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* Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada;
Medical Biotechnology Center, University of Southern Denmark, Odense, Denmark; and
Department of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada
Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation. This involves cellular migration across various structures associated with the blood-brain barrier: the vascular endothelium, the glia limitans, and the perivascular space between them. Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic (Tg) mice that overexpress CCL2 under control of a CNS-specific promoter. The Tg mice show no clinical symptoms, even though leukocytes have crossed the endothelial basement membrane. Pertussis toxin (PTx) given i.p. induced encephalopathy and weight loss in Tg mice. We used flow cytometry, ultra-small superparamagnetic iron oxide-enhanced magnetic resonance imaging, and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma, identifying this as the critical step in inducing clinical symptoms. Metalloproteinase (MPs) enzymes are implicated in leukocyte infiltration in neuroinflammation. Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-10, and -12 mRNA in the brain. PTx further induced expression of tissue inhibitor of metalloproteinase-1, metalloproteinase disintegrins-12, MMP-8, and -10 in brains of Tg mice. Levels of the microglial-associated MP MMP-15 were not affected in control or PTx-treated Tg mice. PTx also up-regulated expression of proinflammatory cytokines IL-1β and TNF-
mRNA in Tg CNS. Weight loss and parenchymal infiltration, but not perivascular accumulation, were significantly inhibited by the broad-spectrum MP inhibitor BB-94/Batimastat. Our finding that MPs mediate PTx-induced parenchymal infiltration to the chemokine-overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation, such as multiple sclerosis.
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 an Interdisciplinary Health Research Team grant from the Canadian Institutes of Health Research. H.T.-H. was supported by the Canadian Institutes for Health Research Neuroinflammation Training Grant, Knud Højgaards Fund, and Civilingeniør Bent Bøgh of Hustru Inge Bøghs Fund. H.T.-H. received a studentship from the Multiple Sclerosis Society of Canada.
2 Address correspondence and reprint requests to Dr. Trevor Owens, Medical Biotechnology Center, University of Southern Denmark, J. B. Winsløwsvej 25, 2. sal, 5000 Odense C, Denmark. E-mail address: towens{at}health.sdu.dk
3 Abbreviations used in this paper: MS, multiple sclerosis; MBP, myelin basic protein; EAE, experimental autoimmune encephalomyelitis; ADAM, a disintegrin and metalloprotease; PTx, pertussis toxin; PREMO, PTx-induced reversible encephalopathy dependent on MCP-1/CCL2 overexpression; BBB, blood-brain barrier; MP, metalloproteinase; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; Tg, transgenic; USPIO, ultra-small superparamagnetic iron oxide; PB, Prussian blue; MRI, magnetic resonance imaging; WT, wild type.
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