Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity.
References
[1]
Allen JE, Maizels RM (2011) Diversity and dialogue in immunity to helminths. Nat Rev Immunol 11: 375–388. doi: 10.1038/nri2992
[2]
Artis D, Grencis RK (2008) The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol 1: 252–264. doi: 10.1038/mi.2008.21
Sonnenberg GF, Fouser LA, Artis D (2011) Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol May;12: 383–390. doi: 10.1038/ni.2025
[5]
Dumoutier L, Van Roost E, Colau D, Renauld J-C (2000) Human interleukin-10-related T cell-derived inducible factor: Molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc Natl Acad Sci U S A 97: 10144–10149. doi: 10.1073/pnas.170291697
[6]
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, et al. (2004) IL-22 increases the innate immunity of tissues. Immunity 21: 241–254. doi: 10.1016/j.immuni.2004.07.007
[7]
Nagalakshmi ML, Rascle A, Zurawski S, Menon S, de Waal Malefyt R (2004) Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int Immunopharmacol 4: 679–691. doi: 10.1016/j.intimp.2004.01.008
[8]
Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, et al. (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206: 1465–1472. doi: 10.1084/jem.20082683
[9]
Neufert C, Pickert G, Zheng Y, Wittkopf N, Warntjen M, et al. (2010) Activation of epithelial STAT3 regulates intestinal homeostasis. Cell Cycle 9: 652–655. doi: 10.4161/cc.9.4.10615
[10]
Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, et al. (2005) Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129: 969–984. doi: 10.1053/j.gastro.2005.06.071
[11]
Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst SrT, et al. (2006) IL-22 is increased in active Crohns disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 290: G827–G838. doi: 10.1152/ajpgi.00513.2005
[12]
Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, et al. (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14: 282–289. doi: 10.1038/nm1720
[13]
Basu R, O'Quinn DB, Silberger DJ, Schoeb TR, Fouser L, et al. (2012) Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37: 1061–1075. doi: 10.1016/j.immuni.2012.08.024
[14]
Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, et al. (2008) Innate and adaptive Interleukin-22 protects mice from inflammatory bowel disease. Immunity 29: 947–957. doi: 10.1016/j.immuni.2008.11.003
[15]
Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, et al. (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118: 534–544. doi: 10.1172/jci33194
[16]
Radaeva S, Sun R, Pan H-n, Hong F, Gao B (2004) Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39: 1332–1342. doi: 10.1002/hep.20184
[17]
Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, et al. (2007) Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity Oct; 27: 647–659. doi: 10.1016/j.immuni.2007.07.023
[18]
Broadhurst MJ, Leung JM, Kashyap V, McCune JM, Mahadevan U, et al. (2010) IL-22+ CD4+ T cells are associated with therapeutic Trichuris trichiura infection in an ulcerative colitis patient. Sci Transl Med Dec 1;2: 60ra88. doi: 10.1126/scitranslmed.3001500
[19]
Gaze S, McSorley HJ, Daveson J, Jones D, Bethony JM, et al. (2012) Characterising the mucosal and systemic immune responses to experimental human hookworm infection. PLoS Pathog Feb;8: e1002520. doi: 10.1371/journal.ppat.1002520
[20]
Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, et al. (2007) IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol Dec 15;179: 8090–8104. doi: 10.4049/jimmunol.179.12.8098
[21]
Camberis M, Le Gros G, Urban JJ (2003) Animal model of Nippostrongylus brasiliensis and Heligmosomoides polygyrus. Curr Protoc Immunol Chapter 19: Unit 19.12. doi: 10.1002/0471142735.im1912s55
[22]
Helmby H, Takeda K, Akira S, Grencis RK (2001) Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13. J Exp Med 194: 355–364. doi: 10.1084/jem.194.3.355
Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, et al. (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29: 958–970. doi: 10.1016/j.immuni.2008.11.001
[25]
Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D (2011) CD4+ Lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34: 122–134. doi: 10.1016/j.immuni.2010.12.009
[26]
Herbert DR, Yang JQ, Hogan SP, Groschwitz K, Khodoun M, et al. (2009) Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med 206: 2947–2957. doi: 10.1084/jem.20091268
[27]
Komiya T, Tanigawa Y, Hirohashi S (1999) Cloning and identification of the gene Gob-5, which is expressed in intestinal goblet cells in mice. Biochem Biophys Res Commun 255: 347–351. doi: 10.1006/bbrc.1999.0168
[28]
Kim Y, Ho S (2010) Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 12: 319–330. doi: 10.1007/s11894-010-0131-2
[29]
Hasnain SZ, Wang H, Ghia J-E, Haq N, Deng Y, et al. (2010) Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology 138: 1763–1771. doi: 10.1053/j.gastro.2010.01.045
[30]
Hasnain SZ, Evans CM, Roy M, Gallagher AL, Kindrachuk KN, et al. (2011) Muc5ac: a critical component mediating the rejection of enteric nematodes. J Exp Med 208: 893–900. doi: 10.1084/jem.20102057
[31]
Artis D, Wang ML, Keilbaugh SA, He W, Brenes M, et al. (2004) RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 101: 13596–13600. doi: 10.1073/pnas.0404034101
[32]
Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, et al. (2012) IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491: 259–263. doi: 10.1038/nature11535
[33]
Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, et al. (2013) Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med 210: 917–931. doi: 10.1084/jem.20122308
[34]
Wilson MS, Feng CG, Barber DL, Yarovinsky F, Cheever AW, et al. (2010) Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth Infections. J Immunol 184: 4378–4390. doi: 10.4049/jimmunol.0903416
[35]
Linden SK, Florin THJ, McGuckin MA (2008) Mucin dynamics in intestinal bacterial infection. PLoS One 3: e3952. doi: 10.1371/journal.pone.0003952
[36]
Hasnain SZ, Gallagher AL, Grencis RK, Thornton DJ (2013) A new role for mucins in immunity: Insights from gastrointestinal nematode infection. Int J Biochem Cell Biol 45: 364–374. doi: 10.1016/j.biocel.2012.10.011
[37]
Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, et al. (1998) Interleukin-13: central mediator of allergic asthma. Science 282: 2258–2261. doi: 10.1126/science.282.5397.2258
[38]
Dabbagh K, Takeyama K, Lee H-M, Ueki IF, Lausier JA, et al. (1999) IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol 162: 6233–6237.
[39]
Jarry A, Vallette G, Branka JE, Laboisse C (1996) Direct secretory effect of interleukin-1 via type I receptors in human colonic mucous epithelial cells (HT29-C1.16E). Gut 38: 240–242. doi: 10.1136/gut.38.2.240
[40]
Enss ML, Cornberg M, Wagner S, Gebert A, Henrichs M, et al. (2000) Proinflammatory cytokines trigger MUC gene expression and mucin release in the intestinal cancer cell line LS180. Inflamm Res 49: 162–169. doi: 10.1007/s000110050576
[41]
McKenzie GJ, Bancroft A, Grencis RK, McKenzie ANJ (1998) A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Current Biology 8: 339–342. doi: 10.1016/s0960-9822(98)70134-4
[42]
Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, et al. (2002) IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17: 7–17. doi: 10.1016/s1074-7613(02)00332-1
[43]
Khan WI, Blennerhasset P, Ma C, Matthaei KI, Collins SM (2001) Stat6 dependent goblet cell hyperplasia during intestinal nematode infection. Parasite Immunol 23: 39–42. doi: 10.1046/j.1365-3024.2001.00353.x
[44]
Marillier R, Michels C, Smith E, Fick L, Leeto M, et al. (2008) IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections. BMC Immunology 9: 11. doi: 10.1186/1471-2172-9-11
[45]
Shekels LL, Anway RE, Lin J, Kennedy MW, Garside P, et al. (2001) Coordinated Muc2 and Muc3 Mucin gene expression in Trichinella spiralis infection in wild-type and cytokine-deficient mice. Dig Dis Sci 46: 1757–1764.
