Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
UD-Genomed, Debrecen, Hungary.
Nat Immunol. 2019 May;20(5):626-636. doi: 10.1038/s41590-019-0356-7. Epub 2019 Apr 1.
Muscle damage elicits a sterile immune response that facilitates complete regeneration. Here, we used mass spectrometry-based lipidomics to map the mediator lipidome during the transition from inflammation to resolution and regeneration in skeletal muscle injury. We observed temporal regulation of glycerophospholipids and production of pro-inflammatory lipid mediators (for example, leukotrienes and prostaglandins) and specialized pro-resolving lipid mediators (for example, resolvins and lipoxins) that were modulated by ibuprofen. These time-dependent profiles were recapitulated in sorted neutrophils and Ly6C and Ly6C muscle-infiltrating macrophages, with a distinct pro-resolving signature observed in Ly6C macrophages. RNA sequencing of macrophages stimulated with resolvin D2 showed similarities to transcriptional changes found during the temporal transition from Ly6C macrophage to Ly6C macrophage. In vivo, resolvin D2 increased Ly6C macrophages and functional improvement of the regenerating muscle. These results reveal dynamic lipid mediator signatures of innate immune cells and provide a proof of concept for their exploitable effector roles in muscle regeneration.
肌肉损伤会引发非感染性免疫反应，从而促进完全再生。在这里，我们使用基于质谱的脂质组学技术，在骨骼肌肉损伤中从炎症到消退和再生的转变过程中，对介质脂质组进行了图谱绘制。我们观察到甘油磷脂的时间调节以及促炎脂质介质（例如白三烯和前列腺素）和专门的促解决脂质介质（例如，消退素和脂氧素）的产生，这些介质受布洛芬调节。这些时间依赖性谱在分选的中性粒细胞和 Ly6C 和 Ly6C 肌内浸润巨噬细胞中得到了重现，在 Ly6C 巨噬细胞中观察到了明显的促解决特征。用消退素 D2 刺激的巨噬细胞的 RNA 测序显示与 Ly6C 巨噬细胞到 Ly6C 巨噬细胞的时间过渡中发现的转录变化相似。在体内，消退素 D2 增加了 Ly6C 巨噬细胞，并改善了再生肌肉的功能。这些结果揭示了先天免疫细胞中动态的脂质介质特征，并为它们在肌肉再生中的可利用效应器作用提供了概念验证。
