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

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

Yang Z ，Cao J ，Yu C ，Yang Q ，Zhang Y ，Han L ... -  《-》

TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis.

Liu Y ，Wei W ，Wang Y ，Wan C ，Bai Y ，Sun X ，Ma J ，Zheng F ... -  《-》

Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis.

Choulaki C ，Papadaki G ，Repa A ，Kampouraki E ，Kambas K ，Ritis K ，Bertsias G ，Boumpas DT ，Sidiropoulos P ... -  《-》

Neutrophil IL-1β processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux.

Although neutrophils are the most abundant cells in acute infection and inflammation, relatively little attention has been paid to their role in inflammasome formation and IL-1β processing. In the present study, we investigated the mechanism by which neutrophils process IL-1β in response to Streptococcus pneumoniae. Using a murine model of S. pneumoniae corneal infection, we demonstrated a requirement for IL-1β in bacterial clearance, and we showed that Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 are essential for IL-1β production and bacterial killing in the cornea. Neutrophils in infected corneas had multiple specks with enzymatically active caspase-1 (YVAD-FLICA 660), and bone marrow neutrophils stimulated with heat-killed S. pneumoniae (signal 1) and pneumolysin (signal 2) exhibited multiple specks when stained for NLRP3, ASC, or Caspase-1. High-molecular mass ASC complexes were also detected, consistent with oligomer formation. Pneumolysin induced K(+) efflux in neutrophils, and blocking K(+) efflux inhibited caspase-1 activation and IL-1β processing; however, neutrophils did not undergo pyroptosis, indicating that K(+) efflux and IL-1β processing is not a consequence of cell death. There was also no role for lysosomal destabilization or neutrophil elastase in pneumolysin-mediated IL-1β processing in neutrophils. Taken together, these findings demonstrate an essential role for neutrophil-derived IL-1β in S. pneumoniae infection, and they elucidate the role of the NLRP3 inflammasome in cleavage and secretion of IL-1β in neutrophils. Given the ubiquitous presence of neutrophils in acute bacterial and fungal infections, these findings will have implications for other microbial diseases.

Karmakar M ，Katsnelson M ，Malak HA ，Greene NG ，Howell SJ ，Hise AG ，Camilli A ，Kadioglu A ，Dubyak GR ，Pearlman E ... -  《-》

NLRP3 inflammasome regulates Th17 differentiation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Th17 has been shown to play am important role in the pathogenesis of RA. Accumulating data suggest the involvement of NLRP3 inflammasome in Th17 differentiation in autoimmune diseases. In the current study, we found that NLRP3 inflammasome is activated in CD4 T cells from RA patients. The activation of NLRP3 inflammasome was correlated with disease activities and IL-17A concentration in RA sera. Knockdown of NLRP3 suppressed Th17 differentiation. In addition, caspase-1 or IL-1 receptor inhibitor inhibits Th17 differentiation significantly. Further, ROS production is increased in CD4 T cells from RA patients. The inhibition of ROS production decreased NLRP3 inflammasome activation and IL-1β production in CD4 T cells, leading to the suppression of Th17 differentiation. These findings suggest a pathogenic role of NLRP3 inflammasome in RA by promoting Th17 cell differentiation. NLRP3 inflammasome could be a potential therapeutic target for the treatment of RA.

Zhao C ，Gu Y ，Zeng X ，Wang J ... -  《-》