Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health. No. 3333 Binsheng Road, Hangzhou 310052, PR China.
Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health. No. 3333 Binsheng Road, Hangzhou 310052, PR China.
Cytokine. 2023 Sep;169:156304. doi: 10.1016/j.cyto.2023.156304. Epub 2023 Jul 22.
By using GWAS(genome-wide association studies) and linkage disequilibrium analysis to investigate the susceptibility genes of KD(Kawasaki disease), previous studies have identified that the CaN(calcineurin)-NFAT(the nuclear factor of activated T cell) signal pathway were significantly associated with susceptibility to KD. However, little is known about the molecular basis of the CaN/NFAT pathway involved in KD. Therefore, in our study we investigate the role of Ca2+/CaN/NFAT signaling pathway in macrophages in vitro and in vivo on coronary artery lesions induced by LCWE (Lactobacillus casei cell wall extract).
We observed that LCWE could increase the expression of NFAT1 and NFAT2 in macrophages in vitro, and also enhance the transcriptional activity of NFAT by promoting the nucleus translocation. Similarly, in LCWE-induced mice model, the expression of NFAT1 and NFAT2 and associated proinflammatory factors were increased significantly. In addition, by knocking down or overexpressing NFAT1 or NFAT2 in macrophages, the results indicated that NFAT signaling pathway mediated LCWE-induced immune responses in macrophages and regulated the synthesis of IL(interleukin)-6, IL-1β and TNF(tumor necrosis factor)-α in LCWE-induced macrophage activation. As well, we found that this process could be suppressed by CaN inhibitor CsA(cyclosporinA).
Therefore, the CaN/NFAT signaling pathway mediated LCWE-induced immune responses in macrophages, and also participated in the LCWE-induced CALs(coronary artery lesions). And also the inhibitory effect of CsA in LCWE-induced cell model towards a strategy to modulate the CaN/NFAT pathway during the acute course of KD might be helpful in alleviate KD-induced CALs.
通过全基因组关联研究（GWAS）和连锁不平衡分析，研究川崎病（KD）的易感基因，先前的研究表明钙调神经磷酸酶（CaN）-活化 T 细胞核因子（NFAT）信号通路与 KD 的易感性显著相关。然而，关于 CaN/NFAT 通路在 KD 中涉及的分子基础知之甚少。因此，在我们的研究中，我们研究了 Ca2+/CaN/NFAT 信号通路在体外和体内对 LCWE（鼠李糖乳杆菌细胞壁提取物）诱导的冠状动脉损伤中巨噬细胞的作用。
我们观察到 LCWE 可以增加体外巨噬细胞中 NFAT1 和 NFAT2 的表达，并通过促进核易位增强 NFAT 的转录活性。同样，在 LCWE 诱导的小鼠模型中，NFAT1 和 NFAT2 的表达及其相关促炎因子显著增加。此外，通过敲低或过表达巨噬细胞中的 NFAT1 或 NFAT2，结果表明 NFAT 信号通路介导了 LCWE 诱导的巨噬细胞免疫反应，并调节了 LCWE 诱导的巨噬细胞活化中白细胞介素（IL）-6、IL-1β 和肿瘤坏死因子（TNF）-α 的合成。同样，我们发现这个过程可以被 CaN 抑制剂 CsA（环孢菌素 A）抑制。
因此，CaN/NFAT 信号通路介导了 LCWE 诱导的巨噬细胞免疫反应，并参与了 LCWE 诱导的冠状动脉损伤。CsA 在 LCWE 诱导的细胞模型中的抑制作用可能有助于减轻 KD 诱导的冠状动脉损伤，从而为在 KD 急性病程中调节 CaN/NFAT 通路提供一种策略。
