Transmissible endoplasmic reticulum stress from myocardiocytes to macrophages is pivotal for the pathogenesis of CVB3-induced viral myocarditis.
Transmissible endoplasmic reticulum stress from myocardiocytes to macrophages is pivotal for the pathogenesis of CVB3-induced viral myocarditis.
复制标题
从心肌细胞到巨噬细胞的传染性内质网应激对于 CVB3 诱导的病毒性心肌炎的发病机制至关重要
DOI：
10.1038/srep42162
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发表时间：
2017-02-08
影响因子：
4.6
通讯作者：
Xiong S
中科院分区：
文献类型：
--
作者：
Zhang H;Yue Y;Sun T;Wu X;Xiong S
浸润性巨噬细胞已被证明是柯萨奇病毒B3（CVB3）诱导的病毒性心肌炎中关键的病理性炎症细胞亚群。然而，巨噬细胞促炎反应起始和促进的潜在机制仍不清楚。我们先前报道过，心脏内质网应激通过增强炎症促进了CVB3诱导的心肌炎。在本研究中，我们重点关注内质网应激对病毒性心肌炎中巨噬细胞炎症反应的影响。我们发现，在CVB3感染小鼠的心脏浸润性巨噬细胞中，内质网应激被强烈诱导，并强烈促进促炎细胞因子（白细胞介素 - 6、白细胞介素 - 12、单核细胞趋化蛋白 - 1和干扰素诱导蛋白 - 10）的产生。一致地，过继转移内质网应激的巨噬细胞显著加重了病毒性心肌炎；而转移内质网应激受抑制的巨噬细胞则明显减轻了心肌炎。令我们惊讶的是，这种显著激活的内质网应激不是由病毒刺激直接引起的，而是通过可溶性分子以不依赖Toll样受体2、4的方式从CVB3感染的、内质网应激的心肌细胞传递而来。在本研究中，我们报道了从感染的心肌细胞到巨噬细胞的可传递内质网应激能够增强促炎反应并促进病毒性心肌炎的发病机制。阻断内质网应激传递，而非抑制其起始，可能代表针对病毒性心肌炎的新型治疗策略。
Infiltrating macrophages have been proven as a pivotal pathological inflammatory cell subset in coxsackievirus B3 (CVB3) induced viral myocarditis. However, the mechanisms underlying the initiation and promotion of macrophage pro-inflammatory responses are still blur. We previously reported that cardiac ER stress contributed to CVB3-induced myocarditis by augmenting inflammation. In this study, we focused on the influence of ER stress on the macrophage inflammatory responses in the viral myocarditis. We found that ER stress was robustly induced in the cardiac infiltrating macrophages from CVB3-infected mice, and robustly facilitated the production of pro-inflammatory cytokines (IL-6, IL-12, MCP-1 and IP-10). Consistently, adoptive transfer of ER stressed macrophages significantly worsened the viral myocarditis; while transfer of ER stress-inhibited macrophages obviously alleviated the myocarditis. To our surprise, this significantly activated ER stress was not directly caused by the virus stimulation, but was transferred from the CVB3-infected, ER stressed myocardiocytes via soluble molecules in a TLR2, 4-independent way. In the present study, we reported that the transmissible ER stress from the infected myocardiocytes to macrophages could augment the pro-inflammatory responses and promoted the pathogenesis of viral myocarditis. Blocking ER stress transmission, instead of inhibiting its initiation, may represent novel therapeutic strategies against viral myocarditis.