NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis.
NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis.
复制标题
NLRP3 炎症小体介导血管炎中的免疫基质相互作用。
DOI：
10.1161/circresaha.121.319153
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发表时间：
2021-10-15
影响因子：
20.1
通讯作者：
Noval Rivas M
中科院分区：
文献类型：
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作者：
Porritt RA;Zemmour D;Abe M;Lee Y;Narayanan M;Carvalho TT;Gomez AC;Martinon D;Santiskulvong C;Fishbein MC;Chen S;Crother TR;Shimada K;Arditi M;Noval Rivas M
NLRP3的激活和IL-1β的产生与川崎病（KD）的发病机制有关，然而，关于参与心血管病变发展的分子网络和细胞亚群的详细和完整的表征仍然缺乏。在小鼠KD血管炎模型中，我们使用单细胞RNA测序和空间转录组学来确定炎症血管组织的细胞景观。我们观察到小鼠KD心血管病变的先天和适应性免疫细胞浸润，与Nlrp3和Il1b的表达增加有关。单核细胞、巨噬细胞和树突状细胞是IL-1β的主要来源，而成纤维细胞和血管平滑肌细胞（VSMCs）则表达高水平的IL-1受体。冠状动脉炎症周围的1型VSMCs经历表型转换成为2型VSMCs，其特征是与收缩减少、迁移和增殖增强相关的基因表达改变。IL-1β信号在VSMCs上的遗传抑制有效地减弱了小鼠KD血管炎期间VSMCs 2型表型开关和心血管病变的发展。此外，NLRP3的药理抑制可防止心血管炎症的发生。我们的研究揭示了小鼠KD心血管病变中参与IL-1β产生和信号传导的细胞多样性，并为靶向NLRP3抑制KD相关心血管病变的治疗策略提供了理论依据。川崎病（KD）是一种病因不明的发热性血管炎，是美国儿童获得性心脏病的主要原因。目前的治疗方法是静脉注射免疫球蛋白（IVIG），这是非特异性的，高达20%的KD患者对IVIG有抵抗性，并且发生冠状动脉病变的风险更高。对介导KD心血管后遗症的分子机制和细胞亚群的不完全理解阻碍了更有针对性和更有效的治疗选择的发展。在目前的研究中，我们应用多组学方法来表征小鼠KD期间血管炎症发展中涉及的细胞网络和分子改变。该分析使我们能够生成小鼠KD心血管病变的综合细胞图谱，并确定NLRP3-IL-1β/IL-18轴是KD发病的关键驱动因素。我们还确定血管组织浸润的单核细胞、巨噬细胞和树突状细胞是小鼠KD过程中IL-1β产生的主要细胞来源，血管平滑肌细胞（VSMCs）对IL-1信号的反应能力最强，集中在冠状动脉周围区域。事实上，我们表明，在小鼠KD中，VSMCs中IL-1受体的体内细胞特异性缺失强烈降低了血管病变的严重程度。此外，我们对新疗法的开发非常感兴趣，我们证明直接药物靶向NLRP3，可以阻断IL-1β和IL-18的成熟，也可以阻止lcwe诱导的KD血管炎的发展。
NLRP3 activation and IL-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. 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. 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. 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. Kawasaki disease (KD), a febrile vasculitis of unknow etiology, is the main cause of acquired heart disease in children in the USA. The current therapy, intravenous immunoglobulin (IVIG), is non-specific, and up to 20% of KD patients are IVIG-resistant and at higher risks of developing coronary artery lesions. The incomplete understanding of the molecular mechanisms and the cellular subsets mediating the cardiovascular sequelae of KD have hampered the development of more targeted and effective treatment options. In the current study, we applied a multi-omics approach to characterize the cellular networks and molecular alterations involved in vascular inflammation development during murine KD. This analysis allowed us to generate a comprehensive cellular atlas of murine KD cardiovascular lesions and to identify the NLRP3-IL-1β/IL-18 axis as a key driver of KD pathogenesis. We also determined that vascular tissue-infiltrating monocytes, macrophages and dendritic cells are the main cellular sources of IL-1β production during murine KD, and that vascular smooth muscle cells (VSMCs) have the greatest capacity to respond to IL-1 signaling and are concentrated in areas surrounding the coronary artery. Indeed, we show that in vivo cell-specific deletion of IL-1 receptor specifically in VSMCs strongly decreased the severity of vascular lesions in murine KD. Moreover, of high interest for the development of novel therapeutics, we demonstrate that direct pharmacological targeting of NLRP3, which blocks maturation of both IL-1β and IL-18, also prevented the development of LCWE-induced KD vasculitis.