Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection

Nature Medicine volume 18, pages 260–266 (2012)Cite this article

Subjects

Abstract

Helminths induce potent T helper 2 (TH2)-type immune responses that can mediate worm expulsion, but the role of this response in controlling the acute tissue damage caused by migrating multicellular parasites through vital tissues remains uncertain. We used a helminth infection model in which parasitic nematode larvae migrate transiently through the lung, resulting in hemorrhage and inflammation. We found that IL-17 initially contributed to inflammation and lung damage, whereas subsequent IL-4 receptor (IL-4R) signaling reduced elevations in IL-17 mRNA levels, enhanced the expression of insulin-like growth factor 1 (IGF-1) and IL-10 and stimulated the development of M2 macrophages, all of which contributed to the rapid resolution of tissue damage. These studies indicate an essential role for TH2-type immune responses in mediating acute wound healing during helminth infection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Kinetics of N. brasiliensis–induced lung damage.
Figure 2: IL-4R signaling controls acute lung hemorrhaging and IL-17–dependent neutrophil infiltration.
Figure 3: Blockade of IL-4R–dependent IGF-1 signaling inhibits control of inflammation and hemorrhaging in N. brasiliensis–inoculated mice.
Figure 4: IL-10 downregulates lung inflammation and elevations in Il17 mRNA level in N. brasiliensis–inoculated mice.
Figure 5: Macrophages control both lung hemorrhaging and inflammation during infection with N. brasiliensis.
Figure 6: Model of acute resolution of lung damage mediated by a helminth-induced TH2-type response.

Similar content being viewed by others

References

  1. Anthony, R.M. et al. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat. Med. 12, 955–960 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu, Q. et al. B cells have distinct roles in host protection against different nematode parasites. J. Immunol. 184, 5213–5223 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Herbert, D.R. et al. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J. Exp. Med. 206, 2947–2957 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhao, A. et al. Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves. J. Immunol. 171, 948–954 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Enobe, C.S. et al. Early stages of Ascaris suum induce airway inflammation and hyperreactivity in a mouse model. Parasite Immunol. 28, 453–461 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Sakamoto, T. & Gutierrez, C. Pulmonary complications of cystic echinococcosis in children in Uruguay. Pathol. Int. 55, 497–503 (2005).

    Article  PubMed  Google Scholar 

  7. Girod, N., Brown, A., Pritchard, D.I. & Billett, E.E. Successful vaccination of BALB/c mice against human hookworm (Necator americanus): the immunological phenotype of the protective response. Int. J. Parasitol. 33, 71–80 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Anthony, R.M., Rutitzky, L.I., Urban, J.F. Jr., Stadecker, M.J. & Gause, W.C. Protective immune mechanisms in helminth infection. Nat. Rev. Immunol. 7, 975–987 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McNeil, K.S., Knox, D.P. & Proudfoot, L. Anti-inflammatory responses and oxidative stress in Nippostrongylus brasiliensis-induced pulmonary inflammation. Parasite Immunol. 24, 15–22 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Loke, P. et al. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J. Immunol. 179, 3926–3936 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Martin, P. & Leibovich, S.J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Shirey, K.A. et al. Control of RSV-induced lung injury by alternatively activated macrophages is IL-4R alpha-, TLR4-, and IFN-beta-dependent. Mucosal Immunol. 3, 291–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nembrini, C., Marsland, B.J. & Kopf, M. IL-17-producing T cells in lung immunity and inflammation. J. Allergy Clin. Immunol. 123, 986–994 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Laan, M. et al. Neutrophil recruitment by human IL-17 via C–X-C chemokine release in the airways. J. Immunol. 162, 2347–2352 (1999).

    CAS  PubMed  Google Scholar 

  15. Finkelman, F.D., Hogan, S.P., Hershey, G.K., Rothenberg, M.E. & Wills-Karp, M. Importance of cytokines in murine allergic airway disease and human asthma. J. Immunol. 184, 1663–1674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cooper, A.M. IL-17 and anti-bacterial immunity: protection versus tissue damage. Eur. J. Immunol. 39, 649–652 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Edgerton, C. et al. IL-17 producing CD4+ T cells mediate accelerated ischemia/reperfusion-induced injury in autoimmunity-prone mice. Clin. Immunol. 130, 313–321 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Steinman, L. A rush to judgment on Th17. J. Exp. Med. 205, 1517–1522 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Seno, H. et al. Efficient colonic mucosal wound repair requires Trem2 signaling. Proc. Natl. Acad. Sci. USA 106, 256–261 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Peranteau, W.H. et al. IL-10 overexpression decreases inflammatory mediators and promotes regenerative healing in an adult model of scar formation. J. Invest. Dermatol. 128, 1852–1860 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Bliss, S.K., Alcaraz, A. & Appleton, J.A. IL-10 prevents liver necrosis during murine infection with Trichinella spiralis. J. Immunol. 171, 3142–3147 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Apewokin, S., Steciuk, M., Griffin, S. & Jhala, D. Strongyloides hyperinfection diagnosed by bronchoalveolar lavage in an immunocompromized host. Cytopathology 21, 345–347 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Kolosionek, E., Crosby, A., Harhay, M.O., Morrell, N. & Butrous, G. Pulmonary vascular disease associated with schistosomiasis. Expert Rev. Anti Infect. Ther. 8, 1467–1473 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Patel, N., Kreider, T., Urban, J.F. Jr. & Gause, W.C. Characterisation of effector mechanisms at the host:parasite interface during the immune response to tissue-dwelling intestinal nematode parasites. Int. J. Parasitol. 39, 13–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Herbert, D.R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Brunet, L.R., Finkelman, F.D., Cheever, A.W., Kopf, M.A. & Pearce, E.J. IL-4 protects against TNF-alpha-mediated cachexia and death during acute schistosomiasis. J. Immunol. 159, 777–785 (1997).

    CAS  PubMed  Google Scholar 

  27. Brunet, L.R., Dunne, D.W. & Pearce, E.J. Cytokine Interaction and Immune Responses during Schistosoma mansoni Infection. Parasitol. Today 14, 422–427 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Gause, W.C., Urban, J.F. Jr. & Stadecker, M.J. The immune response to parasitic helminths: insights from murine models. Trends Immunol. 24, 269–277 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R.M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. & Locksley, R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203, 1435–1446 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Reece, J.J., Siracusa, M.C. & Scott, A.L. Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect. Immun. 74, 4970–4981 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marsland, B.J., Kurrer, M., Reissmann, R., Harris, N.L. & Kopf, M. Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages. Eur. J. Immunol. 38, 479–488 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Li, B. et al. Pulmonary epithelial CCR3 promotes LPS-induced lung inflammation by mediating release of IL-8. J. Cell. Physiol. 226, 2398–2405 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Krzyzaniak, M. et al. Burn-induced acute lung injury requires a functional toll-like receptor 4. Shock 36, 24–29 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Rickel, E.A. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J. Immunol. 181, 4299–4310 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Rom, W.N. et al. Alveolar macrophages release an insulin-like growth factor I-type molecule. J. Clin. Invest. 82, 1685–1693 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wynes, M.W., Frankel, S.K. & Riches, D.W. IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. J. Leukoc. Biol. 76, 1019–1027 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kreider, T., Anthony, R.M., Urban, J.F. Jr. & Gause, W.C. Alternatively activated macrophages in helminth infections. Curr. Opin. Immunol. 19, 448–453 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mirza, R., DiPietro, L.A. & Koh, T.J. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am. J. Pathol. 175, 2454–2462 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cailhier, J.F. et al. Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation. J. Immunol. 174, 2336–2342 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Herbert, D.R. et al. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J. Immunol. 184, 6438–6446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sandler, N.G., Mentink-Kane, M.M., Cheever, A.W. & Wynn, T.A. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J. Immunol. 171, 3655–3667 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Balic, A., Harcus, Y.M., Taylor, M.D., Brombacher, F. & Maizels, R.M. IL-4R signaling is required to induce IL-10 for the establishment of T(h)2 dominance. Int. Immunol. 18, 1421–1431 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Gillery, P., Leperre, A., Maquart, F.X. & Borel, J.P. Insulin-like growth factor-I (IGF-I) stimulates protein synthesis and collagen gene expression in monolayer and lattice cultures of fibroblasts. J. Cell. Physiol. 152, 389–396 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167, 6533–6544 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Martinez, F.O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Pesce, J.T. et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mosser, D.M. & Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Varin, A., Mukhopadhyay, S., Herbein, G. & Gordon, S. Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion. Blood 115, 353–362 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, J.J. & Lee, N.A. Eosinophil degranulation: an evolutionary vestige or a universally destructive effector function? Clin. Exp. Allergy 35, 986–994 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Asti, C. et al. Lipopolysaccharide-induced lung injury in mice. I. Concomitant evaluation of inflammatory cells and haemorrhagic lung damage. Pulm. Pharmacol. Ther. 13, 61–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Dovi, J.V., He, L.K. & DiPietro, L.A. Accelerated wound closure in neutrophil-depleted mice. J. Leukoc. Biol. 73, 448–455 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Simpson, D.M. & Ross, R. The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J. Clin. Invest. 51, 2009–2023 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pesce, J.T. et al. Neutrophils clear bacteria associated with parasitic nematodes augmenting the development of an effective Th2-type response. J. Immunol. 180, 464–474 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Daley, J.M., Thomay, A.A., Connolly, M.D., Reichner, J.S. & Albina, J.E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Pribul, P.K. et al. Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development. J. Virol. 82, 4441–4448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mionnet, C. et al. CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nat. Med. 16, 1305–1312 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Kim, J.H. et al. Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L580–L587 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health grants AI031678.

Author information

Author notes

  1. Zhugong Liu

    Present address: Present address: Food and Drug Administration, Center for Biologics Evaluation and Research/Office of Blood Research and Review/Division of Blood Applications, Laboratory of Immunohematology and Molecular Testing, Rockville, Maryland, USA.,

  2. Fei Chen and Zhugong Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine and Center for Immunity and Inflammation, New Jersey Medical School, University of Medicine & Dentistry of New Jersey, Newark, New Jersey, USA

    Fei Chen, Zhugong Liu, Wenhui Wu, Cristina Rozo, Scott Bowdridge, Ariel Millman & William C Gause

  2. Department of Molecular Cell Biology, Vrije Universiteit, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Nico Van Rooijen

  3. US Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, Maryland, USA

    Joseph F Urban Jr

  4. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Thomas A Wynn

Authors
  1. Fei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhugong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenhui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristina Rozo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Scott Bowdridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ariel Millman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nico Van Rooijen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joseph F Urban Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas A Wynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. William C Gause
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.C. performed the majority of the experiments and contributed to experimental design. Z.L. contributed to the initial experimental design and essential experiments before leaving the laboratory. W.W. performed experiments with F.C., particularly the flow cytometry experiments, and contributed to the experimental design. C.R. performed experiments with Z.L. and F.C. and contributed to the experimental design. S.B. performed experiments with F.C. and helped develop techniques for tracking parasites. A.M. performed experiments with F.C., maintained and genotyped mouse strains and also prepared parasites for inoculation. N.V.R. provided fresh clodronate liposomes for in vivo experiments and provided advice for use of this reagent for macrophage depletion. J.F.U. maintained parasite stocks and provided them as needed and gave crucial input to the experimental design. T.A.W. provided immunodeficient mice for experiments and gave important input to the experimental design and writing of the paper. W.C.G. designed most of research project, provided oversight of experiments and wrote the majority of the paper.

Corresponding author

Correspondence to William C Gause.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 870 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, F., Liu, Z., Wu, W. et al. An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med 18, 260–266 (2012). https://doi.org/10.1038/nm.2628

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2628

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing