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Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization

Oncogene volume 34, pages 1865–1871 (2015)Cite this article

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Abstract

Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Although the specific mechanisms by which this pathogen induces carcinogenesis have not been fully elucidated, high-expression interleukin (IL)-1β alleles are associated with increased gastric cancer risk among H. pylori-infected persons. In addition, loss of matrix metalloproteinase 7 (MMP7) increases mucosal inflammation in mouse models of epithelial injury, and we have shown that gastric inflammation is increased in H. pylori-infected MMP7−/− C57BL/6 mice. In this report, we define mechanisms that underpin such responses and extend these results into a genetic model of MMP7 deficiency and gastric cancer. Wild-type (WT) or MMP7−/− C57BL/6 mice were challenged with broth alone as an uninfected control or the H. pylori strain PMSS1. All H. pylori-challenged mice were successfully colonized. As expected, H. pylori-infected MMP7−/− C57BL/6 mice exhibited a significant increase in gastric inflammation compared with uninfected or infected WT C57BL/6 animals. Loss of MMP7 resulted in M1 macrophage polarization within H. pylori-infected stomachs, as assessed by Luminex technology and immunohistochemistry, and macrophages isolated from infected MMP7-deficient mice expressed significantly higher levels of the M1 macrophage marker IL-1β compared with macrophages isolated from WT mice. To extend these findings into a model of gastric cancer, hypergastrinemic WT INS-GAS or MMP7−/− INS-GAS mice were challenged with H. pylori strain PMSS1. Consistent with findings in the C57BL/6 model, H. pylori-infected MMP7-deficient INS-GAS mice exhibited a significant increase in gastric inflammation compared with either uninfected or infected WT INS-GAS mice. In addition, the incidence of gastric hyperplasia and dysplasia was significantly increased in H. pylori-infected MMP7−/− INS-GAS mice compared with infected WT INS-GAS mice, and loss of MMP7 promoted M1 macrophage polarization. These results suggest that MMP7 exerts a restrictive role on H. pylori-induced gastric injury and the development of premalignant lesions by suppressing M1 macrophage polarization.

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Acknowledgements

This study was supported by T32CA009592 (MSK), F32CA153539 (JMN), T32GM008554 (DMH), K01AT007324 (RC), P01CA028842 (KTW and PC), R01DK053620 and 1I01BX001453 from the Department of Veterans Affairs (KTW), R01DK058587, R01CA077955, P30DK058404 and P01CA116087 (RMP).

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Author notes

  1. M S Krakowiak and J M Noto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    M S Krakowiak, K T Wilson & R M Peek Jr

  2. Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    J M Noto, M B Piazuelo, D M Hardbower, J Romero-Gallo, A Delgado, R Chaturvedi, P Correa, K T Wilson & R M Peek Jr

  3. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    D M Hardbower & K T Wilson

  4. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    K T Wilson

Authors
  1. M S Krakowiak
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  2. J M Noto
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  3. M B Piazuelo
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  9. K T Wilson
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  10. R M Peek Jr
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Correspondence to R M Peek Jr.

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Krakowiak, M., Noto, J., Piazuelo, M. et al. Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization. Oncogene 34, 1865–1871 (2015). https://doi.org/10.1038/onc.2014.135

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