Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis of unknown etiology that predominantly afflicts children <5 yrs of age, often causes coronary artery abnormalities, coronary artery (CAA) as well as systemic artery aneurysms, and myocarditis. KD can lead to long-term cardiovascular sequelae, including vascular remodeling, ischemic heart disease, myocardial infarction, myocardial fibrosis and even death, and is the leading cause of acquired heart disease among children in the US. Although high dose IVIG treatment plus aspirin reduces the cardiovascular complications of KD (CAA) from 25% down to 5%, up to 20- 25% of KD patients are IVIG-resistant and are at even higher risk for developing CAA. Therefore, discovery of more effective treatments for KD to prevent or attenuate coronary artery damage is one of the highest priorities in Pediatric research. IL-1, a cytokine linked to many immunopathologies, has been implicated in human KD. Recently, genetic susceptibility studies in patients as well as experimental animal studies converged in a common pathway of IL-1 in the pathogenesis of KD vasculitis. Very limited availability of tissue samples from patients with KD has significantly impeded our progress in understanding the pathogenesis of the disease. Fortunately, a well-accepted mouse model of KD vasculitis, CAA and myocarditis is available that closely mimics the immune-pathologic features of the cardiovascular lesions observed in KD patients. In the previous funding cycle we demonstrated that Caspase-1 activation and IL-1 are crucial for the development of KD vasculitis, aneurysm and myocarditis in this mouse model. This has led to two recent clinical trials using the IL-1 R antagonist (Anakinra) in KD patients resistant to IVIG. IL-1 usually requires the NLRP3 inflammasome to be activated. Autophagy, the mechanism by which cells recycle organelles etc., plays an opposing role to inflammasome activation and may be an attractive target for preventing IL-1 based diseases. However the exact mechanisms by which IL-1 plays a role in KD pathogenesis is still unknown. Both IL-1? and IL-1? can bind to and activate the IL-1 R, and target cell(s) of IL-1 is unknown. In preliminary chimera experiments, we have found that IL-1 signaling is only critically required in non-endothelial stromal cells. Based on these data we propose the CENTRAL HYPOTHESIS that both IL-1? and IL-1? play a key role in the development of KD vasculitis, aneurysm and myocarditis and that IL-1 signaling in vascular SMCs drives the KD vasculitis pathology, including IL-1 and MMP-3- driven VSMC proliferation to induced the hallmark pathology of KD. We also hypothesize that autophagy and mitophagy inhibit inflammasome-mediated IL-1 secretion, thereby preventing KD vasculitis. To investigate these hypothesis, we propose the following SPECIFIC AIMS: 1) The role of IL-1? and IL-1? in LCWE-induced coronary arteritis, aneurysm, and myocarditis; 2) To investigate the role of IL-1 R1 in vascular smooth muscle cells (VSMC) during KD vasculitis, and aneurysm; and 3) To investigate autophagy/mitophagy during KD vasculitis, aneurysm and myocarditis.

Public Health Relevance

Kawasaki Disease (KD) is the leading cause of acquired heart disease among children. In this application we will identify novel mechanisms underlying IL-1-mediated vasculitis, aortic aneurysm formation as well as myocarditis associated with KD, which will lead to new avenues for both prevention and treatment of cardiovascular complications in KD and possibly in other immune vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072726-10
Application #
9854871
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Davidson, Wendy F
Project Start
2008-03-15
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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