Phagocytic microglia and macrophages in brain injury and repair

Aims 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. Discussion 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. Conclusion 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).