LAUSR

Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Recent experimental data from mouse models, as well as clinical, genetic and transcriptome evidence from KD patients suggest a key role of the NLRP3-IL-1β pathway in the pathogenesis of KD. NLRP3 can be activated by mitochondrial (mt) DNA released in the setting of defective autophagy/mitophagy, but a potential role for autophagy/mitophagy in KD cardiovascular inflammation has not been determined. In the Lactobacillus casei cell wall extract (LCWE) mouse model of KD vasculitis, LCWE injection in WT mice results in coronary arteritis, aortitis and myocarditis, mimicking human KD. We found that expression of the autophagy/mitophagy markers Parkin and p62 was significantly higher in whole lysate and mitochondrial fractions of heart tissue of LCWE-injected mice than controls, indicating impaired autophagic flux and mitophagy. Parkin -/- mice developed significantly more LCWE-induced cardiovascular lesions than control mice, and treatment of WT mice with a GLP-1 receptor agonist, known to activate Parkin, significantly reduced LCWE-induced inflammation. LCWE-induced cardiovascular lesions were amplified in mice deficient in OGG1, a base excision repair protein sensitive to mtDNA damage. Finally, inhibiting autophagy with chloroquine exacerbated LCWE-induced KD vasculitis, whereas inducing autophagy by intermittent fasting decreased cardiovascular inflammation in the model. Altogether, our data suggest that impaired autophagy/mitophagy exacerbates KD and supports a role for mtDNA damage in the disease. These findings enhance our understanding of KD pathogenesis and may provide novel therapeutic targets.