NLRP3 inflammasome as a key player in pericarditis: rationale for a targeted therapeutic strategy

Objectives. To (i) determine the formation of the NLRP3 inflammasome in the pathogenesis of pericarditis and (ii) recreate pericardial inflammation in mice with a toll-like-receptor-2/inflammasome inducer and assess the effect of anti-inflammatory drugs on inflammasome-mediated disease. Background. Acute pericarditis is typically responsive to colchicine, an anti-inflammatory drug blocking the NLRP3 inflammasome. Methods. Pericardial biopsies from patients with chronic pericarditis were stained for the inflammasome components – NLRP3, caspase-1, and ASC. A murine model of pericarditis was developed through intrapericardial injection of zymosan A. Ibuprofen and different inflammasome pathway blockers (colchicine, NLRP3 inhibitor 16673-34-0 [NLRP3inh], anakinra, and IL-1 trap) were administered, and echocardiography and tissue pathology were performed. Results. Patients with pericarditis showed increased inflammasome presence compared with controls (NLRP3: 1.9±0.15 vs. 1.21±0.1; Caspase-1: 2.5±0.2 vs 1.4±0.09; ASC: 2.4±0.2 vs. 1.1±0.3). The mouse model showed pericardial effusion (+83%), pericardial thickness (+45%), and an increased staining of inflammasome, IL-1alpha, and IL-1beta compared with sham. Treatment with ibuprofen reduced effusion compared to vehicle (-42%). Colchicine and NLRP3inh significantly reduced effusion (-28% and -46%) and inflammasome activation (-93% and -78%). NLRP3inh reduced pericardial thickness (-32%). Anakinra and IL-1 trap attenuated pericardial effusion (-13% and -43%), pericardial thickness (-20% and -44%), and inflammasome staining compared to vehicle (-75% and -96%). Conclusions. The NLRP3 activity was assessed in human pericarditis samples. Our new experimental mouse model replicated the key elements of acute pericarditis phenotype and shows the therapeutic efficacy of IL-1 blockers. NLRP3 pathway inhibition of could represent a valid therapeutic approach for the treatment of pericarditis.