title: Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia.
abstract: OBJECTIVE
  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 cell-to-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.
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China. hux2@upmc.edu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: Yanling
authors.initials: Y
authors.lastname: Guo
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.forename: Songela
authors.initials: S
authors.lastname: Chen
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D016764:Cell Polarity; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D037502:Galectin 3 / Q000378:metabolism; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D037502:Galectin 3; D016177:Macrophage-1 Antigen