Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair
Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair
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Lgr4 控制巨噬细胞中的促炎程序以对抗梗塞后心脏修复
DOI：
10.1161/circresaha.119.315807
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发表时间：
2020-09-25
影响因子：
20.1
通讯作者：
Yan, Xiaoxiang
中科院分区：
文献类型：
--
作者：
Huang, Chun-Kai;Dai, Daopeng;Yan, Xiaoxiang
补充数字内容可在文本中找到。基本原理：巨噬细胞在心肌梗死（MI）后的伤口愈合中发挥重要作用。Lgr 4是LGR（leucine-rich repeat-containing G protein-coupled receptor）家族的一员，是巨噬细胞相关免疫反应的调节因子。然而，在MI的背景下，Lgr 4对巨噬细胞表型和功能的贡献仍不清楚。目的：探讨巨噬细胞Lgr 4在心肌梗死中的作用及其机制。方法和结果：在MI的早期炎症阶段，梗死的巨噬细胞而不是中性粒细胞表达高水平的Lgr 4。巨噬细胞特异性Lgr 4基因敲除小鼠没有基线心血管缺陷，但表现出改善的心脏功能，适度减少梗死面积，降低心脏破裂导致的早期死亡率，并改善MI后的不良重塑。巨噬细胞特异性Lgr 4基因敲除小鼠心肌梗死后改善的结果与减轻缺血性损伤和最佳梗死愈合相关，如通过减少梗死周围区的心脏凋亡、减弱局部心肌炎症反应、减少梗死中基质金属蛋白酶表达、增强血管生成、肌成纤维细胞增殖、I型胶原在修复性肉芽组织中沉积，并形成富含胶原的瘢痕。更重要的是，巨噬细胞特异性Lgr 4敲除梗死灶浸润白细胞和炎性巨噬细胞数量减少，但含有丰富的修复性巨噬细胞亚群。Lgr 4-null梗死巨噬细胞表现出较少的炎症转录签名。这些发现得到了转录组学分析数据的进一步支持，这些数据显示了与巨噬细胞特异性Lgr 4敲除梗死中促炎反应相关的多种途径和广谱基因的抑制。值得注意的是，我们发现，Lgr 4介导的功能表型编程在梗死巨噬细胞至少部分归因于AP（激活蛋白）-1活性的调节。我们进一步证明，Lgr 4对炎症巨噬细胞中AP-1活化的协同作用是通过增强CREB（cAMP反应元件结合蛋白）介导的c-Fos、Fosl 1和Fosb反式激活而发生的。结论：总之，我们的数据突出了Lgr 4在控制梗死巨噬细胞的促炎表型和梗死后修复中的重要性。
Supplemental Digital Content is available in the text. Rationale: Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled receptor) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear. Objective: To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms. Methods and Results: During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in macrophage-specific Lgr4 knockout mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, macrophage-specific Lgr4 knockout infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with proinflammatory responses in macrophage-specific Lgr4 knockout infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of AP (activator protein)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing CREB (cAMP response element-binding protein)-mediated c-Fos, Fosl1, and Fosb transactivation. Conclusions: Together, our data highlight the significance of Lgr4 in governing proinflammatory phenotype of infarct macrophages and postinfarction repair.