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Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-a activation.

Authors: Lee, Eun-Jung  Han, Jeong Eun  Woo, Moon-Sook  Shin, Jin A  Park, Eun-Mi  Kang, Jihee Lee  Moon, Pyong Gon  Baek, Moon-Chang  Son, Woo-Sung  Ko, Young Tag  Choi, Ji Woong  Kim, Hee-Sun 
Citation: Lee EJ, etal., J Immunol. 2014 Sep 1;193(5):2384-93. doi: 10.4049/jimmunol.1303240. Epub 2014 Jul 21.
Pubmed: (View Article at PubMed) PMID:25049354
DOI: Full-text: DOI:10.4049/jimmunol.1303240

Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood-brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. Biochemical analysis of the underlying anti-inflammatory mechanisms of M8I revealed that it inhibits MAPK phosphorylation, NF-κB/AP-1 activity, and reactive oxygen species production. Further support for the proinflammatory role of microglial MMP-8 was obtained from an in vivo animal model of neuroinflammatory disorder. MMP-8 is upregulated in septic conditions, particularly in microglia. Administration of M8I or MMP-8 short hairpin RNA significantly inhibits microglial activation and expression/secretion of TNF-α in brain tissue, serum, and cerebrospinal fluid of LPS-induced septic mice. These results demonstrate that MMP-8 critically mediates microglial activation by modulating TNF-α activity, which may explain neuroinflammation in septic mouse brain.

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CRRD Object Information
CRRD ID: 13792525
Created: 2018-09-12
Species: All species
Last Modified: 2018-09-12
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.