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* Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
Department of Pathology, University of Washington, Seattle, WA 98104;
The Parkinson’s Institute, Sunnyvale, CA 940852;
Neurochemistry Laboratory, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079; and
¶ Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA 23298
Neuronal death is known to trigger reactive microgliosis. However, little is known regarding the manner by which microglia are activated by injured neurons and how microgliosis participates in neurodegeneration. In this study we delineate the critical role of macrophage Ag complex-1 (MAC1), a member of the β2 integrin family, in mediating reactive microgliosis and promoting dopaminergic (DAergic) neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease. MAC1 deficiency greatly attenuated the DAergic neurodegeneration induced by MPTP or 1-methyl-4-phenyl-pyridium iodide (MPP+) exposure both in vivo and in vitro, respectively. Reconstituted experiments created by adding microglia from MAC1–/– or MAC1+/+ mice back to MAC1+/+ neuron-enriched cultures showed that microglia with functional MAC1 expression was mandatory for microglia-enhanced neurotoxicity. Both in vivo and in vitro morphological and Western blot studies demonstrated that MPTP/MPP+ produced less microglia activation in MAC1–/– mice than MAC1+/+ mice. Further mechanistic studies revealed that a MPP+-mediated increase in superoxide production was reduced in MAC1–/– neuron-glia cultures compared with MAC1+/+ cultures. The stunted production of superoxide in MAC1–/– microglia is likely linked to the lack of translocation of the cytosolic NADPH oxidase (PHOX) subunit (p47phox) to the membrane. In addition, the production of PGE2 markedly decreased in neuron plus MAC1–/– microglia cocultures vs neuron plus MAC1+/+ microglia cocultures. Taken together, these results demonstrate that MAC1 plays a critical role in MPTP/MPP+-induced reactive microgliosis and further support the hypothesis that reactive microgliosis is an essential step in the self-perpetuating cycle leading to progressive DAergic neurodegeneration observed in Parkinson’s disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. M.L.B. was supported by the National Institutes of Health Pathway to Independence Award (NIEHS 1K99ES01549-01).
2 Address correspondence and reprint requests to Dr. Jau-Shyong Hong, Mail Drop F1-01 National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709. E-mail address: hong3{at}niehs.nih.gov
3 Abbreviations used in this paper: PD, Parkinson’s disease; DAergic, dopaminergic; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; MAC1, macrophage antigen complex-1; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenyl-pyridium iodide; PHOX, NADPH oxidase; SNpc, substantia nigra pars compacta; SOD, superoxide dismutase; TH, tyrosine hydroxylase; DA, dopamine; ECM, extracellular matrix.
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