NALP1 inflammasome activation in adjuvant arthritis rats is a novel therapeutic target of carboxyamidotrizole in the treatment of rheumatoid arthritis

Abstract

Abstract BACKGROUND AND PURPOSE Pro-inflammatory cytokines play an important role in rheumatoid arthritis (RA) and their production is mainly regulated by NF-κB and inflammasomes. Carboxyamidotrizole (CAI) has been reported to exhibit potent anti-inflammatory activities by decreasing cytokines. Therefore, we investigated NALP inflammasomes in the synoviums of a rat RA model, and explored the therapeutic effects of CAI on RA model and the involvement of inflammasomes relative pathways in the actions of CAI. EXPERIMENTAL APPROACH The anti-arthritic effects of CAI were assessed in rat adjuvant arthritis (AA) model. NALP1 and NALP3 inflammasomes, nuclear factor (NF)-κB pathway, and pro-inflammatory cytokines levels were determined. RESULTS CAI administration significantly decreased arthritis index, improved radiological and histological manifestation, and reduced synovial IL-1β, IL-6, IL-18 and TNF-α levels in AA rats. As compared to the normal rats, the level of 70 kDa NALP1 isoform was significantly up-regulated, NALP3 was down-regulated, and the levels of 165kDa NALP1 isoform and the adaptor protein ASC were unchanged in AA synoviums. CAI reduced 70kDa NALP1 isoform and restored NALP3 level in synoviums of AA rats. And CAI inhibited caspase-1 activation in AA synoviums, although it did not directly inhibit the enzymatic activity in vitro. In addition, CAI reduced p65 NF-κB subunit expression and IκBα phosphorylation and degradation in AA rats. CONCLUSION NALP1 inflammasome was activated in arthritic synoviums, which might be a novel therapeutic target for RA. CAI may have therapeutic value in RA by inhibiting the activation of NALP1 inflammasome and NF-κB and by decreasing pro-inflammatory cytokines.