Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease.
Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease.
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DOI：
10.1161/circulationaha.111.072769
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发表时间：
2012-03-27
期刊：
影响因子：
37.8
通讯作者：
Arditi M
中科院分区：
文献类型：
--
作者：
Lee Y;Schulte DJ;Shimada K;Chen S;Crother TR;Chiba N;Fishbein MC;Lehman TJ;Arditi M
川崎病(KD)是美国儿童急性脉管炎和获得性心脏病的最常见原因。如果不进行治疗，儿童可能会因这种疾病而患上冠状动脉动脉瘤、心肌梗死和猝死。多达三分之一的KD患者对静脉注射丙种球蛋白(IVIG)没有反应，这是标准疗法，替代疗法正在研究中。遗传学研究表明，IL-1β可能在KD发病中起作用。因此，我们探讨了IL-1β在KD小鼠模型中的作用。采用干酪乳杆菌细胞壁提取液建立的KD小鼠模型，研究IL-1β和Caspase-1(由炎症小体激活，是IL-1β成熟所必需的)在冠脉炎中的作用，并评价IL-1受体拮抗剂(IL-1ra)作为一种潜在的治疗方法的疗效。LCWE诱导的IL-1β的成熟和分泌依赖于巨噬细胞中的NLRP3炎性小体。Caspase1基因缺陷和IL-1R基因缺陷的小鼠均可免受LCWE诱导的冠状动脉病变的影响。将重组IL-1β注射到半胱氨酸天冬氨酸蛋白酶-1缺陷小鼠体内，可恢复小鼠对小鼠冠状动脉病变的反应能力。此外，每天注射IL-1ra可预防LCWE介导的冠状动脉病变，最长可达注射后三天。我们的结果有力地表明，Caspase-1和IL-1β在这个被IL-1ra阻断的KD小鼠模型的冠状动脉病变的发展中起着关键作用。因此，抗IL-1的β治疗策略可能构成一种有效、更有针对性的治疗川崎病预防冠状动脉病变的方法。
Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease in US children. Untreated, children may develop coronary artery aneurysms, myocardial infarction and sudden death as a result of the illness. Up to a third of KD patients fail to respond to intravenous gammaglobulin (IVIG), the standard therapy, and alternative treatments are being investigated. Genetic studies have indicated a possible role for IL-1β in KD. We therefore explored the role of IL-1β in a murine model of KD. Using an established mouse model of KD that involves injection of Lactobacillus casei cell wall extract (LCWE), we investigated the role of IL- 1β and caspase-1 (activated by the inflammasome and required for IL-1β maturation) in coronary arteritis, and evaluated the efficacy of IL-1 receptor antagonist (IL-1Ra) as a potential treatment. LCWE-induced IL-1β maturation and secretion was dependent on the NLRP3 inflammasome in macrophages. Both caspase1-deficient and IL-1R-deficient mice were protected from LCWE-induced coronary lesions. Injection of recombinant IL-1β to caspase-1-deficient mice restored the ability of LCWE to cause coronary lesions in response to LCWE. Furthermore, daily injections of the IL-1Ra prevented LCWE-mediated coronary lesions, up to three days after LCWE injection. Our results strongly suggest that caspase-1 and IL-1β play critical roles in the development of coronary lesions in this KD mouse model, blocked by IL-1Ra. Therefore, anti-IL-1β treatment strategies may constitute an effective, more targeted treatment of KD to prevent coronary lesions.