title: Macrophage-Derived Angiopoietin-Like Protein 2 Exacerbates Brain Damage by Accelerating Acute Inflammation after Ischemia-Reperfusion.
abstract: Ischemic stroke is a leading cause of death and disability worldwide. Several reports suggest that acute inflammation after ischemia-reperfusion exacerbates brain damage; however, molecular mechanisms underlying this effect remain unclear. Here, we report that MAC-3-positive immune cells, including infiltrating bone marrow-derived macrophages and activated microglia, express abundant angiopoietin-like protein (ANGPTL) 2 in ischemic mouse brain in a transient middle cerebral artery occlusion (MCAO) model. Both neurological deficits and infarct volume decreased in transient MCAO model mice established in Angptl2 knockout (KO) relative to wild-type mice. Acute brain inflammation after ischemia-reperfusion, as estimated by expression levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor alpha (TNF)-α, was significantly suppressed in Angptl2 KO compared to control mice. Moreover, analysis employing bone marrow chimeric models using Angptl2 KO and wild-type mice revealed that infiltrated bone marrow-derived macrophages secreting ANGPTL2 significantly contribute to acute brain injury seen after ischemia-reperfusion. These studies demonstrate that infiltrating bone marrow-derived macrophages promote inflammation and injury in affected brain areas after ischemia-reperfusion, likely via ANGPTL2 secretion in the acute phase of ischemic stroke.
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.|Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Amadatsu
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.|Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Kasamo
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kuratsu
authors.affiliation: Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics*; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology*
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger