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IL-17C is required for lethal inflammation during systemic fungal infection

Cellular & Molecular Immunology volume 13, pages 474–483 (2016)Cite this article

Abstract

Within the interleukin-17 (IL-17) family of cytokines, IL-17A is known to be critical in the host defense against fungal infections; however, the function of the other IL-17 family members in anti-fungal immunity remains largely unknown. Here, we show that IL-17C expression was highly induced in kidney epithelial cells after fungal infection. Mice that lacked IL-17C exhibited increased survival and attenuated kidney tissue damage, although they had similar fungal loads. IL-17C deficiency resulted in decreased pro-inflammatory cytokine expression compared with wild-type control mice. Additionally, IL-17C directly acted on renal epithelial cells in vitro to promote pro-inflammatory cytokine production. Taken together, our data demonstrate that IL-17C is a critical factor that potentiates inflammatory responses and causes host injury during fungal infection.

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References

  1. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC . Hidden killers: human fungal infections. Sci Transl Med 2012; 4: 165rv13 .

    Article  PubMed  Google Scholar 

  2. Brown GD, Denning DW, Levitz SM . Tackling human fungal infections. Science 2012; 336: 647.

    Article  CAS  PubMed  Google Scholar 

  3. Perfect JR . The impact of the host on fungal infections. Am J Med 2012; 125: S39–S51.

    Article  CAS  PubMed  Google Scholar 

  4. Romani L . Immunity to fungal infections. Nat Rev Immunol 2011; 11: 275–288.

    Article  CAS  PubMed  Google Scholar 

  5. Spellberg B, Ibrahim AS, Edwards JE, Filler SG . Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis 2005; 192: 336–343.

    Article  PubMed  Google Scholar 

  6. Cohen J . The immunopathogenesis of sepsis. Nature 2002; 420: 885–891.

    Article  CAS  PubMed  Google Scholar 

  7. Netea M . Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol 2003; 24: 254–258.

    Article  CAS  PubMed  Google Scholar 

  8. Dong C . Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev 2008; 226: 80–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jin W, Dong C . IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect 2013; 2: e60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Iwakura Y, Ishigame H, Saijo S, Nakae S . Functional specialization of interleukin-17 family members. Immunity 2011; 34: 149–162.

    Article  CAS  PubMed  Google Scholar 

  11. Kolls JK, Lindén A . Interleukin-17 family members and inflammation. Immunity 2004; 21: 467–476.

    Article  CAS  PubMed  Google Scholar 

  12. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang Y-H et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–1141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 2009; 206: 299–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, Akitsu A et al. Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 2010; 32: 681–691.

    Article  CAS  PubMed  Google Scholar 

  15. Dejima T, Shibata K, Yamada H, Hara H, Iwakura Y, Naito S et al. Protective role of naturally occurring interleukin-17A-producing γδ T cells in the lung at the early stage of systemic candidiasis in mice. Infect Immun 2011; 79: 4503–4510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang W, Na L, Fidel PL, Schwarzenberger P . Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 2004; 190: 624–631.

    Article  CAS  PubMed  Google Scholar 

  17. Kagami S, Rizzo HL, Kurtz SE, Miller LS, Blauvelt A . IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans. J Immunol 2010; 185: 5453–5462.

    Article  CAS  PubMed  Google Scholar 

  18. Ma CS, Chew GYJ, Simpson N, Priyadarshi A, Wong M, Grimbacher B et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 2008; 205: 1551–1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008; 452: 773–776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. d’Ostiani CF, Del Sero G, Bacci A, Montagnoli C, Spreca A, Mencacci A et al. Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans: implications for initiation of T helper cell immunity in vitro and in vivo. J Exp Med 2000; 191: 1661–1674.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li H, Chen J, Huang A, Stinson J, Heldens S, Foster J et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A 2000; 97: 773–778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamaguchi Y, Fujio K, Shoda H, Okamoto A, Tsuno NH, Takahashi K et al. IL-17B and IL-17C are associated with TNF-α production and contribute to the exacerbation of inflammatory arthritis. J Immunol 2007; 179: 7128–7136.

    Article  CAS  PubMed  Google Scholar 

  23. Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol 2011; 12: 1159–1166.

    Article  CAS  PubMed  Google Scholar 

  24. Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C . Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity 2011; 35: 611–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD et al. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol 2011; 12: 1151–1158.

    Article  CAS  PubMed  Google Scholar 

  26. Szabo EK, MacCallum DM . The contribution of mouse models to our understanding of systemic candidiasis. FEMS Microbiol Lett 2011; 320: 1–8.

    Article  CAS  PubMed  Google Scholar 

  27. Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S . Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol 2013; 190: 521–525.

    Article  CAS  PubMed  Google Scholar 

  28. Wüthrich M, Deepe GS, Klein B . Adaptive immunity to fungi. Annu Rev Immunol 2012; 30: 115–148.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007; 8: 639–646.

    Article  CAS  PubMed  Google Scholar 

  30. Ichimura T . Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 1998; 273: 4135–4142.

    Article  CAS  PubMed  Google Scholar 

  31. Iliev ID, Funari VA, Taylor KD, Nguyen Q, Reyes CN, Strom SP et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 2012; 336: 1314–1317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lionakis MS, Fischer BG, Lim JK, Swamydas M, Wan W, Richard Lee C-C et al. Chemokine receptor Ccr1 drives neutrophil-mediated kidney immunopathology and mortality in invasive candidiasis. PLoS Pathog 2012; 8: e1002865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 2002; 169: 443–453.

    Article  CAS  PubMed  Google Scholar 

  34. De Filippo K, Dudeck A, Hasenberg M, Nye E, van Rooijen N, Hartmann K et al. Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. Blood 2013; 121: 4930–4937.

    Article  CAS  PubMed  Google Scholar 

  35. McInnes IB, Schett G . Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7: 429–442.

    Article  CAS  PubMed  Google Scholar 

  36. Biburger M, Tiegs G . α-Galactosylceramide-induced liver injury in mice is mediated by TNF-α but independent of Kupffer cells. J Immunol 2005; 175: 1540–1550.

    Article  CAS  PubMed  Google Scholar 

  37. Dinarello CA . Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. CHEST J 1997; 112: 321S–329S.

    Article  CAS  Google Scholar 

  38. Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008; 133: 235–249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shoham S, Levitz SM . The immune response to fungal infections. Br J Haematol 2005; 129: 569–582.

    Article  PubMed  Google Scholar 

  40. Ley K, Smith E, Stark MA . IL-17A-producing neutrophil-regulatory Tn lymphocytes. Immunol Res 2006; 34: 229–242.

    Article  CAS  PubMed  Google Scholar 

  41. Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O’Brien RL . Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing γδ T cells. J Immunol 2007; 179: 5576–5583.

    Article  CAS  PubMed  Google Scholar 

  42. Hamada S, Umemura M, Shiono T, Tanaka K, Yahagi A, Begum MD et al. IL-17A produced by γδ T cells plays a critical role in innate immunity against Listeria monocytogenes infection in the liver. J Immunol 2008; 181: 3456–3463.

    Article  CAS  PubMed  Google Scholar 

  43. Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med 2006; 203: 1105–1116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhao A, Urban JF, Sun R, Stiltz J, Morimoto M, Notari L et al. Critical role of IL-25 in nematode infection-induced alterations in intestinal function. J Immunol 2010; 185: 6921–6929.

    Article  CAS  PubMed  Google Scholar 

  45. Huang Y, Guo L, Qiu J, Chen X, Hu-Li J, Siebenlist U et al. IL-25-responsive, lineage-negative KLRG1 hi cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat Immunol 2014; 16: 161–170.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang Y-H, Dong C . Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol 2012; 189: 4226–4230.

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Shaoshuai Meng

    Present address: 1Current address: School of Life Sciences, Peking University, Beijing, 100871, China,

Authors and Affiliations

  1. Institute for Immunology, Tsinghua University, Beijing, 100084, China

    Jinling Huang, Shaoshuai Meng, Shanjuan Hong, Xin Lin, Wei Jin & Chen Dong

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  1. Jinling Huang
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Correspondence to Wei Jin or Chen Dong.

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Supplementary information of this article can be found on Cellular & Molecular Immunology website: http://www.nature.com/cmi.

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Huang, J., Meng, S., Hong, S. et al. IL-17C is required for lethal inflammation during systemic fungal infection. Cell Mol Immunol 13, 474–483 (2016). https://doi.org/10.1038/cmi.2015.56

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