AIM2 Targeting of Nuclear DNA Leakage in Dendritic Cells Exacerbates Vasculitis in a Murine Model of Kawasaki Disease.

Abstract

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 Candida albicans water-soluble fraction (CAWS)-induced vasculitis in a murine model mimicking KD. Aim2^-/- 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 (BMDC) isolated from wild-type (WT) and Aim2^-/- 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.