In vitro and in vivo models of cerebral ischemia show discrepancy in therapeutic effects of M2 macrophages

PLoS One. 2013 Jun 25;8(6):e67063. doi: 10.1371/journal.pone.0067063. Print 2013.

Abstract

THE INFLAMMATORY RESPONSE FOLLOWING ISCHEMIC STROKE IS DOMINATED BY INNATE IMMUNE CELLS: resident microglia and blood-derived macrophages. The ambivalent role of these cells in stroke outcome might be explained in part by the acquisition of distinct functional phenotypes: classically (M1) and alternatively activated (M2) macrophages. To shed light on the crosstalk between hypoxic neurons and macrophages, an in vitro model was set up in which bone marrow-derived macrophages were co-cultured with hippocampal slices subjected to oxygen and glucose deprivation. The results showed that macrophages provided potent protection against neuron cell loss through a paracrine mechanism, and that they expressed M2-type alternative polarization. These findings raised the possibility of using bone marrow-derived M2 macrophages in cellular therapy for stroke. Therefore, 2 million M2 macrophages (or vehicle) were intravenously administered during the subacute stage of ischemia (D4) in a model of transient middle cerebral artery occlusion. Functional neuroscores and magnetic resonance imaging endpoints (infarct volumes, blood-brain barrier integrity, phagocytic activity assessed by iron oxide uptake) were longitudinally monitored for 2 weeks. This cell-based treatment did not significantly improve any outcome measure compared with vehicle, suggesting that this strategy is not relevant to stroke therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / complications
  • Brain Ischemia / immunology*
  • Brain Ischemia / pathology
  • Brain Ischemia / therapy*
  • Cell Death / immunology
  • Cell Hypoxia / immunology
  • Disease Models, Animal
  • Hippocampus / immunology
  • Hippocampus / pathology
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / immunology
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / therapy
  • Macrophages / cytology
  • Macrophages / immunology*
  • Male
  • Mice
  • Neurons / pathology
  • Rats
  • Stroke / complications
  • Translational Research, Biomedical*
  • Treatment Outcome

Grant support

This work was supported by the ANR “INFLAM” and a grant from the Fondation pour la Recherche pour le Cerveau (FRC). AR was supported by a grant from the Rhône-Alpes Region (Cluster 11). MRI experiments were performed on the “Animage” platform of Centre d’Exploration et de Recherche Médicale par Emission de Positons (CERMEP) -Imagerie du Vivant, Lyon, France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.