甘露糖受体MR通过PPARγ/NF-κB信号通路对心肌梗死后炎症表型的影响及其机制研究

Excessive inflammation in myocardial infarction plays an important role in the mechanism of myocardial damage, thus the best strategy is targeting against a harmful product while promoting beneficial function of inflammatory cells. Our preliminary experiment revealed that mannose receptor reduced the inflammatory damage in myocardial infarction by removing MPO; in addition, mannose receptor was found to increase reparative inflammation through macrophage M2 polarization. However, the underlying mechanism remains unclear. Previous studies indicated that, in tumor and pulmonary infection, mannose receptor regulate macrophage polarization via PPARγ/NF-κB signal pathway. Hence, we hypothesized that, via PPARγ/NF-κB signal pathway, mannose receptor would have a role in regulating macrophage polarization, thus the inflammatory phenotype (detrimental inflammation or reparative inflammation) in myocardial infarction. As indicated in our previous studies, MPO-Gd and CLIO molecular imaging is helpful in identifying the inflammatory phenotype in experimental stroke. Since inflammation in myocardial infarction and stroke are both ischemia induced sterile inflammation, aforementioned imaging method will be applied to track inflammatory phenotype in myocardial infarction, gene knock-out animal model, qPCR, Western and other techniques will be used to investigate the underlying regulatory mechanism of mannose receptor subsequently, the present study would provide new theoretical basis and monitoring tools for the precisely targeted anti-inflammatory therapy strategy.

炎症反应过度是心肌梗死后心肌损伤的重要机制，最佳治疗策略是减少炎症损伤作用同时放大炎症修复作用。我们前期发现：心肌梗死后，甘露糖受体MR可通过清除MPO减少炎症损伤；此外，MR还可以促进巨噬细胞M2型极化，但机制不明。既往研究发现，在肿瘤等疾病中，MR可通过PPARγ/NF-κB通路调控巨噬细胞极化。据此，我们推测心肌梗死中MR可能通过PPARγ/NF-κB通路调控心肌内巨噬细胞极化，影响炎症表型(损伤性或修复性炎症)。我们前期运用基于MPO-Gd和CLIO两种造影剂的分子影像学方法可有效鉴别中风动物模型中的炎症表型。心肌梗死和中风后的炎症反应同为缺血导致的无菌炎症，因此本项目拟运用该无创成像方法动态示踪心肌梗死后的炎症表型，并探讨MR对其影响。随后采用基因敲除动物、qPCR、Western等方法阐明MR对心肌梗死后炎症反应的调控机制，从而为心肌梗死精准抗炎治疗提供理论依据和监控手段。

炎症反应过度是心肌梗死后心肌损伤的重要机制，最佳治疗策略是减少炎症损伤作用同时放大炎症修复作用。我们前期发现：心肌梗死后，甘露糖受体MR可通过清除MPO减少炎症损伤；此外，MR还可以促进巨噬细胞M2型极化，但其机制不明。既往研究发现，在肿瘤等疾病中，MR可通过PPARγ/NF-κB通路调控巨噬细胞极化。我们通过本课题研究证明：1. 基于靶向巨噬细胞和髓过氧化物酶的多模态分子成像能够追踪心肌梗死后心肌内炎症表型（损伤性或修复性炎症）的分布和变化；2.我们利用该成像方法监测MR激动剂D-mmanose治疗的心肌梗死小鼠心肌内的炎症表型变化，发现其由损伤性为主的炎症反应向修复性为主的炎症反应转化；3. MR可通过PPARγ/NF-κB通路调控巨噬细胞极化，进而影响炎症表型。通过本课题的研究，将为心肌梗死精准抗炎治疗提供理论依据和影像学监控手段。