Genetic deletion of dectin-1 does not affect the course of murine experimental colitis

BMC Gastroenterology

Wouter J de Jonge⁵  Siamon Gordon³  Anje te Velde⁵  Shobhit Dhawan⁵  Joris JTH Roelofs¹  Anneke Oei²  Sigrid EM Heinsbroek⁴ 

[1] Department of Pathology, Academic Medical Center, University of Amsterdam, AMC, Amsterdam, The Netherlands;Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, AMC, Amsterdam, The Netherlands;Sir William Dunn School of Pathology, University of Oxford, Oxford, UK;Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Meibergdreef 69-71, 1105, BK Amsterdam, The Netherlands;Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, AMC, Amsterdam, The Netherlands

关键词: Intestine;    Fungi;    Innate immunity;    Colitis;    Macrophages;    Dectin-1;   

Others  :  1113103
DOI  :  10.1186/1471-230X-12-33

 received in 2011-10-19, accepted in 2012-04-16,  发布年份 2012

【 摘 要 】

Background

It is believed that inflammatory bowel diseases (IBD) result from an imbalance in the intestinal immune response towards the luminal microbiome. Dectin-1 is a widely expressed pattern recognition receptor that recognizes fungi and upon recognition it mediates cytokine responses and skewing of the adaptive immune system. Hence, dectin-1 may be involved in the pathogenesis of IBD.

Methods

We assessed the responses of dectin-1 deficient macrophages to the intestinal microbiota and determined the course of acute DSS and chronic Helicobacter hepaticus induced colitis in dectin-1 deficient mice.

Results

We show that the mouse intestinal microbiota contains fungi and the cytokine responses towards this microbiota were significantly reduced in dectin-1 deficient macrophages. However, in two different colitis models no significant differences in the course of inflammation were found in dectin-1 deficient mice compared to wild type mice.

Conclusions

Together our data suggest that, although at the immune cell level there is a difference in response towards the intestinal flora in dectin-1 deficient macrophages, during intestinal inflammation this response seems to be redundant since dectin-1 deficiency in mice does not affect intestinal inflammation in experimental colitis.

【 授权许可】

   
2012 Heinsbroek et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Cario E: Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm Bowel Dis 2010, 16:1583-1597.
• [2]Werts C, Rubino S, Ling A, Girardin SE, Philpott DJ: Nod-like receptors in intestinal homeostasis, inflammation, and cancer. J Leukoc Biol 2011, 90:471-482.
• [3]Vijay-Kumar M, Sanders CJ, Taylor RT, Kumar A, Aitken JD, Sitaraman SV, et al.: Deletion of TLR5 results in spontaneous colitis in mice. J Clin Invest 2007, 117:3909-3921.
• [4]Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, et al.: Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 2005, 288:G1055-G1065.
• [5]Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, et al.: MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J Gastroenterol 2005, 40:16-23.
• [6]Lowe EL, Crother TR, Rabizadeh S, Hu B, Wang H, Chen S, et al.: Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS One 2010, 5:e13027.
• [7]Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ, et al.: Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest 2008, 118:545-559.
• [8]Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD: The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 2010, 32:379-391.
• [9]Rakoff-Nahoum S, Hao L, Medzhitov R: Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 2006, 25:319-329.
• [10]Franchimont D, Vermeire S, El HH, Pierik M, Van SK, Gustot T, et al.: Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut 2004, 53:987-992.
• [11]Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al.: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001, 411:599-603.
• [12]Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al.: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001, 411:603-606.
• [13]Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, et al.: Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nat Genet 2009, 41:71-76.
• [14]Simon GL, Gorbach SL: Intestinal flora in health and disease. Gastroenterology 1984, 86:174-193.
• [15]Osorio F, Reis e Sousa C: Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 2011, 34:651-664.
• [16]Walker LJ, Aldhous MC, Drummond HE, Smith BR, Nimmo ER, Arnott ID, et al.: Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations. Clin Exp Immunol 2004, 135:490-496.
• [17]Dotan I, Fishman S, Dgani Y, Schwartz M, Karban A, Lerner A, et al.: Antibodies against laminaribioside and chitobioside are novel serologic markers in Crohn's disease. Gastroenterology 2006, 131:366-378.
• [18]Rothfuchs AG, Bafica A, Feng CG, Egen JG, Williams DL, Brown GD, et al.: Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells. J Immunol 2007, 179:3463-3471.
• [19]Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S: Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 2003, 197:1119-1124.
• [20]Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, et al.: Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 2005, 22:507-517.
• [21]Herre J, Marshall AS, Caron E, Edwards AD, Williams DL, Schweighoffer E, et al.: Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood 2004, 104:4038-4045.
• [22]Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM: Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 2003, 197:1107-1117.
• [23]LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, et al.: Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 2007, 8:630-638.
• [24]Osorio F, LeibundGut-Landmann S, Lochner M, Lahl K, Sparwasser T, Eberl G, et al.: DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol 2008, 38:3274-3281.
• [25]Reid DM, Montoya M, Taylor PR, Borrow P, Gordon S, Brown GD, et al.: Expression of the {beta}-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions. J Leukoc Biol 2004, 76:86-94.
• [26]de Vries HS, Plantinga TS, van Krieken JH, Stienstra R, van Bodegraven AA, Festen EA, et al.: Genetic association analysis of the functional c.714 T > G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease. PLoS One 2009, 4:e7818.
• [27]Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, et al.: IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006, 203:2485-2494.
• [28]Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, et al.: IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006, 203:2485-2494.
• [29]Heinsbroek SE, Taylor PR, Martinez FO, Martinez-Pomares L, Brown GD, Gordon S: Stage-specific sampling by pattern recognition receptors during Candida albicans phagocytosis. PLoS Pathog 2008, 4:e1000218.
• [30]Christensen HR, Frokiaer H, Pestka JJ: Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. J Immunol 2002, 168:171-178.
• [31]Lammers KM, Brigidi P, Vitali B, Gionchetti P, Rizzello F, Caramelli E, et al.: Immunomodulatory effects of probiotic bacteria DNA: IL-1 and IL-10 response in human peripheral blood mononuclear cells. FEMS Immunol Med Microbiol 2003, 38:165-172.
• [32]Khatib R, Riederer KM, Ramanathan J, Baran J Jr: Faecal fungal flora in healthy volunteers and inpatients. Mycoses 2001, 44:151-156.
• [33]Galan-Sanchez F, Garcia-Martos P, Rodriguez-Ramos C, Marin-Casanova P, Mira-Gutierrez J: Microbiological characteristics and susceptibility patterns of strains of Rhodotorula isolated from clinical samples. Mycopathologia 1999, 145:109-112.
• [34]Miceli MH, Diaz JA, Lee SA: Emerging opportunistic yeast infections. Lancet Infect Dis 2011, 11:142-151.
• [35]Wirtz S, Neurath MF: Mouse models of inflammatory bowel disease. Adv Drug Deliv Rev 2007, 59:1073-1083.
• [36]Fox JG, Ge Z, Whary MT, Erdman SE, Horwitz BH: Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer. Mucosal Immunol 2011, 4:22-30.
• [37]Williams AM, Probert CS, Stepankova R, Tlaskalova-Hogenova H, Phillips A, Bland PW: Effects of microflora on the neonatal development of gut mucosal T cells and myeloid cells in the mouse. Immunology 2006, 119:470-478.
• [38]Morland B, Smievoll AI, Midtvedt T: Comparison of peritoneal macrophages from germfree and conventional mice. Infect Immun 1979, 26:1129-1136.
• [39]Morland B, Midtvedt T: Phagocytosis, peritoneal influx, and enzyme activities in peritoneal macrophages from germfree, conventional, and ex-germfree mice. Infect Immun 1984, 44:750-752.
• [40]Drummond RA, Brown GD: The role of Dectin-1 in the host defence against fungal infections. Curr Opin Microbiol 2011, 14:392-399.
• [41]Standaert-Vitse A, Sendid B, Joossens M, Francois N, Vandewalle-El KP, Branche J, et al.: Candida albicans colonization and ASCA in familial Crohn's disease. Am J Gastroenterol 2009, 104:1745-1753.
• [42]Standaert-Vitse A, Jouault T, Vandewalle P, Mille C, Seddik M, Sendid B, et al.: Candida albicans Is an Immunogen for Anti-Saccharomyces cerevisiae Antibody Markers of Crohn's Disease. Gastroenterology 2006, 130:1764-1775.
• [43]Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, et al.: Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol 2007, 8:31-38.
• [44]Jawhara S, Thuru X, Standaert-Vitse A, Jouault T, Mordon S, Sendid B, et al.: Colonization of mice by Candida albicans is promoted by chemically induced colitis and augments inflammatory responses through galectin-3. J Infect Dis 2008, 197:972-980.
• [45]Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO: Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 1994, 107:1643-1652.
• [46]Wang JE, Warris A, Ellingsen EA, Jorgensen PF, Flo TH, Espevik T, et al.: Involvement of CD14 and toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae. Infect Immun 2001, 69:2402-2406.
• [47]Netea MG, Van Der Graaf CA, Vonk AG, Verschueren I, Van der Meer JW, Kullberg BJ: The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 2002, 185:1483-1489.
• [48]Ezekowitz RA, Sastry K, Bailly P, Warner A: Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells. J Exp Med 1990, 172:1785-1794.
• [49]Sato K, Yang Xl, Yudate T, Chung JS, Wu J, Luby-Phelps K, et al.: Dectin-2 Is a Pattern Recognition Receptor for Fungi That Couples with the Fc Receptor {gamma} Chain to Induce Innate Immune Responses. J Biol Chem 2006, 281:38854-38866.
• [50]Cambi A, Gijzen K, de Vries JM, Torensma R, Joosten B, Adema GJ, et al.: The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 2003, 33:532-538.
• [51]Taylor PR, Brown GD, Herre J, Williams DL, Willment JA, Gordon S: The Role of SIGNR1 and the {beta}-Glucan Receptor (Dectin-1) in the Nonopsonic Recognition of Yeast by Specific Macrophages. J Immunol 2004, 172:1157-1162.