Journal
JOURNAL OF IMMUNOLOGY
Volume 185, Issue 1, Pages 615-623Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903480
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Funding
- Neurobiology Research Program
- Regional Core Research Program/Anti-Aging and Well-Being Research Center
- Ministry of Education, Science, and Technology, Republic of Korea [2009K001250]
- National Research Foundation of Korea [22-2009-00-004-00] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The mutation or overexpression of alpha-synuclein protein plays a pivotal role in the pathogenesis of Parkinson's disease. In our preliminary experiments, we found that alpha-synuclein induced the expression of matrix metalloproteinases (MMPs) (MMP-1, -3, -8, and -9) in rat primary cultured microglia. Thus, the current study was undertaken to determine the roles of MMPs in alpha-synuclein-induced microglial activation. The inhibition of MMP-3, -8, or - 9 significantly reduced NO and reactive oxygen species levels and suppressed the expression of TNF-alpha and IL-1 beta. Notably, MMP-8 inhibitor suppressed TNF-alpha production more efficaciously than MMP-3 or MMP-9 inhibitors. Inhibition of MMP-3 or - 9 also suppressed the activities of MAPK, NF-kappa B, and AP-1. Previously, protease-activated receptor-1 (PAR-1) has been associated with the actions of MMPs, and thus, we further investigated the role of PAR-1 in alpha-synuclein-induced inflammatory reactions. A PAR-1-specific inhibitor and a PAR-1 antagonist significantly suppressed cytokine levels, and NO and reactive oxygen species production in alpha-synuclein-treated microglia. Subsequent PAR-1 cleavage assay revealed that MMP-3, -8, and - 9, but not alpha-synuclein, cleaved the synthetic peptide containing conventional PAR-1 cleavage sites. These results suggest that MMPs secreted by alpha-synuclein-stimulated microglia activate PAR-1 and amplify microglial inflammatory signals in an autocrine or paracrine manner. Furthermore, our findings suggest that modulation of the activities of MMPs and/or PAR-1 may provide a new therapeutic strategy for Parkinson's disease. The Journal of Immunology, 2010, 185: 615-623.
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