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.

  • Letter
  • Published:

A role for the C3a anaphylatoxin receptor in the effector phase of asthma

Nature volume 406, pages 998–1001 (2000)Cite this article

Abstract

Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity1. However, many features of bronchial asthma, such as smooth muscle contraction, mucus secretion and recruitment of inflammatory cells, are consistent with the actions of complement anaphylatoxins, in particular C3a and C5a2. Complement activation forms a central core of innate immune defence against mucosal bacteria, viruses, fungi, helminths and other pathogens. As a system of ‘pattern-recognition molecules’, foreign surface antigens and immune complexes lead to a proteolytic cascade culminating in a lytic membrane attack2,3. The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability2. Here we show that in a murine model of allergic airway disease, genetic deletion of the C3a receptor protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics develop significant levels of ligand C3a following intra-pulmonary deposition of allergen, but not saline. We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Targeted disruption of the mouse C3aR gene.
Figure 2: Pulmonary accumulation of inflammatory cells.
Figure 3: Assessment of AHR to inhaled methacholine (MCh) in conscious mice.
Figure 4: Airway responsiveness to intravenous methacholine (MCh) in anaesthetized mice.

Similar content being viewed by others

References

  1. Burrows, B., Martinez, F. D., Halonen, M., Barbee, R. A. & Cline, M. G. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med. 320, 271–277 ( 1989).

    Article  CAS  Google Scholar 

  2. Gerard, N. P. in Asthma (eds Barnes, P. J., Grunstein, M. M., Leff, A. R. & Woolcock, A. J.) 639–651 (Lippincott-Raven, Philadelphia, 1997).

    Google Scholar 

  3. Medzhitov, R. & Janeway, C. A. Jr. Innate immunity: The virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

    Article  CAS  Google Scholar 

  4. Höpken, U. E., Lu, B., Gerard, N. P. & Gerard, C. The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 383, 86–89 (1996).

    Article  ADS  Google Scholar 

  5. Höpken, U. E., Lu, B., Gerard, N. P. & Gerard, C. Impaired inflammatory responses in the reverse Arthus Reaction through genetic deletion of the C5a receptor. J. Exp. Med. 186, 749– 756 (1997).

    Article  Google Scholar 

  6. Osaka, H. et al. Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration. Neuroscience 88, 1073–1082 (1999).

    Article  CAS  Google Scholar 

  7. Bhatia, M. Complement factor C5a exerts an anti-inflammatory effect in acute pancreatitis and pancreatitis-associated lung injury. Am. J. Physiol. (submitted).

  8. Tornetta, M. A., Foley, J. J., Sarau, H. M. & Ames, R. S. The mouse anaphylatoxin C3a receptor. J. Immunol. 158 , 5277–5282 (1997).

    CAS  PubMed  Google Scholar 

  9. Hsu, M. H. et al. Cloning and functional characterization of the mouse C3a anaphylatoxin receptor gene. Immunogenetics 47, 64– 72 (1997).

    Article  CAS  Google Scholar 

  10. Chao, T. H. et al. Role of the second extracellular loop of human C3a receptor in agonist binding and receptor function. J. Biol. Chem. 274, 9721–9728 (1999).

    Article  CAS  Google Scholar 

  11. Fischer, W. H. et al. Regulation of the B cell response to T-dependent antigens by classical pathway complement. J. Immunol. 157, 549–556 (1996).

    CAS  Google Scholar 

  12. Daffern, P. J. et al. C3a is a chemotaxin for human eosinophils but not for neutrophils. I. C3a stimulation of neutrophils is secondary to eosinophil activation. J. Exp. Med. 181, 2119–2127 (1995).

    Article  CAS  Google Scholar 

  13. Nilsson, G. et al. C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway. J. Immunol. 157, 1693– 1698 (1996).

    CAS  PubMed  Google Scholar 

  14. Stimler-Gerard, N. P. & Galli, S. J. Mast cells in anaphylatoxin-induced spasmogenic activity. J. Immunol. 138, 1908–1913 (1987).

    CAS  PubMed  Google Scholar 

  15. Stimler, N. P., Gerard, C. & O'Flaherty, J. T. in Platelet Activating Factor (eds Benveniste, J & Arnoux, B.) 195–203 (Elsevier, Amsterdam, 1983).

    Google Scholar 

  16. Hamelmann, E. et al. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156, 766–775 ( 1992).

    Article  Google Scholar 

  17. Martin, T. R., Gerard, N. P., Galli, S. J. & Drazen, J. M. Pulmonary responses to bronchoconstrictor agonists in the mouse. J. Appl. Physiol. 64, 2318–2323 (1988).

    Article  CAS  Google Scholar 

  18. Smith, J. K., Chi, D. S., Krish, G., Reynolds, S. & Cambron, G. Effect of exercise on complement activity. Ann. Allergy 65, 304–310 (1990).

    CAS  PubMed  Google Scholar 

  19. Onodera, H. et al. Complement system in status asthmatics: analysis of anti-complementary effects induced by methylprendisolone. Arerugi 41, 1567–1574 (1997).

    Google Scholar 

  20. Pepys, J. & Hutchcroft, B. J. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am. J. Respir. Crit. Care Med. 112, 829–859 ( 1975).

    CAS  Google Scholar 

  21. Bradley, B. L. et al. Eosinophils, T-lymphocytes, mast cells, neutrophils and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness. J. Allergy Clin. Immunol. 88, 661–674 (1991).

    Article  CAS  Google Scholar 

  22. Drazen, J. M. Asthma therapy with agents preventing leukotriene synthesis or action. Proc. Assoc. Am. Physicians 111, 547– 559 (1999).

    Article  CAS  Google Scholar 

  23. Barnes, P. J. & Belvisi, M. G. in Asthma (eds Barnes, P. J., Grunstein, M. M., Leff, A. R. & Woolcock, A. J.) 1051– 1063 (Lippincott–Raven, Philadelphia, 1997).

    Google Scholar 

  24. Mattoli, S., Soloperto, M., Marini, M. & Fasoli, A. Levels of endothelin in the bronchoalveolar lavage fluid of patients with symptomatic asthma and reversible airflow obstruction. J. Allergy Clin. Immunol. 88, 376–384 (1991).

    Article  CAS  Google Scholar 

  25. Schwartz, L. B. et al. Generation of C3a anaphylatoxin from human C3 by mast cell tryptase. J. Immunol. 130, 1891– 1895 (1983).

    CAS  PubMed  Google Scholar 

  26. Humbles, A. A. et al. Kinetics of eotaxin generation and its relationship to eosinophil accumulation in allergic airways disease: analysis in a guinea pig model in vivo. J. Exp. Med. 186, 601– 612 (1997).

    Article  CAS  Google Scholar 

  27. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am. Rev. Respir. Dis. 144, 1202–1218 (1991).

Download references

Acknowledgements

We thank T. Martin and J. Drazen for comments and advice; J. Brewer for assistance; D. Zurakowski for help and advice with analysing the statistics; and the staff of ARCH at Children's Hospital for animal care. This work was supported in part by grants from the NIH to N.P.G. and C.G. at the Perlmutter laboratory and Pfizer Central Research.

Author information

Authors and Affiliations

  1. Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, 02115, Massachusetts , USA

    Alison A. Humbles, Bao Lu, Christy A. Nilsson, Norma P. Gerard & Craig Gerard

  2. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Craig Lilly & Elliot Israel

  3. Division of Hematology and Oncology Children's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Yuko Fujiwara

Authors
  1. Alison A. Humbles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christy A. Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Craig Lilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elliot Israel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuko Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Norma P. Gerard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Craig Gerard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig Gerard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Humbles, A., Lu, B., Nilsson, C. et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma . Nature 406, 998–1001 (2000). https://doi.org/10.1038/35023175

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35023175

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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