title: Functional differences between microglia and monocytes after ischemic stroke.
abstract: BACKGROUND
  The brain's initial innate response to stroke is primarily mediated by microglia, the resident macrophage of the CNS. However, as early as 4 h after stroke, the blood-brain barrier is compromised and monocyte infiltration occurs. The lack of discriminating markers between these two myeloid populations has led many studies to generate conclusions based on the grouping of these two populations. A growing body of evidence now supports the distinct roles played by microglia and monocytes in many disease models.
  
  
  METHODS
  Using a flow cytometry approach, combined with ex-vivo functional assays, we were able to distinguish microglia from monocytes using the relative expression of CD45 and assess the function of each cell type following stroke over the course of 7 days.
  
  
  RESULTS
  We found that at 72 h after a 90-min middle cerebral artery occlusion (MCAO), microglia populations decrease whereas monocytes significantly increase in the stroke brain compared to sham. After stroke, BRDU incorporation into monocytes in the bone marrow increased. After recruitment to the ischemic brain, these monocytes accounted for nearly all BRDU-positive macrophages. Inflammatory activity peaked at 72 h. Microglia produced relatively higher reactive oxygen species and TNF, whereas monocytes were the predominant IL-1β producer. Although microglia showed enhanced phagocytic activity after stroke, monocytes had significantly higher phagocytic capacity at 72 h. Interestingly, we found a positive correlation between TNF expression levels and phagocytic activity of microglia after stroke.
  
  
  CONCLUSIONS
  In summary, the resident microglia population is vulnerable to the effects of severe ischemia, show compromised cell cycle progression, and adopt a largely pro-inflammatory phenotype after stroke. Infiltrating monocytes are primarily involved with early debris clearance of dying cells. These findings suggest that the early wave of infiltrating monocytes may be beneficial to stroke repair and future therapies aimed at mitigating microglia cell death may prove more effective than attempting to elicit targeted anti-inflammatory responses from damaged cells.
authors.affiliation: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. rritzel@uchc.edu.
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Ritzel
authors.affiliation: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. anitarp@umich.edu.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Patel
authors.affiliation: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. jgrenier@uchc.edu.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Grenier
authors.affiliation: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. crapser@uchc.edu.
authors.forename: Joshua
authors.initials: J
authors.lastname: Crapser
authors.affiliation: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. raverma@uchc.edu.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA. jellison@uchc.edu.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Jellison
authors.affiliation: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. lmccullough@uchc.edu.
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology* / Q000502:physiology*; D009000:Monocytes / Q000473:pathology* / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000473:pathology* / Q000503:physiopathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha