Differences in the Phagocytic Response of Microglia and Peripheral Macrophages after Spinal Cord Injury and Its Effects on Cell Death
Differences in the Phagocytic Response of Microglia and Peripheral Macrophages after Spinal Cord Injury and Its Effects on Cell Death
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DOI：
10.1523/jneurosci.4912-13.2014
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发表时间：
2014-04-30
影响因子：
5.3
通讯作者：
David, Samuel
中科院分区：
文献类型：
--
作者：
Greenhalgh, Andrew D.;David, Samuel
受损脊髓中的巨噬细胞来自驻留的小胶质细胞和浸润的外周来源的单核细胞。目前尚不清楚来源于这两个群体的巨噬细胞在CNS损伤后的作用是否不同。本研究的目的是研究这些不同的巨噬细胞亚群对受损轴突和组织碎片的吞噬反应和清除，并评估它们在脊髓损伤（SCI）后的生存能力。溶菌酶M EGFP敲入小鼠标记造血巨噬细胞，但不是小胶质细胞。使用免疫荧光，流式细胞术和神经元示踪技术相结合，我们表明，小胶质细胞接触损伤的轴突早期（24小时）SCI后，是主要类型的巨噬细胞在3天包含吞噬物质。此后，浸润性巨噬细胞成为与退化轴突接触的主要细胞，并含有更多的吞噬物质，与小胶质细胞相反，持续长达42天。此外，在体外吞噬髓磷脂后，骨髓来源的巨噬细胞比CNS小胶质细胞更容易发生凋亡和坏死性细胞死亡，这在体内与浸润巨噬细胞来源的凋亡TUNEL阳性细胞相反映。这项工作表明，小胶质细胞在脊髓损伤的早期反应中起着重要作用，通过吞噬受损和退化的组织，有效地处理吞噬物质，并保持活力。后来，外周来源的巨噬细胞主要参与吞噬作用，但在处理CNS碎片方面效率较低，并且它们的原位死亡可能导致CNS损伤后的继发性损伤。
Macrophages in the injured spinal cord arise from resident microglia and infiltrating, peripherally derived monocytes. It is still not clear if macrophages derived from these two populations differ in their roles after CNS injury. The aims of this study are to investigate the phagocytic response and clearance of damaged axons and tissue debris by these distinct subsets of macrophages and assess their viability after spinal cord injury (SCI). The lysozyme M EGFP-knockin mouse tags hematogenous macrophages, but not microglia. Using a combination of immunofluorescence, flow cytometry, and neuronal tracing techniques, we show that microglia contact damaged axons early (24 h) after SCI and are the main type of macrophage to contain phagocytic material at 3 d. Thereafter, infiltrating macrophages become the predominant cell in contact with degenerating axons and contain more phagocytic material, which in contrast to microglia, persists for up to 42 d. Furthermore, after phagocytosis of myelin in vitro, bone marrow-derived macrophages are much more susceptible to apoptotic and necrotic cell death than CNS microglia, which is mirrored in vivo with apoptotic TUNEL-positive cells of infiltrating macrophage origin. This work suggests that microglia play a major role in the early response to SCI, by phagocytosing damaged and degenerating tissue, processing phagocytic material efficiently, and remaining viable. Later, macrophages of peripheral origin contribute predominantly to phagocytosis but are less efficient at processing CNS debris, and their death, in situ, may contribute to the secondary damage after CNS injury.