Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-alpha 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
- Issue Date
- 1-Sep-2014
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Citation
- JOURNAL OF IMMUNOLOGY, v.193, no.5, pp.2384 - 2393
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Volume
- 193
- Number
- 5
- Start Page
- 2384
- End Page
- 2393
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/12306
- DOI
- 10.4049/jimmunol.1303240
- ISSN
- 0022-1767
- Abstract
- 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, NE-kappa B/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.
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