Background and Purpose-Mononuclear phagocytes are highly plastic cells that assume diverse phenotypes in response to microenvironmental signals. The phenotype-specific roles of microglia/macrophages in ischemic brain injury are poorly understood. A comprehensive characterization of microglia/macrophage polarization after ischemia may advance our knowledge of poststroke damage/recovery. Methods-Focal transient cerebral ischemia was induced in mice for 60 minutes; animals were euthanized at 1 to 14 days of reperfusion. Reverse-transcriptase polymerase chain reaction and immunohistochemical staining for M1 and M2 markers were performed to characterize phenotypic changes in brain cells, including microglia and infiltrating macrophages. In vitro experiments using a transwell system, a conditioned medium transfer system, or a coculture system allowing cellto-cell contacts were used to further elucidate the effect of neuronal ischemia on microglia/macrophage polarization and, conversely, the effect of microglia/macrophage phenotype on the fate of ischemic neurons. Results-Local microglia and newly recruited macrophages assume the M2 phenotype at early stages of ischemic stroke but gradually transformed into the M1 phenotype in peri-infarct regions. In vitro experiments revealed that ischemic neurons prime microglial polarization toward M1 phenotype. M1-polarized microglia or M1-conditioned media exacerbated oxygen glucose deprivation-induced neuronal death. In contrast, maintaining the M2 phenotype of microglia protected neurons against oxygen glucose deprivation. Conclusions-Our results suggest that microglia/macrophages respond dynamically to ischemic injury, experiencing an early "healthy" M2 phenotype, followed by a transition to a "sick" M1 phenotype. These dual and opposing roles of microglia/macrophages suggest that stroke therapies should be shifted from simply suppressing microglia/macrophage toward adjusting the balance between beneficial and detrimental microglia/macrophage responses. (Stroke. 2012;43: 3063-3070.)

The historical view of the adult brain as a static organ has shifted in the last few decades. We now know that the mature brain remains plastic and has some regeneration capacity after injury. The injured brain engages microglia/macrophages to clear cellular debris and fine-tune neurorestorative processes. However, microglia/macrophage activation can also hinder central nervous system (CNS) repair and expand tissue damage. One explanation for this dualistic role of microglia/macrophages in neurological recovery is their polarization into different phenotypes at different stages of injury. This perspective article highlights the specific roles of polarized microglia/macrophages in CNS repair after acute injuries. We propose that therapeutic approaches targeting cerebral inflammation should be shifted from complete microglia/macrophage suppression toward a subtler titration of the balance between various phenotypes. Recent breakthroughs in the identification of regulatory molecules that control this dramatic phenotypic shift are accelerating the pace of research towards curing brain disorders.