Injury to repair: Functions of microglia and monocyte-derived cells in ischemic stroke

Microglia, the central nervous system's resident immune cells, play a complex role in acute ischemic stroke (AIS), contributing to both neuroprotection and secondary neurologic injury. After ischemic injury, microglia activate and adopt a diverse range of phenotypes, from extremes of pro-inflammatory to anti-inflammatory microglia. Coinciding with microglial activation, AIS triggers infiltration of monocytes, which transform into monocyte-derived cells (MdCs) within the ischemic microenvironment. MdCs display many overlapping characteristics with microglia, complicating their identification and role in recovery. This narrative review synthesizes current basic and translational research examining the heterogeneity and interplay of microglia and MdCs in response to AIS. Relevant literature was identified through a comprehensive search of the PubMed database, inclusive of studies published through June 2025. Anti-inflammatory microglial phenotypes promote neuronal survival, phagocytosis of necrotic debris, and blood-brain barrier repair. Pro-inflammatory microglial phenotypes, conversely, exacerbate injury through excitotoxicity, cytokine release, and vascular disruption. Initially, MdCs adopt a neuroprotective, reparative microglia-like role by phagocytizing debris and supporting repair but later shift to a pro-inflammatory phenotype, driving secondary damage. The dynamic interaction between microglia and MdCs is crucial for stroke recovery, with microglia and MdCs initially aiding in tissue repair and angiogenesis while subsequently amplifying secondary injury through pro-inflammatory phenotypes. Although various biomarkers have been proposed to differentiate microglia from MdCs and predict stroke outcomes, none have been clinically validated. Further studies are needed to identify reliable biomarkers for these distinct cell types and develop strategies to minimize secondary injury without impairing recovery after stroke.