title: Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1.
abstract: Polarized microglia play a dual (beneficial/detrimental) role in neurological diseases. However, the status and the factors that modulate microglia polarization in intracerebral hemorrhage (ICH) remain unclear. In the present study, we investigated the role of protease-activated receptor-1 (PAR-1, a thrombin receptor) in ICH-induced microglia polarization in mice. Male wild-type (WT) and PAR-1 knockout (PAR-1 KO) mice received an infusion of 30-μL autologous blood or saline into the right basal ganglia. Mice were euthanized at different time points and the brains were used for Western blotting and immunohistochemistry. Some mice had magnetic resonance imaging. We found that ICH induced microglia activation and polarization. M1 phenotypic markers were markedly increased and reached a peak as early as 4 h, remained high at 3 days and decreased 7 days after ICH. M2 phenotypic markers were upregulated later than M1 markers reaching a peak at day 1 and declining by day 7 after ICH. PAR-1 was upregulated after ICH and expressed in the neurons and microglia. ICH induced less brain swelling and neuronal death in PAR-1 KO mice, and this was associated with less M1 polarization and reduced proinflammatory cytokine levels in the brain. In conclusion, these results suggest that polarized microglia occur dynamically after ICH and that PAR-1 plays a role in the microglia activation and polarization.
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Neurosurgery, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wan
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Neurology, The 1st Affiliated Hospital, School of Medicine, Jilin University, Changchun, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Neurology, The 1st Affiliated Hospital, School of Medicine, Jilin University, Changchun, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Dewei
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA. guohuaxi@umich.edu.|University of Michigan, Room5018 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA. guohuaxi@umich.edu.
authors.forename: Guohua
authors.initials: G
authors.lastname: Xi
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000473:pathology; D002452:Cell Count; D016764:Cell Polarity / Q000502:physiology*; D002543:Cerebral Hemorrhage / Q000000981:diagnostic imaging / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000172:deficiency* / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D016212:Transforming Growth Factor beta; C534582:fluoro-jade C; D016753:Interleukin-10; C079109:N-(3-pyridylmethyl)adriamycin; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9
keywords: Cerebral hemorrhage; Microglia; Mouse; Protease-activated receptor-1