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Functional roles for C5a receptors in sepsis

Nature Medicine volume 14, pages 551–557 (2008)Cite this article

Abstract

The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture–induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis (30–40% survival), blockade or absence of either C5ar or C5l2 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein (HMGB1) required C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.

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Figure 1: Characterization of antibodies to C5a receptors.
Figure 2: Survival curves for mice after mid-grade CLP.
Figure 3: Survival curves for high-grade CLP under various conditions.
Figure 4: Build-up of HMGB1 in plasma during experimental sepsis.
Figure 5: Requirement of C5l2 for the release of HMGB1 in vitro.

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References

  1. Czermak, B.J. et al. Protective effects of C5a blockade in sepsis. Nat. Med. 5, 788–792 (1999).

    Article  CAS  Google Scholar 

  2. Gerard, N.P. & Gerard, C. The chemotactic receptor for human C5a anaphylatoxin. Nature 349, 614–617 (1991).

    Article  CAS  Google Scholar 

  3. Gerard, C. & Gerard, N.P. C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu. Rev. Immunol. 12, 775–808 (1994).

    Article  CAS  Google Scholar 

  4. Cain, S.A. & Monk, P.N. The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg74. J. Biol. Chem. 277, 7165–7169 (2002).

    Article  CAS  Google Scholar 

  5. Johswich, K. et al. Ligand specificity of the anaphylatoxin C5L2 receptor and its regulation on myeloid and epithelial cell lines. J. Biol. Chem. 281, 39088–39095 (2006).

    Article  CAS  Google Scholar 

  6. Okinaga, S. et al. C5L2, a nonsignaling C5A binding protein. Biochemistry 42, 9406–9415 (2003).

    Article  CAS  Google Scholar 

  7. Kalant, D. et al. The chemoattractant receptor–like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein. J. Biol. Chem. 278, 11123–11129 (2003).

    Article  CAS  Google Scholar 

  8. Kalant, D. et al. C5L2 is a functional receptor for acylation-stimulating protein. J. Biol. Chem. 280, 23936–23944 (2005).

    Article  CAS  Google Scholar 

  9. Kildsgaard, J. et al. Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock. J. Immunol. 165, 5406–5409 (2000).

    Article  CAS  Google Scholar 

  10. Takabayashi, T. et al. A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis. J. Immunol. 156, 3455–3460 (1996).

    CAS  PubMed  Google Scholar 

  11. Gerard, N.P. et al. An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J. Biol. Chem. 280, 39677–39680 (2005).

    Article  CAS  Google Scholar 

  12. Johswich, K. & Klos, A. C5L2—an anti-inflammatory molecule or a receptor for acylation stimulating protein (C3a-desArg)? Adv. Exp. Med. Biol. 598, 159–180 (2007).

    Article  Google Scholar 

  13. Chen, N.J. et al. C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 446, 203–207 (2007).

    Article  CAS  Google Scholar 

  14. Ohno, M. et al. A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. Mol. Immunol. 37, 407–412 (2000).

    Article  CAS  Google Scholar 

  15. Huber-Lang, M. et al. Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans. J. Immunol. 174, 1104–1110 (2005).

    Article  CAS  Google Scholar 

  16. Hopken, 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  CAS  Google Scholar 

  17. Otto, M. et al. C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism. J. Biol. Chem. 279, 142–151 (2004).

    Article  CAS  Google Scholar 

  18. Gao, H. et al. Evidence for a functional role of the second C5a receptor C5L2. FASEB J. 19, 1003–1005 (2005).

    Article  CAS  Google Scholar 

  19. Lee, H. et al. Human C5aR knock-in mice facilitate the production and assessment of anti-inflammatory monoclonal antibodies. Nat. Biotechnol. 24, 1279–1284 (2006).

    Article  CAS  Google Scholar 

  20. Czermak, B.J. et al. In vitro and in vivo dependency of chemokine generation on C5a and TNF-α. J. Immunol. 162, 2321–2325 (1999).

    CAS  PubMed  Google Scholar 

  21. Gavrilyuk, V. et al. Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. J. Neurochem. 92, 1140–1149 (2005).

    Article  CAS  Google Scholar 

  22. Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    Article  CAS  Google Scholar 

  23. Muller, S. et al. New EMBO members' review: the double life of HMGB1 chromatin protein: architectural factor and extracellular signal. EMBO J. 20, 4337–4340 (2001).

    Article  CAS  Google Scholar 

  24. Lotze, M.T. & Tracey, K.J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5, 331–342 (2005).

    Article  CAS  Google Scholar 

  25. Suda, K. et al. Anti–high-mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis. World J. Surg. 30, 1755–1762 (2006).

    Article  Google Scholar 

  26. Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl. Acad. Sci. USA 101, 296–301 (2004).

    Article  CAS  Google Scholar 

  27. Qin, S. et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J. Exp. Med. 203, 1637–1642 (2006).

    Article  CAS  Google Scholar 

  28. Hawlisch, H. et al. C5a negatively regulates Toll-like receptor 4–induced immune responses. Immunity 22, 415–426 (2005).

    Article  CAS  Google Scholar 

  29. Zhang, X. et al. Regulation of Toll-like receptor–mediated inflammatory response by complement in vivo. Blood 110, 228–236 (2007).

    Article  CAS  Google Scholar 

  30. Koleva, M. et al. Induction of anaphylatoxin C5a receptors in rat hepatocytes by lipopolysaccharide in vivo: mediation by interleukin-6 from Kupffer cells. Gastroenterology 122, 697–708 (2002).

    Article  CAS  Google Scholar 

  31. Kohl, J. The role of complement in danger sensing and transmission. Immunol. Res. 34, 157–176 (2006).

    Article  CAS  Google Scholar 

  32. Hawlisch, H. & Kohl, J. Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol. Immunol. 43, 13–21 (2006).

    Article  CAS  Google Scholar 

  33. Kim, J.Y. et al. HMGB1 contributes to the development of acute lung injury after hemorrhage. Am. J. Physiol. Lung Cell. Mol. Physiol. 288, L958–L965 (2005).

    Article  CAS  Google Scholar 

  34. Wang, H. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat. Med. 10, 1216–1221 (2004).

    Article  CAS  Google Scholar 

  35. Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560 (2003).

    Article  CAS  Google Scholar 

  36. Godau, J. et al. C5a initiates the inflammatory cascade in immune complex peritonitis. J. Immunol. 173, 3437–3445 (2004).

    Article  CAS  Google Scholar 

  37. Baelder, R. et al. Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation. J. Immunol. 174, 783–789 (2005).

    Article  CAS  Google Scholar 

  38. Yamada, S., Inoue, K., Yakabe, K., Imaizumi, H. & Maruyama, I. High mobility group protein 1 (HMGB1) quantified by ELISA with a monoclonal antibody that does not cross-react with HMGB2. Clin. Chem. 49, 1535–1537 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health grants GM-29507, GM-61656 and HL-31963 (to P.A.W.), AI-057839 (to J.K.) and HL-69511 (to C.G.) and Deutsche Forschungsgemeinschaft grants HU823/2-2 and HU823/2-3 (to M.H.-L.). We thank B. Schumann and S. Scott for secretarial assistance in preparation of the manuscript.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, 48109, Michigan, USA

    Daniel Rittirsch, Michael A Flierl, Brian A Nadeau, Danielle E Day, Firas S Zetoune, J Vidya Sarma & Peter A Ward

  2. Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University Hospital Ulm, Steinhövelstrasse 9, Ulm, D-89075, Germany

    Markus Huber-Lang

  3. Immunology and Inflammation Department, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010, New South Wales, Australia

    Charles R Mackay

  4. Pulmonary Division, Department of Pediatrics, Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Norma P Gerard & Craig Gerard

  5. Department of Medicine, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Norma P Gerard

  6. Centre de Recherche Hôpital Laval, Université Laval, 2725 chemin Ste Foy, Québec, G1V 4G5, Canada

    Katherine Cianflone

  7. Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, 300 Longwood Avenue, Cincinnati, 45229, Ohio, USA

    Jörg Köhl

  8. Institute for Systemic Inflammation Research, University of Lübeck, Ratzeburger Allee 160, Lübeck, D-23538, Germany

    Jörg Köhl

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  1. Daniel Rittirsch
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Contributions

D.R. conducted all experiments and wrote the manuscript. M.A.F., B.A.N., D.E.D. and M.H.-L. contributed to the in vivo studies. C.R.M., F.S.Z. and N.P.G. made contributions to some of the in vitro experiments. K.C., J.K. and C.G. provided knockout mice and receptor antagonists. J.V.S. and P.A.W. supervised the project and edited the manuscript.

Corresponding author

Correspondence to Peter A Ward.

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Rittirsch, D., Flierl, M., Nadeau, B. et al. Functional roles for C5a receptors in sepsis. Nat Med 14, 551–557 (2008). https://doi.org/10.1038/nm1753

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