Role of Sex in Immune Stromal cell Interactions driving cardiovascular lesions in Kawasaki Disease vasculitis

PROJECT ABSTRACT Kawasaki disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children in the US. Coronary artery aneurysms (CAA) develop in as many as 25% of untreated KD patients, resulting in ischemic heart disease, myocardial infarction, and even death. Although intravenous IgG (IVIG) treatment within the first 10 days of illness significantly reduces the likelihood of cardiovascular complications, up to 25% of KD patients are IVIG-resistant and at higher risk of developing CAA. Therefore, a better understanding of the immune and pathological mechanisms leading to the development of KD vasculitis is needed to identify more efficacious KD therapeutics and prevent the long-term cardiovascular sequelae stemming from tissue inflammation and coronary remodeling. KD occurs more frequently in males, and male patients experience more severe disease than female patients. However, the mechanisms underlying this sex disparity are unknown. In both the human disease and a murine model of KD vasculitis, the NLRP3-IL-1β axis has been identified as a key driver of pathogenesis. Our preliminary data indicate that vascular tissue- infiltrating monocytes, macrophages and dendritic cells are the main cellular sources of IL-1β during murine KD. We have also shown that vascular smooth muscle cells (VSMCs) surrounding the coronary artery undergo a phenotype switch, acquiring properties of fibromyocytes and synthetic VSMCs. This phenotype switch may contribute to luminal myofibroblast proliferation in the murine model of KD vasculitis. Importantly, we find enhanced IL-1β production and signaling, increased inflammatory monocytes and neutrophils, and enhanced VSMC phenotype switching in male KD mice compared with females. Based on our strong published and preliminary evidence, our central hypothesis is that differences in IL-1β-mediated immune-stromal cell interactions drive the sex disparity in KD. We will test this hypothesis in the following aims: Establish the contribution of monocytes, macrophages, and neutrophils to disease pathogenesis in male and female mice during LCWE-induced KD vasculitis (Aim 1); Establish the contribution of sex differences in vascular smooth muscle cell function to sexual dimorphism in LCWE-induced vasculitis (Aim 2). The completion of these studies will determine the fundamental mechanisms that mediate sex-based differences in cardiovascular lesion development in KD, which may lead to novel therapeutic approaches.