In a mouse model of Kawasaki disease, genetic deficiency of caspase-1 or IL-1 receptor, as well as treatment with an IL-1 receptor antagonist, protected against LCWE-induced coronary lesions.
Does IL-1 receptor antagonism or deficiency prevent coronary artery lesions in a mouse model of Kawasaki disease?
IL-1 receptor antagonism prevents coronary artery lesions in a mouse model of Kawasaki disease, providing a mechanistic rationale for targeted anti-IL-1β therapy in patients.
BACKGROUND: Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease in US children. Untreated, children may develop coronary artery aneurysms, myocardial infarction, and sudden death as a result of the illness. Up to a third of KD patients fail to respond to intravenous immunoglobulin, the standard therapy, and alternative treatments are being investigated. Genetic studies have indicated a possible role for interleukin (IL)-1β in KD. We therefore explored the role of IL-1β in a murine model of KD. METHODS AND RESULTS: Using an established mouse model of KD that involves injection of Lactobacillus casei cell wall extract (LCWE), we investigated the role of IL-1β and caspase-1 (activated by the inflammasome and required for IL-1β maturation) in coronary arteritis and evaluated the efficacy of IL-1 receptor antagonist as a potential treatment. LCWE-induced IL-1β maturation and secretion were dependent on the NLRP3 inflammasome in macrophages. Both caspase-1-deficient and IL-1 receptor-deficient mice were protected from LCWE-induced coronary lesions. Injection of recombinant IL-1β into caspase-1-deficient mice restored the ability of LCWE to cause coronary lesions in response to LCWE. Furthermore, daily injections of the IL-1 receptor antagonist prevented LCWE-mediated coronary lesions up to 3 days after LCWE injection. CONCLUSIONS: Our results strongly suggest that caspase-1 and IL-1β play critical roles in the development of coronary lesions in this KD mouse model, blocked by IL-1 receptor antagonist. Therefore, anti-IL-1β treatment strategies may constitute an effective, more targeted treatment of KD to prevent coronary lesions.
Lee et al. (Fri,) conducted a other in Kawasaki disease (mouse model). IL-1 receptor antagonist and genetic deficiency of caspase-1 or IL-1 receptor vs. Untreated/wild-type LCWE-injected mice was evaluated on Coronary lesions. In a mouse model of Kawasaki disease, genetic deficiency of caspase-1 or IL-1 receptor, as well as treatment with an IL-1 receptor antagonist, protected against LCWE-induced coronary lesions.