Matrix Metalloproteinase-8 is a Novel Pathogenetic Factor in Focal Cerebral Ischemia

Jeong Eun Han, Eun Jung Lee, Eunjung Moon, Jong Hoon Ryu, Ji Woong Choi, Hee Sun Kim

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 languageEnglish
Pages (from-to)231-239
Number of pages9
JournalMolecular Neurobiology
Volume53
Issue number1
DOIs
StatePublished - 1 Jan 2016

Keywords

  • Microglia
  • Middle cerebral artery occlusion/reperfusion
  • MMP8
  • MMP8 inhibitor
  • MMP8 shRNA
  • TNF-α

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