IL-1β triggered by peptidoglycan and lipopolysaccharide through TLR2/4 and ROS-NLRP3 inflammasome-dependent pathways is involved in ocular Behçet's disease.

PURPOSE. Behcet's disease (BD) is a chronic systemic inflam- matory disorder of unknown etiology. Toll-like receptors (TLRs) are critical in the innate immune response to microbial invaders. In this study we investigated the role of TLRs in the pathogenesis of BD. METHODS. TLR2/4 expression and IL-1b and reactive oxygen species (ROS) production were studied in monocyte-derived macrophages (MDMs) obtained from BD patients, acute anterior uveitis (AAU) patients, and healthy controls using real-time PCR, flow cytometry, and ELISA. The NLRP3 inflammasome of MDMs was downregulated by RNA interfer- ence. The levels of phosphorylated P38, Erk1/2, and JNK MAPK were evaluated using flow cytometry. RESULTS. TLR2/4 expression was significantly increased in MDMs from active BD patients. IL-1b and ROS production of peptidoglycan (PGN)/lipopolysaccharide (LPS)-induced MDMs from active BD patients was significantly increased compared with inactive BD patients, AAU patients, and healthy controls. ROS activator and inhibitor significantly increased and decreased the production of IL-1b, respectively. The produc- tion of IL-1b was significantly decreased after the NLRP3 inflammasome was downregulated. The phosphorylation levels of p38 and ERK1/2 in MDMs from BD patients and controls were increased following stimulation with either PGN or LPS. Both SB203580 (p38 inhibitor) and PD98059 (ERK1/2 inhibitor) significantly decreased the production of IL-1b. CONCLUSIONS. The results suggest that TLR2/4 expression in MDMs from active BD patients is significantly increased. Interaction of TLR2/4 with their ligands PGN/LPS is involved in BD pathogenesis, possibly by the induction of IL-1b through a ROS-NLRP3-dependent pathway. (Invest Ophthalmol Vis Sci. 2013;54:402-414) DOI:10.1167/iovs.12-11047