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  • 1 Charité — University Medicine Berlin, Berlin, Germany
  • 2 Charité — University Medicine Berlin, Berlin, Germany
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Matrix metalloproteinases (MMP)-2 and -9 (also referred to gelatinases-A and -B, respectively) are upregulated in the inflamed gut of mice and men. We recently demonstrated that synthetic gelatinase blockage reduced large intestinal pro-inflammatory immune responses and apoptosis following murine Campylobacter (C.) jejuni infection. In order to address which gelatinase mediates C. jejuni-induced immune responses, gnotobiotic MMP-2−/−, MMP-9−/−, and wildtype (WT) mice were generated by broadspectrum antibiotic treatment and perorally infected with C. jejuni strain 81-176. The pathogen stably colonized the murine intestinal tract irrespective of the genotype but did not translocate to extra-intestinal compartments. At days 8 and 14 postinfection (p.i.), less pronounced colonic histopathological changes were observed in infected MMP-2−/− mice, less distinct epithelial apoptosis, but more epithelial proliferation in both MMP-2−/− and MMP-9−/− mice, as compared to WT controls. Reduced immune responses in gelatinase- deficient mice were characterized by lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa and lamina propria. The expression of IL-22, IL-18, IL-17A, and IL-1β mRNA was higher in the colon of MMP-2−/− as compared to WT mice. In conclusion, both MMP-2 and MMP-9 are differentially involved in mediating C. jejuni-induced intestinal immunopathology.

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  • 1.

    Young KT , Davis LM, Dirita VJ: Campylobacter jejuni: molecular biology and pathogenesis. Nat Rev Microbiol 5, 665679 (2007)

  • 2.

    Dasti JI , Tareen AM, Lugert R, Zautner AE, Gross U: Campylobacter jejuni: a brief overview on pathogenicityassociated factors and disease-mediating mechanisms. Int J Med Microbiol 300, 205211 (2010)

    • Search Google Scholar
    • Export Citation
  • 3.

    Lane JA , Mehra RK, Carrington SD, Hickey RM: The food glycome: a source of protection against pathogen colonization in the gastrointestinal tract. Int J Food Microbiol 142, 113 (2010)

    • Search Google Scholar
    • Export Citation
  • 4.

    Guerry P , Szymanski CM: Campylobacter sugars sticking out. Trends Microbiol 16, 428435 (2008)

  • 5.

    Alter T , Bereswill S, Glunder G, Haag LM, Hanel I, et al.: [Campylobacteriosis of man: livestock as reservoir for Campylobacter species]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 54, 728734 (2011)

    • Search Google Scholar
    • Export Citation
  • 6.

    Kist M , Bereswill S: Campylobacter jejuni. Contrib Microbiol 8, 150165 (2001)

  • 7.

    Wakerley BR , Uncini A, Yuki N, Group GBSC, Group GBSC: Guillain-Barre and Miller Fisher syndromes –new diagnostic classification. Nat Rev Neurol 10, 537544 (2014)

    • Search Google Scholar
    • Export Citation
  • 8.

    van Spreeuwel JP , Duursma GC, Meijer CJ, Bax R, Rosekrans PC, et al.: Campylobacter colitis: histological immunohistochemical and ultrastructural findings. Gut 26, 945951 (1985)

    • Search Google Scholar
    • Export Citation
  • 9.

    Walker RI , Caldwell MB, Lee EC, Guerry P, Trust TJ, et al.: Pathophysiology of Campylobacter enteritis. Microbiol Rev 50, 8194 (1986)

  • 10.

    Masanta WO , Heimesaat MM, Bereswill S, Tareen AM, Lugert R, et al.: Modification of intestinal microbiota and its consequences for innate immune response in the pathogenesis of campylobacteriosis. Clin Dev Immunol 2013, 526860 (2013)

    • Search Google Scholar
    • Export Citation
  • 11.

    Bereswill S , Fischer A, Plickert R, Haag LM, Otto B, et al.: Novel murine infection models provide deep insights into the “menage a trois” of Campylobacter jejuni, microbiota and host innate immunity. PLoS One 6, e20953 (2011)

    • Search Google Scholar
    • Export Citation
  • 12.

    Birkedal-Hansen H , Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, et al.: Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4, 197250 (1993)

    • Search Google Scholar
    • Export Citation
  • 13.

    Goetzl EJ , Banda MJ, Leppert D: Matrix metalloproteinases in immunity. J Immunol 156, 14 (1996)

  • 14.

    Brinckerhoff CE , Matrisian LM: Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3, 207214 (2002)

    • Search Google Scholar
    • Export Citation
  • 15.

    Nelson AR , Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18, 11351149 (2000)

    • Search Google Scholar
    • Export Citation
  • 16.

    Crawford HC , Matrisian LM: Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. Enzyme Protein 49, 2037 (1996)

    • Search Google Scholar
    • Export Citation
  • 17.

    Saren P , Welgus HG, Kovanen PT: TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 157, 41594165 (1996)

    • Search Google Scholar
    • Export Citation
  • 18.

    Salmela MT , MacDonald TT, Black D, Irvine B, Zhuma T, et al.: Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation. Gut 51, 540547 (2002)

    • Search Google Scholar
    • Export Citation
  • 19.

    Munoz M , Heimesaat MM, Danker K, Struck D, Lohmann U, et al.: Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17. J Exp Med 206, 30473059 (2009)

    • Search Google Scholar
    • Export Citation
  • 20.

    Heimesaat MM , Dunay IR, Fuchs D, Trautmann D, Fischer A, et al.: The distinct roles of MMP-2 and MMP-9 in acute DSS colitis. Eur J Microbiol Immunol (Bp) 1, 302310 (2011)

    • Search Google Scholar
    • Export Citation
  • 21.

    Bailey CJ , Hembry RM, Alexander A, Irving MH, Grant ME, et al.: Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn’s disease and normal intestine. J Clin Pathol 47, 113116 (1994)

    • Search Google Scholar
    • Export Citation
  • 22.

    Baugh MD , Perry MJ, Hollander AP, Davies DR, Cross SS, et al.: Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 117, 814822 (1999)

    • Search Google Scholar
    • Export Citation
  • 23.

    von Lampe B , Barthel B, Coupland SE, Riecken EO, Rosewicz S: Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 47, 6373 (2000)

    • Search Google Scholar
    • Export Citation
  • 24.

    Vanlaere I , Libert C: Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock. Clin Microbiol Rev 22, 224239 (2009), Table of Contents

    • Search Google Scholar
    • Export Citation
  • 25.

    Handley SA , Miller VL: General and specific host responses to bacterial infection in Peyer’s patches: a role for stromelysin-1 (matrix metalloproteinase-3) during Salmonella enterica infection. Mol Microbiol 64, 94110 (2007)

    • Search Google Scholar
    • Export Citation
  • 26.

    Kundu P , Mukhopadhyay AK, Patra R, Banerjee A, Berg DE, et al.: Cag pathogenicity island-independent up-regulation of matrix metalloproteinases-9 and -2 secretion and expression in mice by Helicobacter pylori infection. J Biol Chem 281, 3465134662 (2006)

    • Search Google Scholar
    • Export Citation
  • 27.

    Bergin PJ , Raghavan S, Svensson H, Starckx S, Van Aelst I, et al.: Gastric gelatinase B/matrix metalloproteinase-9 is rapidly increased in Helicobacter felis-induced gastritis. FEMS Immunol Med Microbiol 52, 8898 (2008)

    • Search Google Scholar
    • Export Citation
  • 28.

    Takeda M , Imada K, Sato T, Ito A: Activation of human progelatinase A/promatrix metalloproteinase 2 by Escherichia coli-derived serine proteinase. Biochem Biophys Res Commun 268, 128132 (2000)

    • Search Google Scholar
    • Export Citation
  • 29.

    Alutis ME , Grundmann U, Fischer A, Kuhl AA, Bereswill S, et al.: Selective gelatinase inhibition reduces apoptosis and pro-inflammatory immune cell responses in Campylobacter jejuni-infected gnotobiotic IL-10 deficient mice. Eur J Microbiol Immunol (Bp) 4, 213222 (2014)

    • Search Google Scholar
    • Export Citation
  • 30.

    Heimesaat MM , Bereswill S, Fischer A, Fuchs D, Struck D, et al.: Gram-negative bacteria aggravate murine small in testinal Th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol 177, 87858795 (2006)

    • Search Google Scholar
    • Export Citation
  • 31.

    Haag LM , Fischer A, Otto B, Plickert R, Kuhl AA, et al.: Campylobacter jejuni induces acute enterocolitis in gnotobiotic IL-10–/–mice via Toll-like-receptor-2 and -4 signaling. PLoS One 7, e40761 (2012)

    • Search Google Scholar
    • Export Citation
  • 32.

    Heimesaat MM , Lugert R, Fischer A, Alutis M, Kuhl AA, et al.: Impact of Campylobacter jejuni cj0268c knockout mutation on intestinal colonization, translocation, and induction of immunopathology in gnotobiotic IL-10 deficient mice. PLoS One 9, e90148 (2014)

    • Search Google Scholar
    • Export Citation
  • 33.

    Heimesaat MM , Alutis M, Grundmann U, Fischer A, Tegtmeyer N, et al.: The role of serine protease HtrA in acute ulcerative enterocolitis and extra-intestinal immune responses during Campylobacter jejuni infection of gnotobiotic IL-10 deficient mice. Front Cell Infect Microbiol 4. 77 (2014)

    • Search Google Scholar
    • Export Citation
  • 34.

    Paclik D , Danese S, Berndt U, Wiedenmann B, Dignass A, et al.: Galectin-4 controls intestinal inflammation by selective regulation of peripheral and mucosal T cell apoptosis and cell cycle. PLoS One 3, e2629 (2008)

    • Search Google Scholar
    • Export Citation
  • 35.

    Heimesaat MM , Nogai A, Bereswill S, Plickert R, Fischer A, et al.: MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 59, 10791087 (2010)

    • Search Google Scholar
    • Export Citation
  • 36.

    Bereswill S , Munoz M, Fischer A, Plickert R, Haag LM, et al.: Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS One 5, e15099 (2010)

    • Search Google Scholar
    • Export Citation
  • 37.

    Heimesaat MM , Fischer A, Alutis M, Grundmann U, Boehm M, et al.: The impact of serine protease HtrA in apoptosis, intestinal immune responses and extra-intestinal histopathology during Campylobacter jejuni infection of infant mice. Gut Pathog 6, 16 (2014)

    • Search Google Scholar
    • Export Citation
  • 38.

    Haag LM , Fischer A, Otto B, Grundmann U, Kuhl AA, et al.: Campylobacter jejuni infection of infant mice: acute enterocolitis is followed by asymptomatic intestinal and extra-intestinal immune responses. Eur J Microbiol Immunol (Bp) 2, 211 (2012)

    • Search Google Scholar
    • Export Citation
  • 39.

    Scholzen T , Gerdes J: The Ki-67 protein: from the known and the unknown. J Cell Physiol 182, 311322 (2000)

  • 40.

    Heimesaat MM , Dunay IR, Fuchs D, Trautmann D, Fischer A, et al.: Selective gelatinase blockage ameliorates acute DSS colitis. Eur J Microbiol Immunol (Bp) 1, 228236 (2011)

    • Search Google Scholar
    • Export Citation
  • 41.

    Haag LM , Fischer A, Otto B, Plickert R, Kuhl AA, et al.: Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice. PLoS One 7, e35988 (2012)

    • Search Google Scholar
    • Export Citation
  • 42.

    Heimesaat MM , Bereswill S: Murine infection models for the investigation of Campylobacter jejuni–host interactions and pathogenicity. Berl Munch Tierarztl Wochenschr 128, 98103 (2015)

    • Search Google Scholar
    • Export Citation
  • 43.

    Alutis ME , Grundmann U, Hagen U, Fischer A, Kuhl AA, Gobel UB, et al.: Matrix metalloproteinase-2 mediates intestinal immunopathogenesis in Campylobacter jejuni-infected infant mice. Eur J Microbiol Immunol (Bp) (2015), doi: 10.1556/1886.2015.00025.

    • Search Google Scholar
    • Export Citation
  • 44.

    Eidenschenk C , Rutz S, Liesenfeld O, Ouyang W: Role of IL-22 in microbial host defense. Curr Top Microbiol Immunol 380, 213236 (2014)

  • 45.

    Ouyang WJ , Rutz S, Crellin NK, Valdez PA, Hymowitz SG: Regulation and Functions of the IL-10 Family of Cytokines in Inflammation and Disease. Annual Review of Immunology, Vol 29 29, 71109 (2011)

    • Search Google Scholar
    • Export Citation
  • 46.

    Munoz M , Liesenfeld O, Heimesaat MM: Immunology of Toxoplasma gondii. Immunol Rev 240, 269285 (2011)

  • 47.

    Malik A , Sharma D, St Charles J, Dybas LA, Mansfield LS: Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity. Mucosal Immunol 7, 802817 (2014)

    • Search Google Scholar
    • Export Citation
  • 48.

    Edwards LA , Nistala K, Mills DC, Stephenson HN, Zilbauer M, et al.: Delineation of the innate and adaptive T-cell immune outcome in the human host in response to Campylobacter jejuni infection. PLoS One 5, e15398 (2010)

    • Search Google Scholar
    • Export Citation
  • 49.

    Munoz M , Eidenschenk C, Ota N, Wong K, Lohmann U, et al.: Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42, 321331 (2015)

    • Search Google Scholar
    • Export Citation