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Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage

Nature Immunology volume 15, pages 1116–1125 (2014)Cite this article

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Abstract

Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of γδ T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in γδ T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family.

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Figure 1: The expression of CLPs in mouse lungs.
Figure 2: Overexpression of Ym1 in the lungs induces the accumulation of neutrophils.
Figure 3: Ym1 promotes OVA-induced neutrophilia and regulates IL-17A abundance.
Figure 4: CLPs alter the recruitment of neutrophils into the peritoneal cavity.
Figure 5: Ym1-induced recruitment of neutrophils contributes to acute lung injury following infection with N. brasiliensis.
Figure 6: IL-17A production by γδ T cells contributes to N. brasiliensis–mediated lung injury.
Figure 7: BRP-39 regulates IL-17A production in γδ T cells in the lungs.
Figure 8: IL-17A and Ym1 limit worm burden.

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References

  1. Sutherland, T.E., Maizels, R.M. & Allen, J.E. Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies. Clin. Exp. Allergy 39, 943–955 (2009).

    CAS  PubMed  Google Scholar 

  2. Labadaridis, I. et al. Chitotriosidase in neonates with fungal and bacterial infections. Arch. Dis. Child. Fetal Neonatal Ed. 90, F531–F532 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Barone, R. et al. Plasma chitotriosidase activity in acute Plasmodium falciparum malaria. Clin. Chim. Acta 331, 79–85 (2003).

    CAS  PubMed  Google Scholar 

  4. Nance, J.P. et al. Chitinase dependent control of protozoan cyst burden in the brain. PLoS Pathog. 8, e1002990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bussink, A.P., Speijer, D., Aerts, J.M. & Boot, R.G. Evolution of mammalian chitinase(-like) members of family 18 glycosyl hydrolases. Genetics 177, 959–970 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee, C.G. et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu. Rev. Physiol. 73, 479–501 (2011).

    CAS  PubMed  Google Scholar 

  7. Webb, D.C., McKenzie, A.N. & Foster, P.S. Expression of the Ym2 lectin-binding protein is dependent on interleukin (IL)-4 and IL-13 signal transduction: identification of a novel allergy-associated protein. J. Biol. Chem. 276, 41969–41976 (2001).

    CAS  PubMed  Google Scholar 

  8. Welch, J.S. et al. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J. Biol. Chem. 277, 42821–42829 (2002).

    CAS  PubMed  Google Scholar 

  9. Lee, C.G. et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J. Exp. Med. 206, 1149–1166 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sohn, M.H. et al. The chitinase-like proteins breast regression protein-39 and YKL-40 regulate hyperoxia-induced acute lung injury. Am. J. Respir. Crit. Care Med. 182, 918–928 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hector, A. et al. The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease. PLoS ONE 6, e24399 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Nikota, J.K. et al. Differential expression and function of breast regression protein 39 (BRP-39) in murine models of subacute cigarette smoke exposure and allergic airway inflammation. Respir. Res. 12, 39 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sutherland, T.E. et al. Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chem. Biol. 18, 569–579 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Arora, M. et al. Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells. Proc. Natl. Acad. Sci. USA 103, 7777–7782 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Aujla, S.J. & Alcorn, J.F. TH17 cells in asthma and inflammation. Biochim. Biophys. Acta 1810, 1066–1079 (2011).

    CAS  PubMed  Google Scholar 

  17. Raz, E. Organ-specific regulation of innate immunity. Nat. Immunol. 8, 3–4 (2007).

    CAS  PubMed  Google Scholar 

  18. Lalor, S.J. et al. Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity. J. Immunol. 186, 5738–5748 (2011).

    CAS  PubMed  Google Scholar 

  19. Van Dyken, S.J. et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ t cells. Immunity 40, 414–424 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nielsen, M.M. et al. IL-1beta-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J. Immunol. 192, 2975–2983 (2014).

    CAS  PubMed  Google Scholar 

  21. Osborne, L.C. et al. Coinfection. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation. Science 345, 578–582 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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. 190, 521–525 (2013).

    CAS  PubMed  Google Scholar 

  23. Kim, H.Y. et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat. Med. 20, 54–61 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Chen, F. et al. An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat. Med. 18, 260–266 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, C. et al. IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus. Cell Res. 22, 528–538 (2012).

    CAS  PubMed  Google Scholar 

  27. Grommes, J. & Soehnlein, O. Contribution of neutrophils to acute lung injury. Mol. Med. 17, 293–307 (2011).

    CAS  PubMed  Google Scholar 

  28. The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur. Respir. J. 22, 470–477 (2003).

  29. Al-Ramli, W. et al. TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 123, 1185–1187 (2009).

    CAS  PubMed  Google Scholar 

  30. Newcomb, D.C. & Peebles, R.S. Jr. Th17-mediated inflammation in asthma. Curr. Opin. Immunol. 25, 755–760 (2013).

    CAS  PubMed  Google Scholar 

  31. Létuvé, S. et al. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J. Immunol. 181, 5167–5173 (2008).

    PubMed  Google Scholar 

  32. Vind, I., Johansen, J.S., Price, P.A. & Munkholm, P. Serum YKL-40, a potential new marker of disease activity in patients with inflammatory bowel disease. Scand. J. Gastroenterol. 38, 599–605 (2003).

    CAS  PubMed  Google Scholar 

  33. Alcorn, J.F., Crowe, C.R. & Kolls, J.K. TH17 cells in asthma and COPD. Annu. Rev. Physiol. 72, 495–516 (2010).

    CAS  PubMed  Google Scholar 

  34. Morrison, P.J., Ballantyne, S.J. & Kullberg, M.C. Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology 133, 397–408 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Konradsen, J.R. et al. The chitinase-like protein YKL-40: A possible biomarker of inflammation and airway remodeling in severe pediatric asthma. J. Allergy Clin. Immunol. 132, 328–335 (2013).

    CAS  PubMed  Google Scholar 

  36. Dela Cruz, C.S. et al. Chitinase 3-like-1 promotes Streptococcus pneumoniae killing and augments host tolerance to lung antibacterial responses. Cell Host Microbe 12, 34–46 (2012).

    CAS  PubMed  Google Scholar 

  37. Sakazaki, Y. et al. Overexpression of chitinase 3-like 1/YKL-40 in lung-specific IL-18-transgenic mice, smokers and COPD. PLoS ONE 6, e24177 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tran, H.T., Barnich, N. & Mizoguchi, E. Potential role of chitinases and chitin-binding proteins in host-microbial interactions during the development of intestinal inflammation. Histol. Histopathol. 26, 1453–1464 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Anthony, R.M. et al. Protective immune mechanisms in helminth infection. Nat. Rev. Immunol. 7, 975–987 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bonne-Année, S. et al. Human and mouse macrophages collaborate with neutrophils to kill larval Strongyloides stercoralis. Infect. Immun. 81, 3346–3355 (2013).

    PubMed  PubMed Central  Google Scholar 

  41. O'Connell, A.E. et al. Major basic protein from eosinophils and myeloperoxidase from neutrophils are required for protective immunity to Strongyloides stercoralis in mice. Infect. Immun. 79, 2770–2778 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    CAS  PubMed  Google Scholar 

  43. Ydens, E. et al. Acute injury in the peripheral nervous system triggers an alternative macrophage response. J. Neuroinflammation 9, 176 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hung, S.I., Chang, A.C., Kato, I. & Chang, N.C. Transient expression of Ym1, a heparin-binding lectin, during developmental hematopoiesis and inflammation. J. Leukoc. Biol. 72, 72–82 (2002).

    CAS  PubMed  Google Scholar 

  45. Pittman, K. & Kubes, P. Damage-associated molecular patterns control neutrophil recruitment. J. Innate Immun. 5, 315–323 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Prakash, M. et al. Diverse pathological implications of YKL-40: answers may lie in 'outside-in' signaling. Cell. Signal. 25, 1567–1573 (2013).

    CAS  PubMed  Google Scholar 

  47. Guo, L., Johnson, R.S. & Schuh, J.C. Biochemical characterization of endogenously formed eosinophilic crystals in the lungs of mice. J. Biol. Chem. 275, 8032–8037 (2000).

    CAS  PubMed  Google Scholar 

  48. Falcone, F.H. et al. A Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection. J. Immunol. 167, 5348–5354 (2001).

    CAS  PubMed  Google Scholar 

  49. Loke, P. et al. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3, 7 (2002).

    PubMed  PubMed Central  Google Scholar 

  50. Voehringer, D., Shinkai, K. & Locksley, R.M. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity 20, 267–277 (2004).

    CAS  PubMed  Google Scholar 

  51. Urban, J.F. Jr. et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8, 255–264 (1998).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Turner, J.E. et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kallal, L.E. et al. Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology. J. Immunol. 185, 4137–4147 (2010).

    CAS  PubMed  Google Scholar 

  55. Lajoie, S. et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat. Immunol. 11, 928–935 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang, M. et al. Immunomodulatory effects of IL-23 and IL-17 in a mouse model of allergic rhinitis. Clin. Exp. Allergy 43, 956–966 (2013).

    CAS  PubMed  Google Scholar 

  57. Lawrence, R.A., Gray, C.A., Osborne, J. & Maizels, R.M. Nippostrongylus brasiliensis: cytokine responses and nematode expulsion in normal and IL-4-deficient mice. Exp. Parasitol. 84, 65–73 (1996).

    CAS  PubMed  Google Scholar 

  58. Holland, M.J., Harcus, Y.M., Riches, P.L. & Maizels, R.M. Proteins secreted by the parasitic nematode Nippostrongylus brasiliensis act as adjuvants for Th2 responses. Eur. J. Immunol. 30, 1977–1987 (2000).

    CAS  PubMed  Google Scholar 

  59. Thurlbeck, W.M. Measurement of pulmonary emphysema. Am. Rev. Respir. Dis. 95, 752–764 (1967).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Duncan and Y. Harcus for technical assistance and R. Zamoyska for discussions. Supported by the Medical Research Council United Kingdom (MRC-UK MR/J001929/1, MR/K01207X/1 and U117512792 to B.S., and MC_UP_1202/13 for V.P.) and Asthma UK (06/057 & 10/040), with support from the Wellcome Trust funded Centre for Immunity, Infection and Evolution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Institute of Immunology and Infection Research, Centre for Immunity Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK

    Tara E Sutherland, Nicola Logan, Dominik Rückerl, Rick M Maizels & Judith E Allen

  2. Department of Respiratory, Inflammation & Autoimmunity, MedImmune, Gaithersburg, Maryland, USA

    Alison A Humbles

  3. Faculty of Life Sciences, University of Manchester, Manchester, UK

    Stuart M Allan

  4. Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, London, UK

    Venizelos Papayannopoulos & Brigitta Stockinger

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T.E.S. designed and performed research, analyzed and interpreted data and wrote the manuscript; N.L. and V.P. performed research; D.R., A.A.H., S.M.A., V.P. and B.S. contributed tools; R.M.M. contributed to data interpretation and manuscript preparation; and J.E.A contributed to experimental design, data interpretation and manuscript preparation.

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Integrated supplementary information

Supplementary Figure 1 Overexpression of Ym1 reduces eosinophil numbers in the lungs.

(a-d) Absolute numbers per mg of tissue of CD8+ T cells (a), CD4+ T cells (b), CD19+ CD11b- B cells (c) and SigF+ CD11c- CD11b+ eosinophils (d) in the lungs of BALB/c wild-type mice transfected intranasally with 20 μg pCDNA3.1 control or plasmids encoding BRP-39, Ym1 or Ym2. Lungs were collected 48 h after transfection. NS not significant; *P < 0.05 compared to pcDNA3.1 transfected mice (analysis of variance with Tukey-Kramer HSD multiple comparison test). Data are pooled from two independent experiments (a-d; mean ± s.e.m., five to nine mice per group).

Supplementary Figure 2 Model of acute allergic inflammation.

BALB/c wild-type mice were sensitized to OVA-Alum (20 μg, i.p.) on day 0 followed by aerosol challenge with PBS or OVA on days 8-10. Mice were treated daily with IgG2a isotype control or α-Ym1 (200 μg, i.p.) prior to and during aerosol challenge. Samples were collected 24 h after the last challenge.

Supplementary Figure 3 Ym1 overexpression increases IL-17A production in γδ T cells in an IL-1-dependent manner.

(a) Percentage of IFNγ+ γδ T cells in PMA and ionomycin stimulated PECs collected at 48 h from BALB/c wild-type mice administered with pcDNA3.1 and plasmids encoding BRP-39, Ym1 or Ym2 (20 μg) or glucose (5 %). (b) Absolute numbers of IL-17- or IL-17+ TCRγδ+ cells per gram of tissue from the lungs of C57BL6 wild-type mice administered with glucose (5 %), pcDNA3.1 or a plasmid encoding Ym1 (20 μg) intranasally. Lung was collected 48 h post-transfection and single cells stimulated ex vivo with PMA and ionomycin. (c-d) Percentage of IFNγ+ (c) and IL-17A+ (d) γδ T cells in PMA and ionomycin stimulated PECs collected at 48 h from BALB/c mice administered with pcDNA3.1 and plasmids encoding BRP-39, Ym1 or Ym2 (20 μg) or glucose (5 %) and treated with PBS or anakinra (Ank, 100 mg/kg, i.p.). NS not significant; *P < 0.05 and ** P < 0.01 compared to pcDNA3.1 mice (a), pcDNA3.1 PBS or Ym1 PBS (c- d) (analysis of variance with Tukey-Kramer HSD multiple comparison test). Data are representative from two independent experiments (a; mean ± s.e.m., six mice per group), one experiment (b; mean ± s.e.m., 3 mice per group) or pooled from two independent experiments (c-d; mean ± s.e.m with ten to thirteen mice per group).

Supplementary Figure 4 Ym1 does not alter IL-17A production in ILCs.

(a) IL-17A expression in PMA and ionomycin stimulated PECs collected 48 h after transfection of BALB/c wild-type (WT) or Rag2-/- mice with pcDNA3.1 or a plasmid encoding Ym1 (20 μg, i.p.). (b) Absolute numbers of IL-17- or IL-17+ ILCs (Lineage- CD90.2+ CD25+) from PECs of mice as in a. (c) Absolute numbers of Ly6G+ CD11b+ F4/80+ neutrophils from PEC of mice as in a. Bars show mean values ± SEM. *P < 0.05; compared to pcDNA3.1 transfected mice, (analysis of variance with Tukey-Kramer HSD multiple comparison test). Data are representative of two independent experiments (mean ± s.e.m. five mice per group).

Supplementary Figure 5 Ym1 reduces secretion of IL-17A and IL-13 from splenocytes following N. brasiliensis infection.

(a) IL-17A secretion in splenocytes cultured with medium, NES antigen (Ag, 1 μg/ml) or α-CD3 (1 μg/ml) from uninfected or N. brasiliensis (500 L3s) infected BALB/c wild-type treated intraperitoneally with anti-Ym1 or isotype IgG2a. (b) IL-13 secretion measured in mice as per a. Data show Ag and α-CD3 responses normalized to the amount of IL-13 secreted in medium for individual mice. *P < 0.05 and **P < 0.01 and ***P < 0.001 compared to IgG2a groups (analysis of variance with Tukey’s test). Data are representative of two independent experiments (mean ± s.e.m. six mice per group).

Supplementary Figure 6 Expression of eYFP in T cell populations from Il17aCreRosa26ReYFP mice.

eYFP expression in PMA and ionomycin stimulated PECs from uninfected or N. brasiliensis (500 L3s) infected Il17aCreRosa26ReYFP mice. Data are representative from two independent experiments.

Supplementary Figure 7 A model of chitinase-like protein function during innate immune responses.

Expression of Ym1 and Ym2 regulates IL-1β and IL-18 expression leading to the expansion of IL-17A-producing γδ T cells triggering epithelial cells to secrete neutrophil-chemotactic factors CXCL1, CXCL5 and CCL3 resulting in neutrophil infiltration. BRP-39 stimulates IL-18 also leading to IL-17A-production by γδ T cells but in a way that does not trigger downstream neutrophil chemotaxis. During these innate settings, Ym1 and Ym2 cause neutrophils to accumulate, a function that can be host-protective by limiting helminth parasite integrity but at the same time is costly to the host by promoting acute lung.

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Sutherland, T., Logan, N., Rückerl, D. et al. Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage. Nat Immunol 15, 1116–1125 (2014). https://doi.org/10.1038/ni.3023

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