Macrophage-Derived Angiopoietin-Like Protein 2 Exacerbates Brain Damage by Accelerating Acute Inflammation after Ischemia-Reperfusion

• Published in: PloS one 2016-11, Vol.11 (11), p.e0166285-e0166285
• Main Authors: Amadatsu, Toshihiro, Morinaga, Jun, Kawano, Takayuki, Terada, Kazutoyo, Kadomatsu, Tsuyoshi, Miyata, Keishi, Endo, Motoyoshi, Kasamo, Daiki, Kuratsu, Jun-Ichi, Oike, Yuichi
• Format: Article
• Language: English
• Subjects: Analysis; Angiopoietin; Angiopoietin-like Proteins; Angiopoietins - genetics; Animal models; Animals; Antigens; Biology and Life Sciences; Biomarkers; Bone marrow; Brain; Brain - blood supply; Brain - metabolism; Brain - pathology; Brain damage; Brain injuries; Brain injury; Brain Ischemia - genetics; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cell Line; Cerebral blood flow; Cytokines; Cytokines - metabolism; Disease Models, Animal; Experiments; Gene Expression; Head injuries; IL-1β; Immune system; Immunohistochemistry; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators - metabolism; Insulin resistance; Interleukins; Ischemia; Kinases; Laboratory animals; Macrophages; Macrophages - metabolism; Medical research; Medicine and Health Sciences; Mice; Mice, Knockout; Microglia; Models, Biological; Molecular modelling; Neurological diseases; Neurons - metabolism; Neurons - pathology; Neurosurgery; Obesity; Occlusion; Pneumoviridae; Proteins; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - pathology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stroke; Traumatic brain injury; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0166285

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.