Caspase-1 mediated interleukin-18 activation in neutrophils promotes the activity of rheumatoid arthritis in a NLRP3 inflammasome independent manner.

Objective: To investigate the role of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the peripheral neutrophils in rheumatoid arthritis (RA).

Methods: RA patients (n=48) and healthy controls (n=41) were enrolled and blood samples were collected for analysis. Protein expression of NLRP3 inflammasome components was detected by Western blot. Messenger RNA expression of NLRP3 inflammasome was detected by quantitative real-time reverse transcription-PCR. Sera levels of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) were detected by enzyme-linked immunosorbent assay (ELISA). Correlations among NLRP3 inflammasome activation, sera cytokines and RA disease activities were analyzed.

Results: Neutrophil count was positively correlated with the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP). In neutrophils, protein expression of NLRP3, apoptosis associated speck-like protein containing a CARD (ASC) and pro-caspase-1 was significantly decreased, while protein expression of activated caspase-1 was significantly increased and positively correlated with DAS28-CRP. Caspase-1 activation was positively correlated with serum level of IL-18 but not IL-1β. Messenger RNA expression of NLRP3 and ASC was also significantly decreased in RA patients. Interestingly, NLRP3 mRNA level was negatively correlated with DAS28-CRP.

Conclusions: Our results indicated that overactivated caspase-1 in neutrophils of RA was likely to mediate IL-18 activation and thus promote the progression of RA in a NLRP3 inflammasome independent manner.