ADAM8调控CCR2+巨噬细胞促炎反应在心肌梗死中的作用机制研究

CCR2+（CC趋化因子受体2+）巨噬细胞及其介导的促炎反应在心肌梗死后心肌损伤中发挥重要作用。前期单细胞测序数据集分析及预实验结果表明：CCR2+巨噬细胞内ADAM8（解整合素样金属蛋白酶8）表达显著上调，而抑制其表达可以减少下游靶向酶解产物EGFR配体的脱落，降低NLRP3、IL-1β和IL-18水平，提示ADAM8可能与CCR2+巨噬细胞分泌炎症因子密切相关，机制仍待深入研究。本项目拟探讨：①ADAM8对小鼠巨噬细胞炎症反应及心梗后心肌损伤的作用（采用巨噬细胞特异性基因敲除技术）；②调控CCR2+巨噬细胞上调表达ADAM8的分子机制（HMGB1-TLR2-Sp1通路？）；③ADAM8调控CCR2+巨噬细胞促炎反应的分子机制(EGFR-MAPK-NLRP3通路？)。旨在阐明ADAM8调节CCR2+巨噬细胞促炎反应参与心梗后心肌损伤的机制，为心肌梗死治疗提供新靶点。

CCR2+ (CC chemokine receptor 2+) macrophage-mediated proinflammatory response plays an important role in ischemic myocardial injury. Bioinformatic analysis based on single-cell sequencing dataset and exploratory experiments showed that CCR2+ macrophages expressed significantly higher ADAM8 (a disintegrin and metalloprotease 8) than CCR2- macrophages; inhibiting ADAM8 expression can reduce the shedding of ADAM8-targeted EGFR ligand (EGF), expression of NLRP3 and secretion of IL-1β and IL-18 in CCR2+ macrophages, suggesting that ADAM8 may be closely related to the secretion of inflammatory cytokines by CCR2+ macrophages. The detailed mechanisms are worthy of further study. This project aims to explore: ① The effect of ADAM8 on macrophages-mediated proinflammatory response and myocardial infarction (using macrophage-specific gene knockout technology); ② The molecular mechanism of up-regulating ADAM8 expression in CCR2+ macrophages (HMGB1-TLR2-Sp1 pathway?); ③ The molecular mechanism of ADAM8 regulating secretion of IL-1β and IL-18 by CCR2+ macrophages (shedding EGFR ligands and activating EGFR-MAPK-NLRP3 pathway?); The objective is to elucidate the mechanisms by which ADAM8 regulates the proinflammatory response of CCR2+ macrophages and participates in ischemic myocardial injury, and to provide a new target for AMI treatment.