Abstract
The neutrophil collagenase matrix metalloproteinase-8 (MMP8) is a recently identified member of MMPs that have important roles in various inflammation-related disorders. Previously, we identified MMP8 as a new neuroinflammatory mediator in activated microglia by regulating TNF-α productivity. Here, we present evidence that MMP8 is a critical factor for brain damage in transient focal cerebral ischemia by modulating neuroinflammation likely microglial activation and TNF-α production. Biochemical analyses showed upregulation of MMP8 expression at mRNA and protein levels in transient middle cerebral artery occlusion/reperfusion (M/R)-challenged brains. Furthermore, double immunolabeling showed that MMP8 expression was upregulated in the activated microglia of M/R-challenged brains. Assessment of infarct volume, neurological score, and survival/death of neural cells revealed that administration of an MMP8 inhibitor (M8I) immediately after reperfusion reduced brain damage. Histological analyses showed that microglial activation and TNF-α expression in ischemic conditions was abrogated by exposure to M8I, as demonstrated in our previous study using cultured microglia. These outcomes from a pharmacological approach were reaffirmed by a genetic approach using a lentiviral system. Intracerebroventricular microinjection of MMP8-specific shRNA lentivirus reduced the extent of ischemia-induced brain damage, as assessed by infarct volume, neurological score, microglial activation, and TNF-α expression. These results suggest a novel pathogenetic role of MMP8 and implicate modulation of its activity as a tractable strategy for therapies against cerebral ischemia.
Original language | English |
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Pages (from-to) | 231-239 |
Number of pages | 9 |
Journal | Molecular Neurobiology |
Volume | 53 |
Issue number | 1 |
DOIs | |
State | Published - 1 Jan 2016 |
Bibliographical note
Publisher Copyright:© 2014, Springer Science+Business Media New York.
Keywords
- MMP8
- MMP8 inhibitor
- MMP8 shRNA
- Microglia
- Middle cerebral artery occlusion/reperfusion
- TNF-α