Single-cell and spatial transcriptomics reveal NLRP3 inflammasome-mediated immunestromal interactions during vasculitis and cardiovascular inflammation

Abstract NLRP3 activation and IL-1β production are implicated in Kawasaki Disease (KD) pathogenesis, however a detailed description of molecular networks and cellular subsets involved is lacking. Here, in a murine model of KD vasculitis, we used single-cell RNA sequencing and spatial transcriptomics to characterize the cellular landscape of vascular tissues and observed infiltrations of innate and adaptive immune cells, associated with increased expression of Nlrp3 and Il1b. Monocytes, macrophages and dendritic cells were the main sources of IL-1β, whereas fibroblasts and vascular smooth muscle cells (VSMCs) expressed high levels of IL-1 receptor. Genetic inhibition of IL-1β signaling on VSMCs efficiently attenuated 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 signaling in KD cardiovascular lesions and demonstrate that therapeutic strategies targeting NLRP3 might be beneficial for human KD.