title: Resident microglia, rather than blood-derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia-ischemia.
abstract: The mechanisms of neuronal injury after hypoxia-ischemia (HI) are different in the immature and the adult brain, but microglia activation has not been compared. The purpose of this study was to phenotype resident microglia and blood-derived macrophages in the hippocampus after HI in neonatal (postnatal day 9, P9) or adult (3 months of age, 3mo) mice. Unilateral brain injury after HI was induced in Cx3cr1(GFP/+) Ccr2(RFP/+) male mice on P9 (n = 34) or at 3mo (n = 53) using the Vannucci model. Resident microglia (Cx3cr1-GFP+) proliferated and were activated earlier after HI in the P9 (1-3 days) than that in the 3mo hippocampus, but remained longer in the adult brain (3-7 days). Blood-derived macrophages (Ccr2-RFP+) peaked 3 days after HI in both immature (P9) and adult (3mo) hippocampi but were twice as frequent in adult brains, 41% vs. 21% of all microglia/macrophages. CCL2 expression was three times higher in the P9 hippocampi, indicating that the proinflammatory response was more pronounced in the immature brain after HI. This corresponded well with the higher numbers of galectin-3-positive resident microglia in the P9 hippocampi, but did not correlate with CD16/32- or CD206-positive resident microglia or blood-derived macrophages. In conclusion, resident microglia, rather than infiltrating blood-derived macrophages, proliferate and are activated earlier in the immature than in the adult brain, but remain increased longer in the adult brain. The inflammatory response is more pronounced in the immature brain, and this correlate well with galectin-3 expression in resident microglia.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umekawa
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Osman
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D006624:Hippocampus / Q000254:growth & development / Q000276:immunology* / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D002135:Calcium-Binding Proteins; C515335:Ccr2 protein, mouse; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D019394:Ki-67 Antigen; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008840:Microfilament Proteins; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D017452:Receptors, IgG
keywords: CCL2; galectin-3; hypoxic-ischemic encephalopathy; neuroinflammation