IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1α and IL-1β.
IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1α and IL-1β.
复制标题
川崎疾病血管炎小鼠模型中的基质细胞中，IL-1信号传导是至关重要的：IL-1α和IL-1β的作用。
DOI：
10.1161/atvbaha.115.306475
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Arditi M
中科院分区：
文献类型：
--
作者：
Lee Y;Wakita D;Dagvadorj J;Shimada K;Chen S;Huang G;Lehman TJ;Fishbein MC;Hoffman HM;Crother TR;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。我们先前已经证明TLR2/MyD88和IL-1β信号在干酪乳杆菌细胞壁提取物诱导的KD血管炎小鼠模型中都是必需的。本研究旨在探讨小鼠血管炎模型中IL-1产生的细胞来源、CD11c+树突状细胞(DC)和巨噬细胞的作用、造血细胞和基质细胞对IL-1反应细胞的相对贡献以及MyD88信号转导途径。利用小鼠基因敲除模型和抗体耗竭模型，我们发现白介素1α和白介素1β都是致病所必需的。DC和巨噬细胞都是必需的，我们发现MyD88信号在造血细胞和基质细胞中都是必需的。然而，IL-1的反应和信号在非内皮基质细胞中是至关重要的，而不是造血细胞。提示IL-1α和IL-1β以及CD11c+树突状细胞和巨噬细胞在KD小鼠血管炎和冠脉炎的发生发展中起重要作用。骨髓嵌合体实验表明，MyD88信号在造血细胞和基质细胞中都很重要，而IL-1信号和反应只在基质细胞中需要，而在内皮细胞中不需要。确定IL-1α和IL-1β以及特定细胞类型在KD血管炎小鼠模型中的作用，可能对设计更有针对性的治疗方法和理解KD免疫病理的分子机制具有重要意义。
Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and IL-1β signaling are required for the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c+ Dendritic Cells (DCs) and macrophages and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling in LCWE-induced KD mouse model of vasculitis. Using mouse knockout models as well as antibody depletion, we found that both IL-1α and IL-1β were required for LCWE-induced KD. Both DCs and macrophages were necessary and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling was critically required in non-endothelial stromal cells, but not hematopoietic cells. Our results suggest that IL-1α and IL-1β as well as CD11c+ DCs and macrophages are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, while IL-1 signaling and response is required only in stromal cells, but not in endothelial cells. Determining the role IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.