Abstract
NLRP3 activation and IL-1β production are implicated in Kawasaki Disease (KD) pathogenesis, however a detailed description of the molecular networks and cellular subsets involved in this process is lacking. Here, we used single-cell RNA sequencing and spatial transcriptomics to characterize the cellular landscape of vascular tissues in a murine model of KD vasculitis. We observed infiltrations of innate and adaptive immune cells associated with increased expression of Nlrp3 , Il1b and Il18 . Monocytes, macrophages and dendritic cells were the main sources of IL-1β. Fibroblasts and vascular smooth muscle cells (VSMCs) expressed high levels of IL-1 receptor, while lymphocytes expressed high levels of IL-18 receptor. VSMCs in vasculitis lesions underwent a phenotypic switch, with upregulation of inflammatory mediators and fibroblast markers, and a downregulation of genes involved in contractile functions. Genetic inhibition of IL-1β signalling on VSMCs efficiently attenuated the phenotypic switch of VSMCs and the development of cardiovascular lesions during murine KD. In addition, pharmacological inhibition of NLRP3 prevented the development of cardiovascular inflammation. Our results unravel the cellular diversity involved in IL-1β production and signalling in KD cardiovascular lesions and demonstrate that therapeutic strategies targeting NLRP3 might be beneficial for human KD.
Published Version
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