Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1
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ORIGINAL ARTICLE
Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1 Shu Wan 1,2 & Yingying Cheng 1,3 & Hang Jin 1,3 & Dewei Guo 1 & Ya Hua 1 & Richard F. Keep 1 & Guohua Xi 1,4
Received: 5 February 2016 / Revised: 10 May 2016 / Accepted: 13 May 2016 # Springer Science+Business Media New York 2016
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 Electronic supplementary material The online version of this article (doi:10.1007/s12975-016-0472-8) contains supplementary material, which is available to authorized users. * Guohua Xi [email protected] 1
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
2
Department of Neurosurgery, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
3
Department of Neurology, The 1st Affiliated Hospital, School of Medicine, Jilin University, Changchun, China
4
University of Michigan, Room5018 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
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. Keywords Cerebral hemorrhage . Microglia . Mouse . Protease-activated receptor-1
Introduction Increasing evidence from preclinical and clinical studies suggests that inflammation contributes to secondary brain injury after intracerebral hemorrhage (ICH) [1, 2]. Such inflammation is characterized by the accumulation and activation of inflammatory cells and release of inflammatory mediators within the hemorrhagic brain. Inflammatory cells include blood-derived leukocytes and macrophages, resident microglia, astrocytes, and mast cells [1, 3]. Microglia act as guardians of neuronal survival and function under homeostatic condition as well as various pathologic co
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