Activation of NLRP3 inflammasome in neutrophils promotes cardiovascular lesions in a mouse model of Kawasaki Disease 4448

Abstract Description Kawasaki Disease (KD) is a febrile systemic vasculitis and the leading cause of acquired heart diseases in children. Intravenous immunoglobulin (IVIG) treatment reduces the incidence of coronary artery aneurysms (CAAs), which occur in up to 25% of untreated children. Autopsies of tissues revealed neutrophils (Neu) infiltrating heart tissues in acute KD. Neu are recruited to injury sites via CXCR2, and they can form NETs induced by IL-1b to kill pathogens. Using the Lactobacillus casei cell-wall extract (LCWE) mouse model of KD vasculitis, we previously showed that Neu in lesions express Nlrp3 and Il1b. However, the role of Neu in KD remains unclear. Our time-course flow cytometric analysis showed increased CXCR2+ Neu in the peritoneum and blood of LCWE-injected mice at 24 hrs & 7d post-injection, respectively. Increased Neu infiltration in the heart and abdominal aorta (AA) of LCWE-injected mice from day 7 after injection had low expression of CXCR2. Cxcr2–/– mice were not protected, but mice with Neu-specific Nlrp3 deletion were significantly protected from vasculitis. Circulating myeloperoxidase (MPO) levels were increased 24 hours after LCWE injection and H3-Cit+MPO+ Neu (NETs) were detected by immunofluorescence in AA tissues of LCWE-injected mice. Our results indicate that Neu are rapidly mobilized, infiltrate the vascular tissues, and significantly contribute to LCWE-induced KD vasculitis through a mechanism driven by the NLRP3/IL-1b axis that may involve NET formation. Funding Sources NIH5R01AI157274-05 Topic Categories Immune Mechanisms of Human Disease (HUM)