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The Journal of Immunology, 2005, 174: 2288-2296.
Copyright © 2005 by The American Association of Immunologists

Poly(ADP-Ribose) Polymerase-1 Promotes Microglial Activation, Proliferation, and Matrix Metalloproteinase-9-Mediated Neuron Death1

Tiina M. Kauppinen and Raymond A. Swanson2

Department of Neurology, University of California, and Veterans Affairs Medical Center, San Francisco, CA 94121

Activated microglia contribute to cell death in ischemic and neurodegenerative disorders of the CNS. Microglial activation is regulated in part by NF-{kappa}B, and the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) enhances NF-{kappa}B binding to DNA. In this study, the role of PARP-1 in microglia-mediated neurotoxicity was assessed using microglia from wild-type (wt) and PARP-1–/– mice. Cultured microglia were incubated with TNF-{alpha}, a cytokine that is up-regulated in many neurological disorders. When stimulated with TNF-{alpha}, wt microglia proliferated, underwent morphological changes characteristic of activation, and killed neurons placed in coculture. The effects of TNF-{alpha} were markedly attenuated both in PARP-1–/– microglia and in wt microglia treated with the PARP enzymatic inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone. These effects were also blocked by (E)-3-(4-methylphenylsulfonyl)-2-propenenenitrile, which inhibits translocation of NF-{kappa}B to the nucleus. TNF-{alpha} also up-regulated microglial release of matrix metalloproteinase-9 (MMP-9), an enzyme with potential neurotoxic properties that is transcriptionally regulated by NF-{kappa}B. This up-regulation was blocked in PARP-1–/– microglia and in wt microglia by the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone. Microglia from MMP-9–/– mice were used to evaluate the contribution of MMP-9 to microglial neurotoxicity. MMP-9–/– microglia treated with TNF-{alpha} showed substantially reduced neurotoxicity relative to the wt microglia. TNF-{alpha}-stimulated wt microglia treated with the MMP inhibitor ilomastat also showed reduced neurotoxicity. These findings suggest that PARP-1 activation is required for both TNF-{alpha}-induced microglial activation and the neurotoxicity resulting from TNF-{alpha}-induced MMP-9 release.




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