NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis

Abstract

Summary Nucleotide‐binding, oligomerization domain (NOD)‐like receptor family, pyrin domain containing 3 (NLRP3) gene polymorphism was reported to be associated with susceptibility, disease activity or anti‐tumour necrosis factor (TNF) treatment response in rheumatoid arthritis (RA). However, the roles of NLRP3 inflammasome in the development of RA have not yet been elucidated fully. The present study aimed to study the role of NLRP3 inflammasome in RA. NLRP3 inflammasome activation in synovial tissues from RA and osteoarthritis (OA) patients were assessed by Western blot. Active caspase‐1 in synovia was stained by a FAM‐FLICA caspase‐1 probe. Mice with collagen‐induced arthritis (CIA) were treated with MCC950, a selective NLRP3 inhibitor, or vehicle for 2 weeks. The clinical score of arthritis, synovial inflammation and cartilage erosion were assessed. Proinflammatory cytokines were measured by enzyme‐linked immunosorbent assay (ELISA). The results showed that NLRP3 inflammasome was highly activated in both synovia from RA patients and CIA mice. Activation of NLRP3 inflammasome occurred mainly in the infiltrating monocyte/macrophages in synovia, but not in fibroblast‐like synoviocytes. Treatment with MCC950 resulted in significantly less severe joints inflammation and bone destruction. NLRP3 inflammasome activation in the synovia was inhibited significantly by MCC950 with reduced production of interleukin (IL)‐1β. The inhibition of NLRP3 inflammasome activation by MCC950 was confirmed further in a human monocytic cell line, THP‐1. In conclusion, NLRP3 inflammasome is involved in the pathogenesis of RA. Targeting NLRP3 inflammasome with a small molecule inhibitor might be a novel therapeutic strategy for RA.

Effect of alcohol on chronic pelvic pain and prostatic inflammation in a mouse model of experimental autoimmune prostatitis

“…NLRP3 inflammasome is also a key tissue damage sensor. The past decade has witnessed many studies, which suggested that the malfunction of NLRP3 inflammasome is a potent trigger of a series of autoinflammatory and autoimmune diseases, including gout, rheumatoid arthritis, and lupus . Moreover, NLRP3 inflammasome has been reported to participate in the chronic inflammation status in the prostate …”

Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

“…These results indicated that inflammasome activation may contribute to pro-inflammatory cytokine secretion in RA patients making inflammasome inhibition a possible therapeutic strategy in the future treatment of RA. In line with this, Guo et al demonstrated the NLRP3 inflammasome to be strongly activated both in synovia of RA patients and in an in vivo mouse model of collagen-induced arthritis [309]. Here, treatment with MCC950, a selective NLRP3 inhibitor, resulted in both significantly reduced joint inflammation and bone destruction as well as reduced production of IL-1β in vivo [310].…”

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells

“…Genetic variants within the NLRP3-inflammasome are associated with susceptibility to RA [97][98][99][100][101], and enhanced activity of NLRP3 inflammasome has been found in peripheral blood cells of patients with active RA [102]. Inhibition of NLRP3 inflammasome activity alleviated arthritis in CIA mice [103]. Given that NLRP3 was one of the PR-targeted gene [34] and that the lack of PR potentiated NLRP3 inflammasome expression in the synovial tissue of the CIA mice, suggesting that although PR might not alter the underlying cause of disease, it might reduce the production of factors such as inflammasomes which are involved in inflammation, cartilage and bone destructions in RA.…”