AIM2 targeting of nuclear DNA leakage in dendritic cells exacerbates vasculitis in a murine model of Kawasaki disease

Kawasaki disease (KD) is an acute vasculitis that mostly affects children and is characterized by inflammation of medium-sized arteries, particularly the coronary arteries. The absent in melanoma 2 (AIM2) inflammasome senses cytosolic dsDNA and regulates IL-1β-driven inflammation. We investigated the role of AIM2 in <i>Candida albicans</i> water-soluble fraction (CAWS)-induced vasculitis in a murine model mimicking KD. <i>Aim2</i>^-/- mice exhibited reduced vasculitis, inflammatory cell infiltration, and vascular fibrosis in the aorta and coronary arteries. In addition, dsDNA damage was detected in Dectin-2⁺ cells infiltrating vasculitis areas. In vitro experiments showed that CAWS induced dsDNA damage in Dectin-2⁺ bone marrow-derived dendritic cells (BMDCs) isolated from wild-type (WT) and <i>Aim2</i>^-/- mice. Furthermore, CAWS induces nuclear membrane deformation and DNA leakage into the cytosol, leading to AIM2 inflammasome activation and subsequent IL-1β production in WT BMDC. These findings suggest that AIM2 inflammasome activation in dendritic cells, triggered by dsDNA damage and leakage, contributes to the development of CAWS-induced vasculitis, and provides important insights into the inflammatory mechanisms underlying KD.<b>NEW & NOTEWORTHY</b> The AIM2 inflammasome in dendritic cells is a significant component of the murine model of Kawasaki disease-like vasculitis induced by CAWS injection. The AIM2 deficiency reduces vasculitis via reduced inflammatory cell infiltration and vascular fibrosis in CAWS-induced vasculitis. CAWS induces the damage and leakage of nuclear DNA in dendritic cells, which triggers AIM2 inflammasome activation, leading to an IL-1β-driven inflammatory response.