HMGB1在病毒性心肌炎内质网应激相关炎症中的作用及其分子机制

ER stress, an important pathophysiological processes against unfavorable factors, contributes greatly to a variety of cardiovascular diseases. Our previous data showed that IRE1 pathway of ER stress was obviously activated in CVB3-induced myocarditis and positively related to the severity of myocardial inflammaiton; however, its initiation and regulation mechanisms remain unclear. We showed that danger signal HMGB1 and its receptor TLR4 could be robustly induced in CVB3-infected cells, and downregulation of HMGB1 signficantly reduced heart IRE1 pathway and associated myocardial inflammation, led to alleviated viral myocarditis. Herein, we raised the scientific hypotheis as follows: By binding TLR4 receptor, HMGB1 released by CVB3-infected myocardium may initiate and regulate the downstream of inflammation-associated IRE1 pathway TRAF2-JNK-AP1, XBP1-FoxO/IKK-NF-κB in myocardial ER stress and consequently promote the proinflammatory cytokine expression and aggravate viral myocarditis. This study may elucidate the initiation and regulation mechanisms of ER stress in CVB3-infected myocardium, and may provide a potential target for prevention and therapy of viral myocarditis.

内质网应激（ER stress）是机体应对不利因素的重要病理生理反应，参与多种心血管疾病的发生发展。我们前期工作显示，柯萨奇病毒B3型（CVB3）诱导的小鼠心肌炎模型中，心肌ER stress IRE1通路及其相关炎症应答显著激活，并与心肌炎症密切相关，但其启动及调控机制尚不明了。我们发现CVB3感染可显著诱导HMGB1分泌并上调其受体TLR4表达，而下调HMGB1可显著削弱CVB3感染小鼠心肌IRE1通路及相关炎症，明显改善心肌炎。因此我们提出如下科学假设： CVB3感染后，心肌释放大量危险信号HMGB1，后者经TLR4受体激活心肌IRE1通路，并对其下游TRAF2-JNK-AP1，XBP1-FoxO/IKK-NF-kB等炎症通路进行调控，进而参与心肌炎发病。本研究不仅有望阐明病毒性心肌炎ER stress相关炎症的启动和调控机制，同时也可能为其防治提供新的靶点。

在本项目的资助下，发现在CVB3诱导心肌炎时，心脏ER stress显著活化且与心肌炎病情发生发展密切相关。进一步研究发现ER stress下游通路IRE1可显著促进心脏炎症细胞因子分泌，加重心肌损伤。同时ER stress可显著促进心肌危险信号分子HMGB1释放，后者可通过RAGE受体促进ER stress 下游IRE1通路活化，并最终通过IKK-IkB- NF-kB通路促进心肌局部炎症因子如IL-6, IL-12, MCP-1和IP-10，加重心肌损伤和炎症。进一步检测感染心脏局部ER stress与HMGB1动态表达发现，ER stress于感染第1天即显著活化，并随着时间推移逐渐增强，而HMGB1则于第3-4天表达量显著增加，当阻断ER stress时心脏HMGB1表达显著减少，而阻断HMGB1时心脏ER stress的活化亦显著抑制，提示ER stress与HMGB1形成了能够显著激活心脏局部IKK-IkB-NF-kB炎症通路的正反馈，共同介导了心脏炎症应答和损伤。此外，心肌ER stress还可通过上清可溶性小分子传递至心脏浸润巨噬细胞，促进后者炎症应答，这一过程极有可能经HMGB1介导。上述结果已在病毒性心肌炎领域发表SCI文章 8篇，同时培养博士研究生1名，培养硕士研究生4名。