Phagocytic microglia and macrophages in brain injury and repair.
Phagocytic microglia and macrophages in brain injury and repair.
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DOI：
10.1111/cns.13899
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发表时间：
2022-09
影响因子：
5.5
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中科院分区：
文献类型：
--
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吞噬作用是细胞对细胞外颗粒（如病原体和垂死细胞）的消化，是中枢神经系统（CNS）疾病进化的关键因素。小胶质细胞和巨噬细胞是中枢神经系统的专业吞噬细胞。通过清除有毒细胞碎片和重塑细胞外基质，小胶质细胞/巨噬细胞帮助引导大脑修复和功能恢复过程。然而，中枢神经系统驻留和入侵的免疫细胞也可以通过点燃失控的炎症和吞噬应激但有活力的神经元来放大组织损伤。小胶质细胞/巨噬细胞帮助介导细胞间通讯，并对死亡/垂死神经元表达的“find - me”信号做出快速反应。激活的小胶质细胞/巨噬细胞随后迁移到损伤部位，在遇到濒危细胞表面的“eat - me”信号时启动吞噬过程。因此，健康细胞试图通过表达“不要吃我”的信号来避免不适当的吞噬。小胶质细胞/巨噬细胞还具有吞噬侵入受损大脑的免疫细胞（如中性粒细胞）并调节其促炎特性的能力。在脑恢复过程中，小胶质细胞/巨噬细胞吞噬髓磷脂碎片，启动突触发生和神经发生，并形成有利的细胞外基质以支持网络重新布线，以及其他有利的作用。在这里，我们回顾了吞噬小胶质细胞/巨噬细胞的多层性质，包括控制急性脑损伤中小胶质细胞/巨噬细胞诱导的吞噬的分子和细胞机制，并讨论了利用这一吞噬过程的治疗潜力的策略。确定能够在不妨碍小胶质细胞/巨噬细胞基本吞噬功能的情况下调节脑损伤后神经炎症的生物学靶点，将加快卒中恢复阶段更好的医疗管理。脑损伤后小胶质细胞/巨噬细胞吞噬途径中的Find - me、Eat - me和Don - Eat - me信号Find - me信号有助于识别趋化调节剂，如核苷酸、CX3CL1和其他分子信号，包括垂死/死亡脑细胞释放的S1P/LPC和HMGB1。Find - me信号被小胶质细胞/巨噬细胞受体P2Y12、TLR、CX3CR1和S1PR识别，导致小胶质细胞/巨噬细胞向损伤脑区域趋化。进食信号是由死亡/垂死的脑细胞（主要是神经元）释放或表达的。当磷脂酰丝氨酸（PS）翻转并暴露在细胞膜外层时，它被多个小胶质细胞/巨噬细胞受体识别并启动吞噬过程。Don - eat - me信号通路抑制吞噬作用，涉及唾液化糖蛋白和脂质。CD47与小胶质受体信号调节蛋白α (SIRPα)相互作用抑制吞噬作用。
Phagocytosis is the cellular digestion of extracellular particles, such as pathogens and dying cells, and is a key element in the evolution of central nervous system (CNS) disorders. Microglia and macrophages are the professional phagocytes of the CNS. By clearing toxic cellular debris and reshaping the extracellular matrix, microglia/macrophages help pilot the brain repair and functional recovery process. However, CNS resident and invading immune cells can also magnify tissue damage by igniting runaway inflammation and phagocytosing stressed—but viable—neurons. Microglia/macrophages help mediate intercellular communication and react quickly to the “find‐me” signals expressed by dead/dying neurons. The activated microglia/macrophages then migrate to the injury site to initiate the phagocytic process upon encountering “eat‐me” signals on the surfaces of endangered cells. Thus, healthy cells attempt to avoid inappropriate engulfment by expressing “do not‐eat‐me” signals. Microglia/macrophages also have the capacity to phagocytose immune cells that invade the injured brain (e.g., neutrophils) and to regulate their pro‐inflammatory properties. During brain recovery, microglia/macrophages engulf myelin debris, initiate synaptogenesis and neurogenesis, and sculpt a favorable extracellular matrix to support network rewiring, among other favorable roles. Here, we review the multilayered nature of phagocytotic microglia/macrophages, including the molecular and cellular mechanisms that govern microglia/macrophage‐induced phagocytosis in acute brain injury, and discuss strategies that tap into the therapeutic potential of this engulfment process. Identification of biological targets that can temper neuroinflammation after brain injury without hindering the essential phagocytic functions of microglia/macrophages will expedite better medical management of the stroke recovery stage. Find‐me, Eat‐me, and Don’t‐eat‐me signals implicated in microglia/macrophage phagocytosis pathways after brain injury. Find‐me signals are instrumental in the recognition of chemotactic modulators, such as nucleotides, CX3CL1, and other molecular signals, including S1P/LPC and HMGB1 released by dying/dead brain cells. Find‐me signals are recognized by microglia/macrophage receptors P2Y12, TLR, CX3CR1 and S1PR, resulting in chemotaxis of microglia/macrophages to injured brain areas. Eat‐me signals are released or expressed by dead/dying brain cells (mostly neurons). When phosphatidylserine (PS) is flipped and exposed on the outer layer of the cell membrane, it is recognized by multiple microglia/macrophage receptors that initiate the phagocytosis process. Don’t‐eat‐me signal pathways inhibit phagocytosis and involve sialylated glycoproteins and lipids. CD47 interacts with microglial receptor signal‐regulatory protein alpha (SIRPα) to inhibit phagocytosis.
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