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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    • "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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    ABSTRACT: Matrix metalloproteinases (MMPs) are involved in the pathogenesis of neuroinflammatory diseases (such as multiple sclerosis) as well as in the expansion of malignant gliomas because they facilitate penetration of anatomical barriers (such as the glia limitans) and migration within the neuropil. This review elucidates pathomechanisms and summarizes the current knowledge of the involvement of MMPs in neuroinflammation and glioma, invasion highlighting microglia as major sources of MMPs. The induction of expression, suppression, and multiple pathways of function of MMPs in these scenarios will also be discussed. Understanding the induction and action of MMPs might provide valuable information and reveal attractive targets for future therapeutic strategies.
    Clinical and Developmental Immunology 08/2013; 2013(3):914104. DOI:10.1155/2013/914104 · 2.93 Impact Factor
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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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    ABSTRACT: During aging the brain displays an increased proinflammatory status, which is associated with the pathogenesis of aging-related diseases such as Alzheimer's and Parkinson diseases. Matrix metalloproteinases (MMPs) facilitate the migration of inflammatory cells in tissues and modulate their inflammatory activity. In this study, we screened expression of MMPs in 3-, 10-, and 18-month-old mice and observed that cerebral MMP-12 expression was strongly upregulated during aging. We compared the neuroinflammation of 3-, 10-, and 18-month-old MMP-12-deficient versus wild type mice by counting microglia and measuring inflammatory gene transcripts in the brain and observed that MMP-12 deficiency reduced neuroinflammation during aging. In order to identify potential mechanisms, we analyzed the inflammatory activity of microglia directly isolated from adult mouse brains or cultured from newborn mice. We observed that MMP-12 deficiency increased the inflammatory activity of adult brain-derived microglia, but did not affect cultured microglia. We found greater numbers of CD11b/CD45(high) cells in the parenchyma of MMP-12 wild type than in the parenchyma of MMP-12-deficient mouse brains. Thus, our study suggested that the upregulated cerebral MMP-12 during aging enhances aging-associated neuroinflammation by facilitating recruitment of bone marrow-derived microglia into the brain.
    Neurobiology of aging 11/2012; 34(4). DOI:10.1016/j.neurobiolaging.2012.10.015 · 5.01 Impact Factor
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    • "Reconstituted lyophilized pertussis toxin (200 ng List Biological Laboratories, Campbell, CA, USA) was injected intraperitoneally immediately after the MOG injection and again 48 h later. Animals were weighed, examined, and graded daily for EAE incidence and severity using a 0–15 rating scale (Weaver et al. 2005) as follows: Tail: 0 reflects no signs, 1 represents a half paralyzed tail, 2 represents a fully paralyzed tail; Limbs: 0 reflects no signs, 1 represents a weak or altered gait, 2 represents paresis, 3 represents a fully paralyzed limb. A fully paralyzed quadriplegic animal would attain a score of 12. Mortality equals a score of 15. "
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    ABSTRACT: Studies with multiple sclerosis patients and animal models of experimental autoimmune encephalomyelitis (EAE) implicate adenosine and adenosine receptors in modulation of neuroinflammation and brain injury. Although the involvement of the A(1) receptor has been recently demonstrated, the role of the adenosine A(2A) receptor (A(2A) R) in development of EAE pathology is largely unknown. Using mice with genetic inactivation of the A(2A) receptor, we provide direct evidence that loss of the A(2A) R exacerbates EAE pathology in mice. Compared with wild-type mice, A(2A) R knockout mice injected with myelin oligodendroglia glycoprotein peptide had a higher incidence of EAE and exhibited higher neurological deficit scores and greater decrease in body weight. A(2A) R knockout mice displayed increased inflammatory cell infiltration and enhanced microglial cell activation in cortex, brainstem, and spinal cord. In addition, demyelination and axonal damage in brainstem were exacerbated, levels of Th1 cytokines increased, and Th2 cytokines decreased. Collectively, these findings suggest that extracellular adenosine acting at A(2A) Rs triggers an important neuroprotective mechanism. Thus, the A(2A) receptor is a potential target for therapeutic approaches to multiple sclerosis.
    Journal of Neurochemistry 05/2012; 123(1):100-12. DOI:10.1111/j.1471-4159.2012.07807.x · 4.28 Impact Factor
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