NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis. Issue 9 (15th October 2021)

• Record Type: Journal Article
• Authors: Porritt, Rebecca A.; Zemmour, David; Abe, Masanori; Lee, Youngho; Narayanan, Meena; Carvalho, Thacyana T.; Gomez, Angela C.; Martinon, Daisy; Santiskulvong, Chintda; Fishbein, Michael C.; Chen, Shuang; Crother, Timothy R.; Shimada, Kenichi; Arditi, Moshe; Noval Rivas, Magali
• Is Part Of: Circulation research. Volume 129:Issue 9(2021)
• Publication Date: 2021-10-15
• Subjects: inflammation -- inflammasomes -- interleukin-1 -- monocytes -- smooth muscle myocytes -- vasculitis; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.121.319153
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: NLRP3 (NLR family pyrin domain containing 3) activation and IL-1β (interleukin-1β) production are implicated in Kawasaki disease (KD) pathogenesis; however, a detailed and complete characterization of the molecular networks and cellular subsets involved in the development of cardiovascular lesions is still lacking. Objective: Here, in a murine model of KD vasculitis, we used single-cell RNA sequencing and spatial transcriptomics to determine the cellular landscape of inflamed vascular tissues. Methods and Results: We observe infiltrations of innate and adaptive immune cells in murine KD cardiovascular lesions, 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. VSMCs type 1 surrounding the inflamed coronary artery undergo a phenotype switch to become VSMCs type 2, which are characterized by gene expression changes associated with decreased contraction and enhanced migration and proliferation. Genetic inhibition of IL-1β signaling on VSMCs efficiently attenuated the VSMCs type 2 phenotypic switch and the development of cardiovascular lesions during murine KD vasculitis. In addition, pharmacological inhibition of NLRP3 prevented the development of cardiovascular inflammation. Conclusions: Our studies unravel the cellular diversity involved in IL-1β production and signaling in murine KD cardiovascular lesions and provide the rationale for therapeutic strategies targeting NLRP3 to inhibit cardiovascular lesions associated with KD. Abstract : Supplemental Digital Content is available in the text.