Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease

Bruyn, Magali de; Breynaert, Christine; Arijs, Ingrid; Hertogh, Gert De; Geboes, Karel; Thijs, Greet; Matteoli, Gianluca; Hu, Jialiang; Damme, Jozef Van; Arnold, Bernd; Ferrante, Marc; Vermeire, Séverine; Assche, Gert Van; Opdenakker, Ghislain

doi:10.1038/ncomms15384

Cited by 41 publications

(40 citation statements)

References 53 publications

(122 reference statements)

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“…We tested the protein levels of MMP-2 in our mmp-9 -/- mice and these were not significantly altered. In addition, by RNAseq analysis we found that basal levels of all mouse MMP mRNAs, except that of MMP-9, were not altered in our WT (n = 8) versus mmp-9 -KO mice (n = 8) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, our knockout line has a severe subfertility phenotype [ 22 ]. For these reasons and in view of the increasing awareness about possible confounding influences imposed by differences in genetic backgrounds between wild-type and knockout mice [ 23 , 24 ] and by possible interference by differences in environmental conditions [ 25 ] and to avoid clinical bias on the basis of fur color, we further backcrossed our mmp-9 knockout mice (mmp-9 -/- ) till these became black [ 26 ]. We used in all forthcoming experiments black animals from the 13 th generation backcross into C57Bl/6.…”

Section: Methodsmentioning

confidence: 99%

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Gelatinase B/matrix metalloproteinase-9 is a phase-specific effector molecule, independent from Fas, in experimental autoimmune encephalomyelitis

et al. 2018

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Gelatinase B/matrix metalloproteinase-9 (MMP-9) triggers multiple sclerosis (MS) and the animal model of experimental autoimmune encephalomyelitis (EAE) by the breakdown of the blood-brain barrier. Interestingly, MMP-9 is beneficial in systemic autoimmunity caused by Fas-deficiency. Fas-deficient (faslpr) and Fas-ligand-deficient mice are protected against EAE. We here investigated the interaction between Fas and MMP-9 in the setting of induction of EAE and compared short- and long-term effects. We provoked EAE with myelin oligodendrocyte glycoprotein (MOG) peptide and compared EAE development in four genotypes (wild-type (WT), single knockout mmp-9-/-, faslpr, and mmp-9-/-/faslpr) and monitored leukocytes, cytokines and chemokines as immunological parameters. As expected, faslpr mice were resistant against EAE induction, whereas MMP-9 single knockout mice were not. In the double mmp-9-/-/ faslpr mice the effects on disease scores pointed to independent rather than interrelated disease mechanisms. On a short term, after EAE induction leukocytes infiltrated into the brain and cytokine and chemokine levels were significantly higher in all the four genotypes studied, even in the faslpr and mmp-9-/-/faslpr, which did not develop clinical disease. The levels of MMP-9 but not of MMP-2 were increased in the brain and in the peripheral organs after EAE induction. After 40 days all the animals recovered and did not show signs of EAE. However, the absence of MMP-9 in the remission phase suggested a protective role of MMP-9 in the late phase of the disease, because single mmp-9-/- mice presented a delayed remission in comparison with WT animals suggesting a phase-dependent role of MMP-9 in the disease. Nevertheless, the levels of some cytokines and chemokines remained higher than in control animals even 100 days after EAE induction, attesting to a prolonged state of immune activation. We thus yielded new insights and useful markers to monitor this activated immune status. Furthermore, MMP-9 but not MMP-2 levels remained increased in the brains and, to a higher extend, in the spleens of the WT mice even during the remission phase, which is in line with the role of MMP-9 as a useful marker and a protective factor for EAE in the remission phase.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Gelatinase B/matrix metalloproteinase-9 is a phase-specific effector molecule, independent from Fas, in experimental autoimmune encephalomyelitis

et al. 2018

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“…9 During our colitis experiments, WT and MMP-9 -/- mice were co-housed according to phenotype. This implicates that WT and MMP-9 -/- mice received the same drinking bottle with normal drinking water or water supplemented with DSS, which excludes potential DSS intake-related differences within the same cage.…”

Section: Discussionmentioning

confidence: 99%

Comparisons of gut microbiota profiles in wild-type and gelatinase B/matrix metalloproteinase-9-deficient mice in acute DSS-induced colitis

Bruyn

Sabino

Vandeputte

et al. 2018

npj Biofilms Microbiomes

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Gut microbiota help to educate the immune system and a number of involved immune cells were recently characterized. However, specific molecular determinants in these processes are not known, and, reciprocally, little information exists about single host determinants that alter the microbiota. Gelatinase B/matrix metalloproteinase-9 (MMP-9), an innate immune regulator and effector, has been suggested as such a host determinant. In this study, acute colitis was induced in co-housed MMP-9-/- mice (n = 10) and their wild-type (WT) littermates (n = 10) via oral administration of 3% dextran sodium sulfate (DSS) for 7 days followed by 2 days of regular drinking water. Control mice (10 WT and 10 MMP-9-/-) received normal drinking water. Fecal samples were collected at time of sacrifice and immediately frozen at −80 °C. Microbiota analysis was performed using 16S rRNA amplicon sequencing on Illumina MiSeq and taxonomic annotation was performed using the Ribosomal Database Project as reference. Statistical analysis correcting for multiple testing was done using R. No significant differences in clinical or histopathological parameters were found between both genotypes with DSS-induced colitis. Observed microbial richness at genus level and microbiota composition were not significantly influenced by host genotype. In contrast, weight loss, disease activity index, cage, and phenotype did significantly influence the intestinal microbiota composition. After multivariate analysis, cage and phenotype were identified as the sole drivers of microbiota composition variability. In conclusion, changes in fecal microbiota composition were not significantly altered in MMP-9-deficient mice compared to wild-type littermates, but instead were mainly driven by DSS-induced colonic inflammation.

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“…21 However, a recent report argued against its significance because MMP-9 inhibition does not attenuate murine colitis. 33 In addition, recent clinical trials with MMP-9 antagonist have not demonstrated significant efficacy in patients with moderate-to-severe UC or CD. 34 Such results obscure the significance of MMP-9 for the regulation of inflammation.…”

Section: Groupmentioning

confidence: 99%

Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice

et al. 2020

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Background/Aims: Intestinal fibrosis is a major complication of Crohn’s disease (CD). The profibrotic protein transforming growth factor-β (TGF-β) has been considered to be critical for the induction of the fibrotic program. TGF-β has the ability to induce not only the expression of extracellular matrix (ECM) including collagen, but also the production of plasminogen activator inhibitor-1 (PAI-1) that prevents enzymatic degradation of the ECM during the onset of fibrotic diseases. However, the significance of PAI-1 in the developing intestinal fibrosis has not been fully understood. In the present study, we examined the actual expression of <i>PAI-1</i> in fibrotic legion of intestinal inflammation and its correlation with the abnormal ECM deposition.Methods: Chronic intestinal inflammation was induced in BALB/c mice using 8 repeated intrarectal injections of 2,4,6-trinitrobenzene sulfonic acid (TNBS). TM5275, a PAI-1 inhibitor, was orally administered as a carboxymethyl cellulose suspension each day for 2 weeks after the sixth TNBS injection.Results: Using a publicly available dataset (accession number, GSE75214) and TNBS-treated mice, we observed increases in <i>PAI-1</i> transcripts at active fibrotic lesions in both patients with CD and mice with chronic intestinal inflammation. Oral administration of TM5275 immediately after the onset of intestinal fibrosis upregulated MMP-9 (matrix metalloproteinase 9) and decreased collagen accumulation, resulting in attenuation of the fibrogenesis in TNBS-treated mice.Conclusions: PAI-1-mediated fibrinolytic system facilitates collagen degradation suppression. Hence, PAI-1 inhibitor could be applied as an anti-fibrotic drug in CD treatment.

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Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease

Cited by 41 publications

References 53 publications

Gelatinase B/matrix metalloproteinase-9 is a phase-specific effector molecule, independent from Fas, in experimental autoimmune encephalomyelitis

Gelatinase B/matrix metalloproteinase-9 is a phase-specific effector molecule, independent from Fas, in experimental autoimmune encephalomyelitis

Comparisons of gut microbiota profiles in wild-type and gelatinase B/matrix metalloproteinase-9-deficient mice in acute DSS-induced colitis

Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice

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