Resistance of Collagenase-2 (Matrix Metalloproteinase-8)-Deficient Mice to TNF-Induced Lethal Hepatitis

Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology-Ghent University, Ghent, Belgium.
The Journal of Immunology (Impact Factor: 4.92). 12/2005; 175(11):7642-9. DOI: 10.4049/jimmunol.175.11.7642
Source: PubMed


Acute fulminant liver failure is a serious worldwide health problem. Despite maximal supportive intensive care treatment, the disease offers a poor prognosis, with mortality rates of >80%. We have previously shown that a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) confers complete protection in a mouse model of TNF-induced lethal hepatitis, thereby suggesting the possibility of protecting cancer patients against the deleterious side effects of TNF therapy. In our search for the individual matrix metalloproteinases involved, we found that the recently generated MMP-8-deficient mice are significantly protected against TNF-induced acute hepatitis. In contrast to their wild-type counterparts, MMP-8-null mice display very little hepatocyte necrosis and apoptosis, resulting in a much better survival outcome. We found that these animals clearly display impaired leukocyte influx into the liver and no release of the neutrophil-specific, LPS-induced CXC chemokine. Our findings provide evidence that MMP-8 plays an essential role in acute liver failure and might be a promising new target for the treatment for this illness.

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    • "MMP-8, also known as collagenase-2, has emerged as one of the most important regulators of the inflammatory response [5]. Mutant mice lacking MMP-8 show a characteristic inflammatory response, with an initial delay in cell recruitment, but also with a later persistence of the neutrophilic infiltration [6], [13]–[15]. Therefore, absence of this enzyme ameliorates hyperacute inflammation, but also worsens the response later on [7]. Noteworthy, blood cell counts and the migratory properties of neutrophils in knockout mice are normal [8], so the differences between genotypes rely on the regulation of the inflammatory response. "
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    ABSTRACT: Matrix metalloproteinase-8, released mainly from neutrophils, is a critical regulator of the inflammatory response by its ability to cleave multiple mediators. Herein, we report the results of a model of endotoxemia after intraperitoneal LPS injection in mice lacking MMP-8 and their wildtype counterparts. Control, saline-treated animals showed no differences between genotypes. However, there was an increased lung inflammatory response, with a prominent neutrophilic infiltration in mutant animals after LPS treatment. Using a proteomic approach, we identify alarmins S100A8 and S100A9 as two of the main differences between genotypes. Mice lacking MMP-8 showed a significant increase in these two molecules in lung homogenates, but not in spleen and serum. Mice lacking MMP-8 also showed an increase in MIP-1α levels and a marked activation of the non-canonical NF-κB pathway, with no differences in CXC-chemokines such as MIP-2 or LIX. These results show that MMP-8 can modulate the levels of S100A8 and S100A9 and its absence promotes the lung inflammatory response during endotoxemia.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "MMP-8 is a potent collagenolytic enzyme that is involved in the pathogenesis of several inflammatory conditions. Van Lint and colleagues showed that Mmp8-deficient mice were protected against TNF-induced lethal hepatitis [14]. Livers of knockout mice did not show the massive influx of neutrophils seen in wildtype mice, probably due to the functional link between Mmp-8 and lipopolysaccharide-induced CXC chemokine, a PMN chemokine. "
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    ABSTRACT: Rheumatoid arthritis is an autoimmune disease in which joint inflammation leads to progressive cartilage and bone erosion. Matrix metalloproteinases (MMPs) implicated in homeostasis of the extracellular matrix play a central role in cartilage degradation. However, the role of specific MMPs in arthritis pathogenesis is largely unknown. The aim of the present study was to investigate the role of Mmp-8 (collagenase-2) in an arthritis model. Arthritis was induced in Mmp8-deficient and wildtype mice by K/BxN serum transfer. Arthritis severity was measured by a clinical index and ankle sections were scored for synovial inflammation, cartilage damage and bone erosion. cDNA microarray analysis, real-time PCR and western blot were performed to identify differential changes in gene expression between mice lacking Mmp8 and controls. Mmp8 deficiency increased the severity of arthritis, although the incidence of disease was similar in control and deficient mice. Increased clinical score was associated with exacerbated synovial inflammation and bone erosion. We also found that the absence of Mmp8 led to increased expression of IL-1β, pentraxin-3 (PTX3) and prokineticin receptor 2 (PROKR2) in arthritic mice joints. Lack of Mmp-8 is accompanied by exacerbated synovial inflammation and bone erosion in the K/BxN serum-transfer arthritis model, indicating that this Mmp has a protective role in arthritis.
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    • "MMP-8 has some interesting effects in acute and chronic inflammation. Animals lacking this enzyme have a delayed onset of the acute inflammatory response in different experimental models [8], [10], [20]. However, once established, the inflammatory infiltrate persists for longer times than in controls. "
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