Metalloproteinases Control Brain Inflammation Induced by Pertussis Toxin in Mice Overexpressing the Chemokine CCL2 in the Central Nervous System

Abstract

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-α 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.

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

“…As noted previously, leukocytes readily cross the endothelial basement membrane but require MMPs to transmigrate the glia limitans and enter the CNS parenchyma (Mun-Bryce and Rosenberg, 1998;Agrawal et al, 2006;Toft-Hansen et al, 2006). Thus, while the reduction of proteolytic activity with anti-EMMPRIN treatment helps account for the attenuation of parenchymal infiltration of leukocytes, it is surprising that we did not observe large perivascular cuffs that could represent immune cells that were prevented from penetrating across the glia limitans into the CNS parenchyma; instead, we observed fewer and smaller cuffs in the anti-EMMPRIN mice.…”

“…Many members are elevated in the serum, CSF, and brain tissue of patients with MS (for review, see Yong et al, 2007) and in the CNS of mice afflicted with EAE (Weaver et al, 2005;Toft-Hansen et al, 2006). In human subjects, the period between the first and second clinical attacks of MS is accompanied by an increase in levels of MMP-9 in the serum compared with controls (Correale and Bassani Molinas Mde, 2003).…”

“…Available evidence indicates this proteolytic activity is provided principally by MMPs (Mun-Bryce and Rosenberg, 1998;Agrawal et al, 2006;Toft-Hansen et al, 2006). The use of MMP inhibitors (ToftHansen et al, 2006) and mutant mice (Agrawal et al, 2006) resulted in leukocytes being trapped in the perivascular space between the endothelial basement membrane and the glia limitans, and an attenuation of EAE disease.…”

Posttraumatic Invasion of Monocytes across the Blood—Cerebrospinal Fluid Barrier

“…Also, little is known about the possible expression of cell adhesion molecules at ependymal and pial/glial linings bordering the CSF space. Monocytes have the ability to produce a variety of matrix metalloproteinases (Newby, 2008), and the activation of these metalloproteinases have been shown to be a critical factor in the recruitment of inflammatory cells to the brain tissue (Toft-Hansen et al, 2006). Carried by the bulk flow of CSF, monocytes may passage from the lateral cerebral ventricle to the cistern of velum interpositum located above the third cerebral ventricle, and may also enter the subarachnoid CSF space near the injury site.…”

1,25-Dihydroxyvitamin D3selectively and reversibly impairs T helper-cell CNS localization

“…To migrate into the CNS parenchyma, encephalitogenic T H cells must cross the BBB or bloodleptomeningeal barrier (BLMB) and the glia limitans (16). Cell sequestration within the perivascular or leptomeningeal space prevents clinical disease (17,18). Before the onset of the clinical symptoms, inflammatory infiltrates were contained within the leptomeningeal space in approximately half of the vehicle-treated mice, whereas no infiltrates were detected in any of 1,25(OH) 2 D 3 -treated or naive mice (Fig.…”