Microglial Cell Activation is a Source of Metalloproteinase Generation during Hemorrhagic Transformation

• Published in: Journal of cerebral blood flow and metabolism 2012-05, Vol.32 (5), p.919-932
• Main Authors: del Zoppo, Gregory J, Frankowski, Harald, Gu, Yu-Huan, Osada, Takashi, Kanazawa, Masato, Milner, Richard, Wang, Xiaoyun, Hosomi, Naohisa, Mabuchi, Takuma, Koziol, James A
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Biological and medical sciences; Brain Edema - enzymology; Brain Edema - pathology; Brain Edema - physiopathology; Brain injury; Brain Ischemia - enzymology; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cell activation; Cell Hypoxia; Cells, Cultured; Cerebral blood flow; Edema; Enzyme Precursors - secretion; Extravasation; Fibronectin; Fibronectins - metabolism; Gelatinase A; Gelatinase B; Gelatinases - secretion; Glucose; Hemorrhage; Humans; Immunocytochemistry; Injuries of the nervous system and the skull. Diseases due to physical agents; Intracranial Hemorrhages - enzymology; Intracranial Hemorrhages - pathology; Intracranial Hemorrhages - physiopathology; Ischemia; Leakage; Matrix Metalloproteinase 9 - secretion; Medical sciences; Metalloproteinase; Mice; Microglia; Microglia - enzymology; Microglia - pathology; Neurology; Original; Papio anubis; Polymerase chain reaction; Primates; Stroke; Traumas. Diseases due to physical agents; Vascular diseases and vascular malformations of the nervous system; vitronectin; Vitronectin - metabolism
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2012.11

Hemorrhage and edema accompany evolving brain tissue injury after ischemic stroke. In patients, these events have been associated with metalloproteinase (MMP)-9 in plasma. Both the causes and cellular sources of MMP-9 generation in this setting have not been defined. MMP-2 and MMP-9 in nonhuman primate tissue in regions of plasma leakage, and primary murine microglia and astrocytes, were assayed by immunocytochemistry, zymography, and real-time RT-PCR. Ischemia-related hemorrhage was associated with microglial activation in vivo, and with the leakage of plasma fibronectin and vitronectin into the surrounding tissue. In strict serum-depleted primary cultures, by zymography, pro-MMP-9 was generated by primary murine microglia when exposed to vitronectin and fibronectin. Protease secretion was enhanced by experimental ischemia (oxygen-glucose deprivation, OGD). Primary astrocytes, on each matrix, generated only pro-MMP-2, which decreased during OGD. Microglia—astrocyte contact enhanced pro-MMP-9 generation in a cell density-dependent manner under normoxia and OGD. Compatible with observations in a high quality model of focal cerebral ischemia, microglia, but not astrocytes, respond to vitronectin and fibronectin, found when plasma extravasates into the injured region. Astrocytes alone do not generate pro-MMP-9. These events explain the appearance of MMP-9 antigen in association with ischemia-induced cerebral hemorrhage and edema.