Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery. Next, we identified the mechanism by which the engulfment of erythrocytes with exposed phosphatidylserine directly modulated the phenotype of both murine and human MDMs. In mice, loss of receptor tyrosine kinases AXL and MERTK reduced efferocytosis of eryptotic erythrocytes and hematoma clearance, worsened neurological recovery, exacerbated iron deposition, and decreased alternative activation of macrophages after ICH. Patients with higher circulating soluble AXL had poor 1-year outcomes after ICH onset, suggesting that therapeutically augmenting efferocytosis may improve functional outcomes by both reducing tissue injury and promoting the development of reparative macrophage responses. Thus, our results identify the efferocytosis of eryptotic erythrocytes through AXL/MERTK as a critical mechanism modulating macrophage phenotype and contributing to recovery from ICH.

中文翻译：

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红细胞胞吞作用调节巨噬细胞以促进脑出血后的恢复


巨噬细胞是受损组织中通过复杂的动态表型变化发挥促炎和恢复功能的来源。在这里，我们试图确定单核细胞源性巨噬细胞（MDM）是否有助于急性无菌性脑损伤后的恢复。通过分析实验性脑出血 (ICH) 后小鼠大脑中 MDM 的转录动态，我们发现浸润性 MDM 随着时间的推移发生了强烈的表型变化，并证明 MDM 对于最佳血肿清除和神经功能恢复至关重要。接下来，我们确定了暴露的磷脂酰丝氨酸吞噬红细胞直接调节小鼠和人类 MDM 表型的机制。在小鼠中，受体酪氨酸激酶 AXL 和 MERTK 的缺失会减少红细胞的胞吞作用和血肿清除，使神经功能恢复恶化，加剧铁沉积，并减少 ICH 后巨噬细胞的替代激活。循环可溶性 AXL 较高的患者在 ICH 发病后 1 年预后较差，这表明治疗性增强胞吞作用可以通过减少组织损伤和促进修复性巨噬细胞反应的发展来改善功能结果。因此，我们的结果表明，通过 AXL/MERTK 的红细胞胞吞作用是调节巨噬细胞表型并有助于 ICH 恢复的关键机制。