Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis that predominantly afflicts children and is the leading cause of acquired heart disease among children. Coronary artery aneurysms (CAA) develop in 25% of untreated children with KD, leading to ischemic heart disease and myocardial infarction and to long - term cardiovascular complications into adulthood. While high dose IVIG treatment plus aspirin reduces the CAA from 25% down to 5%, up to 30% of KD patients are non-responsive to IVIG and have a higher risk of developing CAA. Therefore, discovery of novel and more effective treatments to prevent the cardiovascular complications (CAA) in KD is one of the highest research priorities.. A well-accepted mouse model of KD vasculitis, CAA and myocarditis is available that closely mimics the immunopathologic features of the cardiovascular lesions observed in KD patients. Recent genetic data, and data from experimental mouse model of KD, have all converged on the critical role of IL-1? signaling in pathogenesis of the KD lesions.. Two clinical trials using the IL-1R antagonist were recently initiated in KD patients who do not respond to IVIG. However, emerging data suggests that inhibiting IL-1? with mAb or the IL-1R antagonist can significantly increase the risk of infections (FDA database). Therefore, strategies to block the IL-1? pathway in more proximal steps may be beneficial in KD and bypass the unwanted effect of increased risk of infection associated with direct IL-1? antagonism. We obtained novel data to suggest that ER stress and mitochondrial oxidative DNA damage may play a role in cardiovascular lesions of KD vasculitis. Several ER stress response genes are significantly upregulated in whole blood cells of acute KD patients and in the LCWE-induced KD vasculitis mouse model, implicating ER stress in KD pathogenesis. Therefore, the central hypothesis of this exploratory R21 application is that ER stress is critical for robust NLRP3 inflammasome activation and IL- 1? release, which drives the cardiovascular pathology in KD. We propose interventions that can reduce ER stress and prevent oxidative mitochondrial DNA damage, thereby preventing NLRP3 activation, mitigate IL-1? release and inflammation, and prevent KD lesions. To investigate these central hypotheses, we propose the following Specific Aims:
Aim 1 : To define the role of ER stress and oxidative mitochondrial DNA stress in the activation of NLRP3 inflammasome and IL-1? production that drives cardiovascular lesions associated with KD vasculitis mouse model, and Aim 2: To determine the therapeutic efficacy of ER stress inhibitors and inhibitors of mitochondrial ROS and oxidative mt DNA damage in the prevention of cardiovascular lesions of KD vasculitis model. Modulation of these upstream pathways that stimulate activation of NLRP3 inflammasome and IL-1? production may be attractive targets for new therapeutic agents to prevent the cardiovascular lesions of KD without the increased risk for infections associated with direct IL-1? antagonism, using an experimental model that has proven to be of translational value to humans.
Kawasaki Disease (KD) vasculitis is the leading cause of acquired heart disease among children and recent studies suggest the key role of the inflammatory molecule IL-1 in this vasculitic disease. In the current proposal we will identify novel cellular mechanisms that induce this inflammatory molecule during KD, in order to improve and develop novel therapeutic approaches for this potentially serious and even fatal illness.
