Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype
Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype
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DOI：
10.1093/eurheartj/ehw002
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发表时间：
2017-01-14
影响因子：
39.3
通讯作者：
Steffens, Sabine
中科院分区：
文献类型：
--
作者：
Horckmans, Michael;Ring, Larisa;Steffens, Sabine
急性心肌梗死（MI）是世界范围内死亡率最高的疾病.减少嗜中性粒细胞驱动的急性心肌梗死后损伤的抗炎策略已被证明可以限制急性心脏组织损伤。另一方面，中性粒细胞是否需要解决MI后炎症和修复是unknow.Methods和结果，我们表明，嗜中性粒细胞耗尽的小鼠心肌梗死恶化的心脏功能，增加纤维化，并逐步发展为心力衰竭。血液、淋巴器官和消化心脏的流式细胞术显示，嗜中性粒细胞耗竭小鼠梗死区Ly6C（高）单核细胞数量减少，而巨噬细胞数量增加，这与脾Ly6C（高）单核细胞动员减少有关，但与心脏巨噬细胞增殖增加有关。巨噬细胞亚型分析显示，M1标记物的心脏表达减少，而M2标记物在嗜中性粒细胞耗尽的小鼠中增加。令人惊讶的是，我们发现吞噬受体骨髓上皮生殖酪氨酸激酶的表达减少，这是介导凋亡细胞清除的修复性M2c巨噬细胞的标志物。与这一发现一致，嗜中性粒细胞耗竭小鼠梗死灶内TUNEL阳性细胞数量增加。我们确定中性粒细胞明胶酶相关脂质运载蛋白（NGAL）在中性粒细胞分泌组作为一个关键的诱导巨噬细胞吞噬凋亡细胞的能力高。中性粒细胞分泌体或NGAL.Conclusion中性粒细胞是至关重要的参与心肌梗死后的心脏修复极化巨噬细胞对修复表型的管理，在嗜中性粒细胞耗竭小鼠的心脏巨噬细胞表型恢复。减少MI后急性嗜酸性粒细胞驱动的炎症的治疗策略应仔细平衡，因为它们可能干扰愈合反应和心脏重塑。
Aims Acute myocardial infarction (MI) is the leading cause of mortality worldwide. Anti-inflammatory strategies to reduce neutrophil-driven acute post-MI injury have been shown to limit acute cardiac tissue damage. On the other hand, whether neutrophils are required for resolving post-MI inflammation and repair is unknown.Methods and results We show that neutrophil-depleted mice subjected to MI had worsened cardiac function, increased fibrosis, and progressively developed heart failure. Flow cytometry of blood, lymphoid organs and digested hearts revealed reduced numbers of Ly6C(high) monocytes in infarcts of neutrophil-depleted mice, whereas the number of macrophages increased, which was paralleled by reduced splenic Ly6C(high) monocyte mobilization but enhanced proliferation of cardiac macrophages. Macrophage subtype analysis revealed reduced cardiac expression of M1 markers, whereas M2 markers were increased in neutrophil-depleted mice. Surprisingly, we found reduced expression of phagocytosis receptor myeloid-epithelial-reproductive tyrosine kinase, a marker of reparative M2c macrophages which mediate clearance of apoptotic cells. In agreement with this finding, neutrophil-depleted mice had increased numbers of TUNEL-positive cells within infarcts. We identified neutrophil gelatinase-associated lipocalin (NGAL) in the neutrophil secretome as a key inducer of macrophages with high capacity to engulf apoptotic cells. The cardiac macrophage phenotype in neutrophil-depleted mice was restored by administration of neutrophil secretome or NGAL.Conclusion Neutrophils are crucially involved in cardiac repair after MI by polarizing macrophages towards a reparative phenotype. Therapeutic strategies to reduce acute neutrophil-driven inflammation after MI should be carefully balanced as they might interfere with the healing response and cardiac remodelling.