Abstract 13069: NLRP3 Inflammasome Promotes Vasculitis of Kawasaki Disease

Abstract

Introduction: Kawasaki disease (KD) is a systemic febrile syndrome which causes coronary arteritis. Candida albicans water-soluble fraction (CAWS) is a mannoprotein-β-glucan complex obtained from the culture supernatant of Candida albicans , and frequently used as a murine KD model, because administration ofCAWS induces coronary arteritis. NLRP3 inflammasome is a large multiprotein complex (NLRP3, ASC and caspase-1), and regulates the release of the potent inflammatory cytokine IL-1β. We hypothesized that NLRP3 inflammasome-mediated IL-1β had a pivotal role in the pathogenesis of CAWS-induced vasculitis. Methods and Results: In vivo : The protein level of IL-1β in the hearts was increased by CAWS administration. Activation of caspase-1 was detected around the coronary arteries by FLICA assay. Histological study showed that incidence and severity of CAWS-induced vasculitis, macrophage infiltration, and fibrosis were suppressed in NLRP3-, ASC- and IL-1β-deficient mice (Fig. A). In vitro : Bone marrow-derived dendritic cells (BMDCs) produced IL-1β by CAWS stimulation, which was suppressed by the anti-Dectin-2 antibody or caspase-1 inhibitor. The CAWS-induced IL-1β production was also suppressed in NLRP3-, ASC-, and caspase-1-deficient BMDCs (Fig. B). CAWS induced mitochondrial reactive oxygen species (mtROS) production, and Mito-TEMPO, a mtROS inhibitor, suppressed CAWS-induced caspase-1 activation (Fig. C) and IL-β production. In addition, CAWS-induced mtROS production was suppressed by Syk or JNK inhibitor. Furthermore, Syk or JNK inhibitor suppressed CAWS-induced NF-κB activation and subsequent IL-1β production. Conclusion: These findings demonstrated that NLRP3 inflammasome activation through Dectin-2/Syk/JNK-mediated mtROS plays a pivotal role in CAWS-induced vasculitis. CAWS also induced priming signal through Dectin-2/Syk/JNK/NF-κB pathway. Our finding indicates NLRP3 inflammasome as a new therapeutic target of KD.