An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization

Laval University, Quebec City, Quebec, Canada
The FASEB Journal (Impact Factor: 5.04). 11/2005; 19(12):1668-70. DOI: 10.1096/fj.04-2030fje
Source: PubMed


Inflammation in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), is manifested by changes in matrix metalloproteinase (MMP) expression and in the ratio of T helper (Th) 1 and 2 effector cytokines. Here, we provide a comprehensive documentation of MMPs in EAE and report that of all the MMPs that could be measured at peak disease in spinal cord tissue, MMP-12 was the most highly up-regulated. In contrast to previously published findings of MMPs in EAE, this increase in MMP-12 expression was associated with protection, as MMP-12 null mice had significantly worse maximum severity and EAE disease burden compared with wild-type (WT) controls. When spleen and lymph node cells were removed from EAE-afflicted WT and MMP-12 null mice at the same disease score before divergence of disease and restimulated in vitro, the MMP-12 null cells had significantly higher Th1 to Th2 cytokine ratio. Measurements of the transcriptional regulators of T cell polarization revealed that MMP-12 null cells had increased T-bet and reduced GATA-3 expression, a condition that favors a Th1 bias. These results emphasize that specific MMPs can have beneficial roles in inflammation, and they implicate MMPs in T effector polarization for the first time.

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Available from: Steven D Shapiro, Aug 19, 2014
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    • "B). EAE reactions were scored and recorded accordingly to a 0–15 scale, as described (Weaver et al., 2005). In the scoring based on a 0–15 scale, the final score is the sum of the state of the tail and all of the four limbs. "
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    • "Usually MMPs are under strict control at various levels: gene transcription, synthesis, secretion, activation, inhibition and glycosylation. Therefore, normal adult CNS contains low levels of most MMP members [30], in contrast to various neurological disorders of the CNS in which several MMPs are significantly upregulated [31]. "
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    • "MMP-12 could play a dual role in the inflammatory disease pathogenesis. After spinal cord trauma or intracerebral hemorrhage, or in Theiler's murine encephalomyelitis, MMP-12 exaggerates disease progression by increasing permeability of the blood-brain/spinal barrier and recruitment of macrophages into the CNS (Hansmann et al., 2012; Wells et al., 2003, 2005); however, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, MMP-12 inhibits pathogenesis by enhancing anti-inflammatory effects (Goncalves DaSilva and Yong, 2009; Weaver et al., 2005). We hypothesized that (1) the inflammatory activation associated with aging alters the expression of cerebral MMPs; and (2) the changed expression of MMPs modulates neuroinflammation . "
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