title: In vitro and in vivo models of cerebral ischemia show discrepancy in therapeutic effects of M2 macrophages.
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.
authors.affiliation: CNRS, UMR 5220; INSERM, U1044; INSA de Lyon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Desestret
authors.forename: Adrien
authors.initials: A
authors.lastname: Riou
authors.forename: Fabien
authors.initials: F
authors.lastname: Chauveau
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Cho
authors.forename: Emilie
authors.initials: E
authors.lastname: Devillard
authors.forename: Marilena
authors.initials: M
authors.lastname: Marinescu
authors.forename: René
authors.initials: R
authors.lastname: Ferrera
authors.forename: Catherine
authors.initials: C
authors.lastname: Rey
authors.forename: Marie
authors.initials: M
authors.lastname: Chanal
authors.forename: Denis
authors.initials: D
authors.lastname: Angoulvant
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.forename: Norbert
authors.initials: N
authors.lastname: Nighoghossian
authors.forename: Yves
authors.initials: Y
authors.lastname: Berthezène
authors.forename: Serge
authors.initials: S
authors.lastname: Nataf
authors.forename: Marlène
authors.initials: M
authors.lastname: Wiart
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016923:Cell Death / Q000276:immunology; D015687:Cell Hypoxia / Q000276:immunology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000473:pathology; D051381:Rats; D020521:Stroke / Q000150:complications; D057170:Translational Research, Biomedical; D016896:Treatment Outcome