Alphonse Martin Prince, Duong Trang T, Shumitzu Chisato, Hoang Truong Long, McCrindle Brian W, Franco Alessandra, Schurmans Stéphane, Philpott Dana J, Hibberd Martin L, Burns Jane, Kuijpers Taco W, Yeung Rae S M
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Cell Biology Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
J Immunol. 2016 Nov 1;197(9):3481-3489. doi: 10.4049/jimmunol.1600388. Epub 2016 Sep 30.
Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1β and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1β and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.
川崎病（KD）是一种多系统血管炎，主要累及儿童冠状动脉。KD与反复发热综合征之间的表型相似性表明炎性小体激活在KD中可能发挥作用。NLRP3突变与反复发热/自身炎症综合征相关。我们发现，肌醇三磷酸3激酶C（ITPKC）中与KD相关的基因多态性（rs28493229）具有重要的功能后果，可调控ITPKC蛋白水平，进而影响细胞内钙水平，而细胞内钙又反过来调节NLRP3表达以及白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的产生。对一组基因分型的KD受试者的匹配连续生物样本进行转录本丰度、蛋白水平和细胞反应谱分析，表明ITPKC在介导NLRP3炎性小体激活中起关键作用。具有高危ITPKC基因型的患者治疗失败与最高的基础和刺激后细胞内钙水平相关，且与细胞IL-1β和IL-18产生增加以及两种细胞因子的循环水平升高有关。在疾病模型中使用Itpkc基因缺陷小鼠进行的机制研究支持了受影响儿童的基因组、细胞和临床研究结果。我们的研究结果揭示了在难治性KD中观察到的IL-1阻断抢救治疗疗效背后的机制，并且我们确定钙动员的调节是KD潜在免疫生物学的基础。
