可转移性心肌内质网应激在柯萨奇病毒B3诱导的病毒性心肌炎发病中的作用及其机制研究

柯萨奇病毒B3型（CVB3）诱导的心肌炎发病日益严重，但机制不清。巨噬细胞是参与病毒性心肌炎发病的重要炎症细胞，我们前期研究发现：心肌炎小鼠巨噬细胞内质网应激(ER stress)明显激活，并显著促进炎症细胞因子分泌。同时我们前期研究也发现，CVB3本身并不能引起巨噬细胞ER stress，但可激活心肌细胞ER stress。有趣的是，当将ER stress活化的心肌细胞与巨噬细胞共孵育时，后者ER stress即显著活化。进一步研究发现，该细胞培养上清中损伤相关分子模式（DMAPs）HSP90和HMGB1表达增加，这些分子均是TLR2/4的配体。因此，我们提出科学假设：感染心肌细胞ER stress可经DAMPs-TLR2/4通路传递至巨噬细胞，并对其下游TRAF2-AP1，XBP1-NF-κB等炎症通路进行调控。本研究有望阐明心肌炎巨噬细胞ER stress的启动和调控机制。

Coxsackievirus B3(CVB3) induced viral myocarditis is a major cardiovascular cause of sudden death in men less than 40 years of age, but its pathological mechanism remains unclear. Macrophages have been proven to play a critical pathological role in viral myocarditis. Our preliminary data showed that ER stress was robustly activated in myocardial macrophages of CVB3-infected mice and potentially promoted the production of proinflammatory cytokines. However, CVB3 could not directly stimulate ER stress in macrophages in vitro, but could directly stimulate ER stress in myocardiocytes. More interestingly, ER stress in macrophages was efficiently induced when co-culturing with the supernatant of ER stress-activated myocardiocytes, in which the expression of damage-associated molecular pattern (DAMPs) HSP90 and HMGB1 was substantially increased. These data prompt us to speculate that: ER stress of CVB3-infected myocardiocytes could transmit to macrophages by the DAMPs-TLR2/4 pathway, and then promote the production of proinflammatory cytokines via activating the downstream TRAF2-AP1, XBP1-NF-κB signaling pathways. This study may elucidate the initiation and regulation mechanism of ER stress in macrophages, and may also provide a potential therapeutic target for CVB3-induced myocarditis.