of patients with RA and healthy controls were analyzed to identify up-regulated genes and pathways. In vitro RA models were established using fibroblast-like synoviocytes (FLSs) from patients with RA, human umbilical vein endothelial cells, and peripheral blood mononuclear cells from patients with RA and RA monkeys and to examine TLR8's role in synoviocyte proliferation, angiogenesis, and inflammation. Additionally, the therapeutic efficacy of a TLR8 inhibitor was evaluated in collagen-induced arthritis (CIA) mouse and RA rabbit models. RESULTS: TLR8 is aberrantly overexpressed in patients with RA and shows strong positive correlations with disease activity. Mechanistically, the up-regulation and activation of TLR8 drives RA progression by promoting synovial hyperplasia, angiogenesis, and inflammation. Notably, TLR8 inhibition effectively alleviates these pathologic processes. In preclinical models, including a CIA mouse model and an RA rabbit model, TLR8 antagonists demonstrated significant therapeutic efficacy, reducing disease severity and ameliorating joint damage. CONCLUSION: TLR8 promotes RA pathogenesis and could serve as a novel therapeutic target for RA.