title: Microglial activation induced by the alarmin S100B is regulated by poly(ADP-ribose) polymerase-1.
abstract: Brain injury resulting from stroke or trauma can be exacerbated by the release of proinflammatory cytokines, proteases, and reactive oxygen species by activated microglia. The microglial activation resulting from brain injury is mediated in part by alarmins, which are signaling molecules released from damaged cells. The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to regulate microglial activation after brain injury, and here we show that signaling effects of the alarmin S100B are regulated by PARP-1. S100B is a protein localized predominantly to astrocytes. Exogenous S100B added to primary microglial cultures induced a rapid change in microglial morphology, upregulation of IL-1β, TNFα, and iNOS gene expression, and release of matrix metalloproteinase 9 and nitric oxide. Most, though not all of these effects were attenuated in PARP-1(-/-) microglia and in wild-type microglia treated with the PARP inhibitor, veliparib. Microglial activation and gene expression changes induced by S100B injected directly into brain were likewise attenuated by PARP-1 inhibition. The anti-inflammatory effects of PARP-1 inhibitors in acutely injured brain may thus be mediated in part through effects on S100B signaling pathways. GLIA 2016;64:1869-1878.
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Repubic of China.|Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Repubic of China.
authors.forename: Handong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.affiliation: Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Jayinee
authors.initials: J
authors.lastname: Basu
authors.affiliation: Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Kapfhamer
authors.affiliation: Department of Neurology, University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California. Raymond.Swanson@ucsf.edu.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
mesh_terms: D000067531:Alarmins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011134:Polysaccharides / Q000633:toxicity; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000067531:Alarmins; D001562:Benzimidazoles; D016207:Cytokines; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011134:Polysaccharides; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; C521013:veliparib; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: MMP9; PARP-1; astrocyte; nitric oxide; stroke; trauma; veliparib