IL-22 Mediates Goblet Cell Hyperplasia and Worm Expulsion in Intestinal Helminth Infection

English version České info

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.

Vyšlo v časopise: IL-22 Mediates Goblet Cell Hyperplasia and Worm Expulsion in Intestinal Helminth Infection. PLoS Pathog 9(10): e32767. doi:10.1371/journal.ppat.1003698
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003698

Souhrn

Zdroje

1. AllenJE, MaizelsRM (2011) Diversity and dialogue in immunity to helminths. Nat Rev Immunol 11: 375–388.

2. ArtisD, GrencisRK (2008) The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol 1: 252–264.

3. McGuckinMA, LindenSK, SuttonP, FlorinTH (2011) Mucin dynamics and enteric pathogens. Nat Rev Microbiol 9: 265–278.

4. SonnenbergGF, FouserLA, ArtisD (2011) Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol May;12: 383–390.

5. DumoutierL, Van RoostE, ColauD, RenauldJ-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.

6. WolkK, KunzS, WitteE, FriedrichM, AsadullahK, et al. (2004) IL-22 increases the innate immunity of tissues. Immunity 21: 241–254.

7. NagalakshmiML, RascleA, ZurawskiS, MenonS, de Waal MalefytR (2004) Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int Immunopharmacol 4: 679–691.

8. PickertG, NeufertC, LeppkesM, ZhengY, WittkopfN, et al. (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206: 1465–1472.

9. NeufertC, PickertG, ZhengY, WittkopfN, WarntjenM, et al. (2010) Activation of epithelial STAT3 regulates intestinal homeostasis. Cell Cycle 9: 652–655.

10. AndohA, ZhangZ, InatomiO, FujinoS, DeguchiY, et al. (2005) Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129: 969–984.

11. BrandS, BeigelF, OlszakT, ZitzmannK, EichhorstSrT, 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.

12. ZhengY, ValdezPA, DanilenkoDM, HuY, SaSM, et al. (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14: 282–289.

13. BasuR, O'QuinnDB, SilbergerDJ, SchoebTR, FouserL, et al. (2012) Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37: 1061–1075.

14. ZenewiczLA, YancopoulosGD, ValenzuelaDM, MurphyAJ, StevensS, et al. (2008) Innate and adaptive Interleukin-22 protects mice from inflammatory bowel disease. Immunity 29: 947–957.

15. SugimotoK, OgawaA, MizoguchiE, ShimomuraY, AndohA, et al. (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118: 534–544.

16. RadaevaS, SunR, PanH-n, HongF, GaoB (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.

17. ZenewiczLA, YancopoulosGD, ValenzuelaDM, MurphyAJ, KarowM, et al. (2007) Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity Oct; 27: 647–659.

18. BroadhurstMJ, LeungJM, KashyapV, McCuneJM, MahadevanU, 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.

19. GazeS, McSorleyHJ, DavesonJ, JonesD, BethonyJM, et al. (2012) Characterising the mucosal and systemic immune responses to experimental human hookworm infection. PLoS Pathog Feb;8: e1002520.

20. KreymborgK, EtzenspergerR, DumoutierL, HaakS, RebolloA, 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.

21. CamberisM, Le GrosG, UrbanJJ (2003) Animal model of Nippostrongylus brasiliensis and Heligmosomoides polygyrus. Curr Protoc Immunol Chapter 19: Unit 19.12.

22. HelmbyH, TakedaK, AkiraS, GrencisRK (2001) Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13. J Exp Med 194: 355–364.

23. SonnenbergGF, MonticelliLA, AlenghatT, FungTC, HutnickNA, et al. (2012) Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336: 1321–1325.

24. Satoh-TakayamaN, VosshenrichCA, Lesjean-PottierS, SawaS, LochnerM, et al. (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29: 958–970.

25. SonnenbergGF, MonticelliLA, EllosoMM, FouserLA, ArtisD (2011) CD4+ Lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34: 122–134.

26. HerbertDR, YangJQ, HoganSP, GroschwitzK, KhodounM, et al. (2009) Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med 206: 2947–2957.

27. KomiyaT, TanigawaY, HirohashiS (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.

28. KimY, HoS (2010) Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 12: 319–330.

29. HasnainSZ, WangH, GhiaJ-E, HaqN, DengY, et al. (2010) Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology 138: 1763–1771.

30. HasnainSZ, EvansCM, RoyM, GallagherAL, KindrachukKN, et al. (2011) Muc5ac: a critical component mediating the rejection of enteric nematodes. J Exp Med 208: 893–900.

31. ArtisD, WangML, KeilbaughSA, HeW, BrenesM, 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.

32. HuberS, GaglianiN, ZenewiczLA, HuberFJ, BosurgiL, et al. (2012) IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491: 259–263.

33. KirchbergerS, RoystonDJ, BoulardO, ThorntonE, FranchiniF, et al. (2013) Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med 210: 917–931.

34. WilsonMS, FengCG, BarberDL, YarovinskyF, CheeverAW, et al. (2010) Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth Infections. J Immunol 184: 4378–4390.

35. LindenSK, FlorinTHJ, McGuckinMA (2008) Mucin dynamics in intestinal bacterial infection. PLoS One 3: e3952.

36. HasnainSZ, GallagherAL, GrencisRK, ThorntonDJ (2013) A new role for mucins in immunity: Insights from gastrointestinal nematode infection. Int J Biochem Cell Biol 45: 364–374.

37. Wills-KarpM, LuyimbaziJ, XuX, SchofieldB, NebenTY, et al. (1998) Interleukin-13: central mediator of allergic asthma. Science 282: 2258–2261.

38. DabbaghK, TakeyamaK, LeeH-M, UekiIF, LausierJA, et al. (1999) IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol 162: 6233–6237.

39. JarryA, ValletteG, BrankaJE, LaboisseC (1996) Direct secretory effect of interleukin-1 via type I receptors in human colonic mucous epithelial cells (HT29-C1.16E). Gut 38: 240–242.

40. EnssML, CornbergM, WagnerS, GebertA, HenrichsM, et al. (2000) Proinflammatory cytokines trigger MUC gene expression and mucin release in the intestinal cancer cell line LS180. Inflamm Res 49: 162–169.

41. McKenzieGJ, BancroftA, GrencisRK, McKenzieANJ (1998) A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Current Biology 8: 339–342.

42. FallonPG, JolinHE, SmithP, EmsonCL, TownsendMJ, 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.

43. KhanWI, BlennerhassetP, MaC, MatthaeiKI, CollinsSM (2001) Stat6 dependent goblet cell hyperplasia during intestinal nematode infection. Parasite Immunol 23: 39–42.

44. MarillierR, MichelsC, SmithE, FickL, LeetoM, et al. (2008) IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections. BMC Immunology 9: 11.

45. ShekelsLL, AnwayRE, LinJ, KennedyMW, GarsideP, 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.