| First Author | Lee EJ | Year | 2014 |
| Journal | J Immunol | Volume | 193 |
| Issue | 5 | Pages | 2384-93 |
| PubMed ID | 25049354 | Mgi Jnum | J:265613 |
| Mgi Id | MGI:6201889 | Doi | 10.4049/jimmunol.1303240 |
| Citation | Lee EJ, et al. (2014) Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-alpha activation. J Immunol 193(5):2384-93 |
| abstractText | 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-alpha secretion. Subsequent experiments showed that MMP-8 exhibits TNF-alpha-converting enzyme (TACE) activity by cleaving the prodomain of TNF-alpha (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-kappaB/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-alpha 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-alpha activity, which may explain neuroinflammation in septic mouse brain. |
