The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia;
Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
J Immunol. 2019 Jun 1;202(11):3151-3160. doi: 10.4049/jimmunol.1801593. Epub 2019 Apr 17.
Kawasaki disease (KD) is a leading cause of pediatric heart disease, characterized by the emergence of life-threatening coronary vasculitis. Identifying which cytokines drive KD has been a major research goal, and both TNF and IL-1 have been identified as potential candidates. Using a murine model of KD induced by the injection of the water-soluble component of , we therefore undertook a mechanistic study to determine how and when these two cytokines mediate cardiac inflammation. In this study, we show that TNF signaling is active in the acute phase of cardiac inflammation, which is characterized by a diffuse myocarditis that precedes the development of coronary vasculitis. Mechanistically, TNF is produced by the myeloid cells and triggers acute cardiac inflammation by stimulating both stromal and immune compartments of the heart. In contrast to this early involvement for TNF, IL-1 signaling is dispensable for the development of acute myocarditis. Critically, although mice deficient in IL-1 signaling have extensive acute inflammation following water-soluble complex challenge, they do not develop coronary vasculitis. Thus, TNF and IL-1 appear to play temporally distinct roles in KD, with TNF being active in acute cardiac inflammation and IL-1 in the subsequent development of coronary vasculitis. These observations have important implications for understanding the progression of cardiac pathology in KD and the relative therapeutic use of targeting these cytokines.
川崎病（KD）是小儿心脏病的主要病因，其特征为危及生命的冠状动脉血管炎。确定哪些细胞因子驱动 KD 一直是一个主要的研究目标，TNF 和 IL-1 已被确定为潜在的候选者。因此，我们使用通过注射可溶性成分 诱导的 KD 小鼠模型进行了一项机制研究，以确定这两种细胞因子如何以及何时介导心脏炎症。在这项研究中，我们表明 TNF 信号在心脏炎症的急性期活跃，其特征为在冠状动脉血管炎发展之前出现弥漫性心肌炎。从机制上讲，TNF 由髓样细胞产生，并通过刺激心脏的基质和免疫区室来引发急性心脏炎症。与 TNF 的早期参与相反，IL-1 信号对于急性心肌炎的发展是可有可无的。至关重要的是，尽管缺乏 IL-1 信号的小鼠在 水溶性复合物挑战后具有广泛的急性炎症，但它们不会发展为冠状动脉血管炎。因此，TNF 和 IL-1 似乎在 KD 中发挥时间上不同的作用，TNF 在急性心脏炎症中活跃，而 IL-1 在随后的冠状动脉血管炎发展中活跃。这些观察结果对理解 KD 中心脏病理学的进展以及针对这些细胞因子的相对治疗用途具有重要意义。
