IRAK-2 Regulates IL-1-Mediated Pathogenic Th17 Cell Development in Helminthic Infection


Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host’s genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1β-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases.


Vyšlo v časopise: IRAK-2 Regulates IL-1-Mediated Pathogenic Th17 Cell Development in Helminthic Infection. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002272
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002272

Souhrn

Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host’s genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1β-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases.


Zdroje

1. PearceEJMacDonaldAS 2002 The immunobiology of schistosomiasis. Nat Rev Immunol 2 499 511

2. AnthonyRMRutitzkyLIUrbanJFJrStadeckerMJGauseWC 2007 Protective immune mechanisms in helminth infection. Nat Rev Immunol 7 975 987

3. FrazerKAEskinEKangHMBogueMAHindsDA 2007 A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature 448 1050 1053

4. YangHBellTAChurchillGAPardo-Manuel de VillenaF 2007 On the subspecific origin of the laboratory mouse. Nat Genet 39 1100 1107

5. GuenetJLBonhommeF 2003 Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet 19 24 31

6. Sancho-ShimizuVMaloD 2006 Sequencing, expression, and functional analyses support the candidacy of Ncf2 in susceptibility to Salmonella typhimurium infection in wild-derived mice. J Immunol 176 6954 6961

7. StaelensJWielockxBPuimegeLVan RoyFGuenetJL 2002 Hyporesponsiveness of SPRET/Ei mice to lethal shock induced by tumor necrosis factor and implications for a TNF-based antitumor therapy. Proc Natl Acad Sci U S A 99 9340 9345

8. GauseWCUrbanJFJrStadeckerMJ 2003 The immune response to parasitic helminths: insights from murine models. Trends Immunol 24 269 277

9. HernandezHJWangYTzellasNStadeckerMJ 1997 Expression of class II, but not class I, major histocompatibility complex molecules is required for granuloma formation in infection with Schistosoma mansoni. Eur J Immunol 27 1170 1176

10. BicaIHamerDHStadeckerMJ 2000 Hepatic schistosomiasis. Infect Dis Clin North Am 14 583 604 viii

11. CheeverAWDuvallRHHallackTAJrMinkerRGMalleyJD 1987 Variation of hepatic fibrosis and granuloma size among mouse strains infected with Schistosoma mansoni. Am J Trop Med Hyg 37 85 97

12. RutitzkyLIHernandezHJStadeckerMJ 2001 Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. Proc Natl Acad Sci U S A 98 13243 13248

13. LangrishCLChenYBlumenscheinWMMattsonJBashamB 2005 IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201 233 240

14. YenDCheungJScheerensHPouletFMcClanahanT 2006 IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116 1310 1316

15. OuyangWKollsJKZhengY 2008 The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28 454 467

16. NakaeSNambuASudoKIwakuraY 2003 Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171 6173 6177

17. IvanovIIMcKenzieBSZhouLTadokoroCELepelleyA 2006 The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126 1121 1133

18. BettelliECarrierYGaoWKornTStromTB 2006 Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441 235 238

19. VeldhoenMHockingRJAtkinsCJLocksleyRMStockingerB 2006 TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24 179 189

20. ZhouLIvanovIISpolskiRMinRShenderovK 2007 IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8 967 974

21. KornTBettelliEGaoWAwasthiAJagerA 2007 IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448 484 487

22. NurievaRYangXOMartinezGZhangYPanopoulosAD 2007 Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448 480 483

23. DongC 2008 TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8 337 348

24. SuttonCBreretonCKeoghBMillsKHLavelleEC 2006 A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203 1685 1691

25. DinarelloCA 2009 Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27 519 550

26. ChungYChangSHMartinezGJYangXONurievaR 2009 Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30 576 587

27. Ben-SassonSZHu-LiJQuielJCauchetauxSRatnerM 2009 IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A 106 7119 7124

28. ShainheitMGSmithPMBazzoneLEWangACRutitzkyLI 2008 Dendritic cell IL-23 and IL-1 production in response to schistosome eggs induces Th17 cells in a mouse strain prone to severe immunopathology. J Immunol 181 8559 8567

29. SmithPMShainheitMGBazzoneLERutitzkyLIPoltorakA 2009 Genetic control of severe egg-induced immunopathology and IL-17 production in murine schistosomiasis. J Immunol 183 3317 3323

30. RutitzkyLIBazzoneLShainheitMGJoyce-ShaikhBCuaDJ 2008 IL-23 Is Required for the Development of Severe Egg-Induced Immunopathology in Schistosomiasis and for Lesional Expression of IL-17. J Immunol 180 2486 2495

31. ConnerJRSmirnovaIIPoltorakA 2009 A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice. J Exp Med 206 1615 1631

32. ConnerJRSmirnovaIIPoltorakA 2008 Forward genetic analysis of Toll-like receptor responses in wild-derived mice reveals a novel antiinflammatory role for IRAK1BP1. J Exp Med 205 305 314

33. DarnellJEJrKerrIMStarkGR 1994 Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264 1415 1421

34. Powolny-BudnickaIRiemannMTanzerSSchmidRMHehlgansT 2011 RelA and RelB transcription factors in distinct thymocyte populations control lymphotoxin-dependent interleukin-17 production in gammadelta T cells. Immunity 34 364 374

35. LiuXKLinXGaffenSL 2004 Crucial role for nuclear factor of activated T cells in T cell receptor-mediated regulation of human interleukin-17. J Biol Chem 279 52762 52771

36. RutitzkyLILopes da RosaJRStadeckerMJ 2005 Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol 175 3920 3926

37. RutitzkyLISmithPMStadeckerMJ 2009 T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammation. Eur J Immunol 39 2470 2481

38. GhoreschiKLaurenceAYangXPTatoCMMcGeachyMJ 2010 Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467 967 971

39. LinSCLoYCWuH 2010 Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465 885 90

40. MuzioMNiJFengPDixitVM 1997 IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278 1612 1615

41. AggarwalSGhilardiNXieMHde SauvageFJGurneyAL 2003 Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278 1910 1914

42. McGeachyMJBak-JensenKSChenYTatoCMBlumenscheinW 2007 TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8 1390 1397

43. ParhamCChiricaMTimansJVaisbergETravisM 2002 A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168 5699 5708

44. SchramlBUHildnerKIseWLeeWLSmithWA 2009 The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460 405 409

45. BrustleAHeinkSHuberMRosenplanterCStadelmannC 2007 The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8 958 966

46. QuintanaFJBassoASIglesiasAHKornTFarezMF 2008 Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453 65 71

47. VeldhoenMHirotaKWestendorfAMBuerJDumoutierL 2008 The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453 106 109

48. KawagoeTSatoSMatsushitaKKatoHMatsuiK 2008 Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 9 684 691

49. WanYXiaoHAffolterJKimTWBulekK 2009 Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. J Biol Chem 284 10367 10375

50. RutitzkyLIHernandezHJYimYSRicklanDEFingerE 2005 Enhanced egg-induced immunopathology correlates with high IFN-gamma in murine schistosomiasis: identification of two epistatic genetic intervals. J Immunol 174 435 440

51. AbelLDesseinAJ 1997 The impact of host genetics on susceptibility to human infectious diseases. Curr Opin Immunol 9 509 516

52. MarquetSAbelLHillaireDDesseinHKalilJ 1996 Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nat Genet 14 181 184

53. Zinn-JustinAMarquetSHillaireDDesseinAAbelL 2001 Genome search for additional human loci controlling infection levels by Schistosoma mansoni. Am J Trop Med Hyg 65 754 758

54. HardyMPO'NeillLA 2004 The murine IRAK2 gene encodes four alternatively spliced isoforms, two of which are inhibitory. J Biol Chem 279 27699 27708

55. JanssensSBeyaertR 2003 Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell 11 293 302

56. SuzukiNSuzukiSMillarDGUnnoMHaraH 2006 A critical role for the innate immune signaling molecule IRAK-4 in T cell activation. Science 311 1927 1932

57. KawagoeTSatoSJungAYamamotoMMatsuiK 2007 Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. J Exp Med 204 1013 1024

58. StaschkeKADongSSahaJZhaoJBrooksNA 2009 IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease. J Immunol 183 568 577

59. VallabhapurapuSKarinM 2009 Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27 693 733

60. AwasthiARiol-BlancoLJagerAKornTPotC 2009 Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 182 5904 5908

61. KornTBettelliEOukkaMKuchrooVK 2009 IL-17 and Th17 Cells. Annu Rev Immunol 27 485 517

62. StockingerBVeldhoenM 2007 Differentiation and function of Th17 T cells. Curr Opin Immunol 19 281 286

63. MartinezGJDongC 2009 BATF: bringing (in) another Th17-regulating factor. J Mol Cell Biol 1 66 68

64. HuberMBrustleAReinhardKGuralnikAWalterG 2008 IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci U S A 105 20846 20851

65. VeldhoenMHirotaKChristensenJO'GarraAStockingerB 2009 Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206 43 49

66. WilsonNJBonifaceKChanJRMcKenzieBSBlumenscheinWM 2007 Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8 950 957

67. BorosDLWarrenKS 1970 Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J Exp Med 132 488 507

68. BazzoneLESmithPMRutitzkyLIShainheitMGUrbanJF 2008 Coinfection with the intestinal nematode Heligmosomoides polygyrus markedly reduces hepatic egg-induced immunopathology and proinflammatory cytokines in mouse models of severe schistosomiasis. Infect Immun 76 5164 5172

69. ChenYLangrishCLMcKenzieBJoyce-ShaikhBStumhoferJS 2006 Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116 1317 1326

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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