Targeted Deletion of Metalloproteinase 9 Attenuates Experimental Colitis in Mice: Central Role of Epithelial-Derived MMP

Castaneda, Florencia E.; Walia, Baljit; Vijay‐Kumar, Matam; Patel, Neal; Roser, Susanne; Kolachala, Vasantha L.; Rojas, Mauricio; Wang, Lixin; Oprea, Gabriela; Garg, Pallavi; Gewirtz, Andrew T.; Roman, Jesse; Merlin, Didier; Sitaraman, Shanthi V.

doi:10.1053/j.gastro.2005.09.017

Cited by 244 publications

(257 citation statements)

References 61 publications

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“…The severe Th17-driven inflammation and pathology seen during the self-limiting E. falciformis infection in the absence of IFN-g have many parallels to murine models of colitis, and thus may prove to be a powerful model for dissecting the immunological mechanisms behind Th1/Th17 disease. For example, MMPs are potent mediators of intestinal pathology, and mice deficient for MMP9 develop less severe inflammation and disease during a mouse model of colitis (26). In line with these findings an increase in MMP9 was observed in IFN-gR 2/2 mice following E. falciformis infection.…”

Section: Discussionsupporting

confidence: 56%

IL-22 Mediates Host Defense against an Intestinal Intracellular Parasite in the Absence of IFN-γ at the Cost of Th17-Driven Immunopathology

Stange

Hepworth

Rausch

et al. 2012

The Journal of Immunology

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The roles of Th1 and Th17 responses as mediators of host protection and pathology in the intestine are the subjects of intense research. In this study, we investigated a model of intestinal inflammation driven by the intracellular apicomplexan parasite Eimeria falciformis. Although IFN-γ was the predominant cytokine during E. falciformis infection in wild-type mice, it was found to be dispensable for host defense and the development of intestinal inflammation. E. falciformis-infected IFN-γR−/− and IFN-γ−/− mice developed dramatically exacerbated body weight loss and intestinal pathology, but they surprisingly harbored fewer parasites. This was associated with a striking increase in parasite-specific IL-17A and IL-22 production in the mesenteric lymph nodes and intestine. CD4+ T cells were found to be the source of IL-17A and IL-22, which drove the recruitment of neutrophils and increased tissue expression of anti-microbial peptides (RegIIIβ, RegIIIγ) and matrix metalloproteinase 9. Concurrent neutralization of IL-17A and IL-22 in E. falciformis-infected IFN-γR−/− mice resulted in a reduction in infection-induced body weight loss and inflammation and significantly increased parasite shedding. In contrast, neutralization of IL-22 alone was sufficient to increase parasite burden, but it had no effect on body weight loss. Treatment of an E. falciformis-infected intestinal epithelial cell line with IFN-γ, IL-17A, or IL-22 significantly reduced parasite development in vitro. Taken together, to our knowledge these data demonstrate for the first time an antiparasite effect of IL-22 during an intestinal infection, and they suggest that IL-17A and IL-22 have redundant roles in driving intestinal pathology in the absence of IFN-γ signaling.

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Section: Discussionsupporting

confidence: 56%

IL-22 Mediates Host Defense against an Intestinal Intracellular Parasite in the Absence of IFN-γ at the Cost of Th17-Driven Immunopathology

Stange

Hepworth

Rausch

et al. 2012

The Journal of Immunology

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“…It is believed that gut bacteria benefit from metabolizing bile acids by acquiring glycine and taurine for subsequent metabolism. However it should be noted that bile acids also exert antimicrobial properties, by being directly toxic to bacteria or by stimulating production of antimicrobial factors [35] and play an important role in preventing small intestinal bacterial overgrowth [36].…”

Section: Discussionmentioning

confidence: 99%

Food Additive P-80 Impacts Mouse Gut Microbiota Promoting Intestinal Inflammation, Obesity and Liver Dysfunction

Singh¹

2016

SOJMID

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Open Access Research Articlethe globalization of unhealthy lifestyle. Key metabolic and physiological changes, including obesity, metabolic syndrome and Nonalcoholic Fatty Liver Disease (NAFLD) are commonly associated with chronic, non-communicable disease that are responsible for approximately 70% of the world's death.There are compelling arguments to include the composition of gut microbiota as a key risk factor for the development of obesity and obesity related metabolic disorders, including insulin resistance, type 2 diabetes, dyslipidemia and non-alcoholic fatty liver disease [3]. The gut microbiota has been implicated in having both direct (i.e. through effect on nutrient uptake) and indirect effect on health [4,5]. In mice, food additives have been demonstrated to affect the host microbiota interaction, leading to low-grade inflammation, adiposity and adiposity associated metabolic effect [6].We set out to elucidate whether alteration in the gut microbial community after P-80 ingestion is a causative agent of liver dysfunction. To explore this possibility, we setup an experiment to examine the impact of P-80 on gut microbiota using wild-type C57BL/ 6 mice. The experimental mice were gavaged with the amount of P-80 equal to 1% of their body weight. This amount correlates to the acceptable daily human intake of 1% per kg of polysorbate-80 to body weight [7]. Methods Mice and dietThe C57BL/6 (000664) mice were purchased from The Jackson Laboratory. The mice were maintained under specific pathogenfree conditions, on a 12-h light-dark cycle, and fed normal diet (12 kcal% fat, 29 kcal% protein, 59% kcal carbohydrate) ad libitum. For this study there were two groups: one control group (ingesting saline via gavage) and one experimental P-80 fed group (ingesting P-80 dissolve in saline, 1% per kg via gavage). This dose corresponds to the FDA Acceptable Daily Intake (ADI) in humans (1% per kg (body weight), adjusted to the mouse AbstractThe increasing prevalence of obesity has emerged as one of the most important global public health issue. The change to the human microbiome as a result of changes in the quality and quantity of food intake over the past several decades has been implicated in the development of obesity and metabolic syndrome. We administered polysorbate-80 to mice via gavage. The researchers monitor liver noninvasively using a bioluminescence imaging. For the liver dysfunction we measure the liver enzymes and PAS stain on liver, electron microscopy liver mitochondria. For the assessment of intestinal inflammation we measured fecal LCN2, LPS, MPO and flagellin by ELISA and qPCR. We use confocal microscopy to detect closet bacteria near the epithelium. 16S sequence was used for the composition of microbiota. Compared with control mice, those receiving emulsifier, showed impaired glycemic tolerance, hyperinsulinemia, altered liver enzymes, larger mitochondria and increased gall bladder size. Additionally, mice in the experimental group showed higher levels of DCA, reduced Muc2 RNA expression, reduced m...

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Section: Discussionmentioning

confidence: 99%

“…MMP-9-deficient mice were shown to be protected from acute colitis induced either by DSS [34,35] or by Salmonella Typhimurium [34]. Studies with bone marrow chimera revealed that MMP-2 and MMP-9 derived from epithelial but not immune cells, mediated colonic inflammation [34,36]. Furthermore, Garg and coworkers could show that besides MMP-2 knockout [36], MMP-2/ MMP-9 double deficient animals [37] also suffered from acute colitis following DSS treatment or Salmonella Typhimurium infection.…”

Section: Discussionmentioning

confidence: 99%

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

Heimesaat¹,

Dunay²,

Fuchs³

et al. 2011

European Journal of Microbiology and Immunology

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Expression of gelatinases A and B, also referred to matrixmetalloproteinases (MMP)-2 and -9, respectively, is increased in inflamed tissues of experimental intestinal inflammation and humans with inflammatory bowel disease (IBDs). Given that we recently reported that treatment with the selective gelatinase inhibitor RO28-2653 ameliorates acute dextrane sulfate sodium (DSS) colitis, we asked whether gelatinase A or B expression is pivotal in mediating large intestinal inflammation. Results from our study reveal that symptoms of acute DSS colitis as well as histopathological colonic changes were ameliorated in MMP-2-, but not MMP-9-deficient mice, and were paralleled by a diminished influx of immune cells. In MMP-2-deficient mice, we observed lower expression of pro-inflammatory cytokines including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 in colonic biopsies and less overgrowth of the colonic lumen by potentially pro-inflammatory enterobacteria from the commensal gut microbiota. We conclude that rather MMP-2 than MMP-9 is causative for the establishment of DSS colitis in mice. The discrepancy of these data to prior reports might be due to substantial differences in the intestinal microbiota composition of the mice bred at different animal facilities impacting susceptibility to inflammatory stimuli. Consequently, a detailed survey of the gut microbiota should be implemented in immunological/inflammatory studies in the future in order to allow comparison of data from different facilities.

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Targeted Deletion of Metalloproteinase 9 Attenuates Experimental Colitis in Mice: Central Role of Epithelial-Derived MMP

Cited by 244 publications

References 61 publications

IL-22 Mediates Host Defense against an Intestinal Intracellular Parasite in the Absence of IFN-γ at the Cost of Th17-Driven Immunopathology

IL-22 Mediates Host Defense against an Intestinal Intracellular Parasite in the Absence of IFN-γ at the Cost of Th17-Driven Immunopathology

Food Additive P-80 Impacts Mouse Gut Microbiota Promoting Intestinal Inflammation, Obesity and Liver Dysfunction

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

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