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Impaired mast cell-dependent natural immunity in complement C3-deficient mice

Nature volume 390, pages 172–175 (1997)Cite this article

Abstract

The complement system is widely regarded as essential for normal inflammation, not least because of its ability to activate mast cells1,2,3,4,5. However, recent studies have called into question the importance of complement in several examples of mast cell-dependent inflammatory responses6,7,8,9. To investigate the role of complement in mast cell-dependent natural immunity, we examined the responses of complement-deficient mice10,11 to caecal ligation and puncture12, a model of acute septic peritonitis12,13 that is dependent on mast cells and tumour necrosis factor-α (TNF-α). We found that C4- or C3-deficient mice10,11 were much more sensitive to caecal ligation and puncture than wild-type (WT) controls (100% versus 20% in 24-h mortality, respectively). C3-deficient mice also exhibited reductions in peritoneal mast cell degranulation, production of TNF-α, neutrophil infiltration and clearance of bacteria. Treating the C3-deficient mice with purified C3 protein enhanced activation of peritoneal mast cells, TNF-α production, neutrophil recruitment, opsonophagocytosis of bacteria and resistance to caecal ligation and puncture, confirming that the defects were complement-dependent. These results provide formal evidence that complement activation is essential for the full expression of innate immunity in this mast cell-dependent model of bacterial infection.

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Figure 1: C3- or C4-deficient mice are highly sensitive to peritoneal bacterial infection.
Figure 2: Activation of mast cells following CLP treatment is complement-dependent.
Figure 3: TNF-α release and neutrophil infiltration are impaired in C3−/− mice during acute septic peritonitis.
Figure 4: Neutrophil clearance of bacteria within the peritoneum is complement-dependent.

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References

  1. Muller-Eberhard, H. J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57, 321–347 (1988).

    Article  CAS  Google Scholar 

  2. Reid, K. B. M. & Porter, R. R. The proteolytic activation system of complement. Annu. Rev. Biochem. 50, 433–464 (1981).

    Article  CAS  Google Scholar 

  3. Lepow, I. H., Wilms-Kretschmer, K., Patrick, R. A. & Rosen, F. S. Gross and ultrasctructural observations on lesions produced by intradermal injection of human C3a in man. Am. J. Pathol. 61, 13–23 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dias Da Silva, W. & Lepow, I. H. Complement as a mediator of inflammation. II. Biological properties of anaphylatoxin prepared with purified components of human complement. J. Exp. Med. 125, 921–946 (1967).

    Article  CAS  Google Scholar 

  5. Johnson, A. R., Hugli, T. E. & Muller-Eberhard, H. J. Release of histamine from rat mast cells by the complement peptides C3a and C5a. Immunology 28, 1067–1080 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Miyajima, I. et al. Systematic anaphylaxis in the mouse can be mediated largely through IgG1 and FcγRIII. Assessment of the cardiopulmonary changes, mast cell degranulation and death associated with active or IgG1-dependent passive anaphylaxis. J. Clin. Invest. 99, 901–914 (1997).

    Article  CAS  Google Scholar 

  7. Sylvestre, D. L. & Ravetch, J. V. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265, 1095–1098 (1994).

    Article  ADS  CAS  Google Scholar 

  8. Hazenbos, W. L. W. et al. Impaired IgG-dependent anaphylaxis and arthus reaction in FcγRIII (CD16) deficient mice. Immunity 5, 181–188 (1996).

    Article  CAS  Google Scholar 

  9. Sylvestre, D., Clynes, R., Ma, M., Carroll, M. C. & Ravetch, J. Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J. Exp. Med. 184, 2385–2392 (1996).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Wessels, M. R. et al. Studies of group B streptococcal infection in mice deficient in complement C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity. Proc. Natl Acad. Sci. USA 12, 11490–11494 (1995).

    Article  ADS  Google Scholar 

  12. Wichterman, K. A., Baue, A. E. & Chaudry, I. H. Sepsis and septic shock; a review of laboratory models and a proposal. J. Surg. Res. 29, 189–201 (1980).

    Article  CAS  Google Scholar 

  13. Echtenacher, B., Männel, D. N. & Hültner, L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381, 75–77 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Fischer, M. B. et al. Increased susceptibility to endotoxin shock in complement C3 and C4 deficient mice is corrected by C1 inhibitor replacement. J. Immunol. 159, 976–982 (1997).

    CAS  PubMed  Google Scholar 

  15. Leal-Berumen, I., Conlon, P. & Marshall, J. S. Interleukin-6 production by rat peritoneal mast cels is not necessarily preceded by histamine release and can be induced by bacterial lipopolysaccharide. J. Immunol. 152, 5468–5476 (1994).

    CAS  PubMed  Google Scholar 

  16. Gordon, J. R. & Galli, S. J. Mast cells are a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 346, 274 (1990).

    Article  ADS  CAS  Google Scholar 

  17. Gordon, J. R. & Galli, S. J. Release of both preformed and newly synthesized tumor nectrosis factor α(TNF-α)/cachectin by mouse mast cells stimulated by the FCεRI. A mechanism for the sustained action of mast cell-derived TNF-α during IgE-dependent biological responses. J. Exp. Med. 174, 103–107 (1991).

    Article  CAS  Google Scholar 

  18. Malaviya, R., Ikeda, T., Ross, E. & Abraham, N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381, 77–80 (1996).

    Article  ADS  CAS  Google Scholar 

  19. Wershil, B. K., Wang, Z.-S., Gordon, J. R. & Galli, S. J. Recruitment of neutrophils during IgE-dependent cutaneous late phase responses in the mouse is mast cell-dependent: partial inhibition of the reaction with antiserum against tumor necrosis factor-alpha. J. Clin. Invest. 87, 446–453 (1991).

    Article  CAS  Google Scholar 

  20. Zhang, Y., Ramos, B. F. & Jakschik, B. A. Augmentation of reverse passive arthus reaction by mast cells in mice. J. Clin. Invest. 88, 841–846 (1991).

    Article  CAS  Google Scholar 

  21. Ramos, B. F., Zhang, Y. & Jakschik, B. A. Neutrophil elicitation in the reverse passive arthus reaction. J. Immunol. 152, 1380–1384 (1994).

    CAS  PubMed  Google Scholar 

  22. Vassalli, P. The pathophysiology of tumor necrosis factor. Annu. Rev. Immunol. 10, 411–452 (1992).

    Article  CAS  Google Scholar 

  23. Gerard, C. & Gerard, N. P. 5a anaphylatoxin and its seven transmembrane-segment receptor. Annu. Rev. Immunol. 12, 775–808 (1994).

    Article  CAS  Google Scholar 

  24. Nilsson, U. R. & Muller-Eberhard, H. J. Deficiency of the fifth component of complement in mice with an inherited complement defect. J. Exp. Med. 125, 1–16 (1967).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  26. Briles, D. et al. Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 Streptococcus pneumoniae. J. Exp. Med. 153, 694–705 (1981).

    Article  CAS  Google Scholar 

  27. Reid, R. R. et al. Unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide. J. Immunol. 159, 970–975 (1997).

    CAS  PubMed  Google Scholar 

  28. Epstein, J., Eichbaum, Q. E., Sheriff, S. & Ezekowitz, R. A. B. The collectins in innate immunity. Curr. Opin. Immunol. 8, 29–35 (1996).

    Article  CAS  Google Scholar 

  29. Vranian, G., Conrad, D. H. & Ruddy, S. Specificity of C3 receptors that mediate phagocytosis by rat peritoneal mast cells. J. Immunol. 126, 2302–2306 (1981).

    PubMed  Google Scholar 

  30. Ahearn, J. et al. Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 4, 251–262 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Ma, J. Xia and L. Fox for excellent technical assistance. This study was supported by grants from the National Institutes of Health and Cambridge Antibodies Technology, UK.

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Authors and Affiliations

  1. Departments of Pathology, Harvard Medical School,

    Andrey P. Prodeus, Xiaoning Zhou, Stephen J. Galli & Michael C. Carroll

  2. Beth Israel Deaconess Medical Center, Boston, 02115, Massachusetts, USA

    Marcus Maurer & Stephen J. Galli

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  2. Xiaoning Zhou
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Correspondence to Michael C. Carroll.

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Prodeus, A., Zhou, X., Maurer, M. et al. Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Nature 390, 172–175 (1997). https://doi.org/10.1038/36586

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