Abstract
BackgroundAstrocytes are an integral component of the blood–brain barrier (BBB) which may be compromised by ischemic or traumatic brain injury. In response to trauma, astrocytes increase expression of the endopeptidase matrix metalloproteinase (MMP)-9. Compromise of the BBB leads to the infiltration of fluid and blood-derived proteins including albumin into the brain parenchyma. Albumin has been previously shown to activate astrocytes and induce the production of inflammatory mediators. The effect of albumin on MMP-9 activation in astrocytes is not known. We investigated the molecular mechanisms underlying the production of MMP-9 by albumin in astrocytes.MethodsPrimary enriched astrocyte cultures were used to investigate the effects of exposure to albumin on the release of MMP-9. MMP-9 expression was analyzed by zymography. The involvement of mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS) and the TGF-β receptor-dependent pathways were investigated using pharmacological inhibitors. The production of ROS was observed by dichlorodihydrofluorescein diacetate fluorescence. The level of the MMP-9 inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 produced by astrocytes was measured by ELISA.ResultsWe found that albumin induces a time-dependent release of MMP-9 via the activation of p38 MAPK and extracellular signal regulated kinase, but not Jun kinase. Albumin-induced MMP-9 production also involves ROS production upstream of the MAPK pathways. However, albumin-induced increase in MMP-9 is independent of the TGF-β receptor, previously described as a receptor for albumin. Albumin also induces an increase in TIMP-1 via an undetermined mechanism.ConclusionsThese results link albumin (acting through ROS and the p38 MAPK) to the activation of MMP-9 in astrocytes. Numerous studies identify a role for MMP-9 in the mechanisms of compromise of the BBB, epileptogenesis, or synaptic remodeling after ischemia or traumatic brain injury. The increase in MMP-9 produced by albumin further implicates both astrocytes and albumin in the acute and long-term complications of acute CNS insults, including cerebral edema and epilepsy.
Highlights
Astrocytes are an integral component of the blood–brain barrier (BBB) which may be compromised by ischemic or traumatic brain injury
Albumin-induced increase in matrix metalloproteinase-9 is suppressed by inhibition of p38 mitogen-activated protein kinase and extracellular signal regulated protein kinase, but not c-Jun N-terminal kinase We have previously shown that activation of astrocytes induced by albumin involves activation of the MAPK pathways [28]
Albumin-induced increase in p38 mitogen-activated protein kinase and Jun kinase is downstream from activation of NADPH oxidase we investigated whether the activation of MAPKs by albumin was dependent on the production of reactive oxygen species (ROS) (Figure 4)
Summary
Astrocytes are an integral component of the blood–brain barrier (BBB) which may be compromised by ischemic or traumatic brain injury. Compromise of the BBB leads to the infiltration of fluid and blood-derived proteins including albumin into the brain parenchyma. Compromise of the BBB by ischemic or traumatic brain injury results in cytotoxic and vasogenic edema, and is a major determinant of outcome after neurological trauma [4,5,6,7]. The endopeptidase matrix metalloproteinase (MMP)-9 plays a pivotal role in BBB proteolysis after injury [8,9,10], and contributes to cell death after prolonged seizures [11]. The proteolytic activity of MMPs including MMP-9 is regulated by tissue inhibitor of matrix metalloproteinase (TIMP)-1. Gene transfer and knockout approaches indicate a protective role for TIMP-1 after cerebral ischemic insults [15,16]
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