Abstract
Complement-derived anaphylatoxins regulate immune and inflammatory responses through G-protein-coupled receptor (GPCR)-mediated signalling1,2,3,4. C5L2 (also known as GPR77) is a relatively new GPCR thought to be a non-signalling receptor binding to C5a, on the basis of sequence information and experimental evidence5,6,7. Here we show, using gene targeting, that C5L2 is required to facilitate C5a signalling in neutrophils, macrophages and fibroblasts in vitro. Deficiency of C5L2 results in reduced inflammatory cell infiltration, suggesting that C5L2 is critical for optimal C5a-mediated cell infiltration in certain in vivo settings. C5L2 is also involved in optimizing C3a-induced signals. Furthermore, like mice incapable of C3a/complement 3a receptor (C3aR) signalling4,8,9, C5L2-deficient mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, show reduced ovalbumin (OVA)-induced airway hyper-responsiveness and inflammation, and are mildly delayed in haematopoietic cell regeneration after γ-irradiation. Our data indicate that C5L2 can function as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Shin, H. S., Snyderman, R., Friedman, E., Mellors, A. & Mayer, M. M. Chemotactic and anaphylatoxic fragment cleaved from the fifth component of guinea pig complement. Science 162, 361–363 (1968)
Bokisch, V. A., Muller-Eberhard, H. J. & Cochrane, C. G. Isolation of a fragment (C3a) of the third component of human complement containing anaphylatoxin and chemotactic activity and description of an anaphylatoxin inactivator of human serum. J. Exp. Med. 129, 1109–1130 (1969)
Höpken, U. E., Lu, B., Gerard, N. P. & Gerard, C. The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 383, 86–89 (1996)
Humbles, A. A. et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406, 998–1001 (2000)
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)
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)
Gerard, N. P. et al. An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J. Biol. Chem. 280, 39677–39680 (2005)
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)
Ratajczak, M. Z. et al. Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells. Leukemia 18, 1482–1490 (2004)
Hsu, M. H. et al. Cloning and functional characterization of the mouse C3a anaphylatoxin receptor gene. Immunogenetics 47, 64–72 (1997)
Perret, J. J., Raspe, E., Vassart, G. & Parmentier, M. Cloning and functional expression of the canine anaphylatoxin C5a receptor. Evidence for high interspecies variability. Biochem. J. 288, 911–917 (1992)
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)
Okinaga, S. et al. C5L2, a nonsignaling C5A binding protein. Biochemistry 42, 9406–9415 (2003)
Kalant, D. et al. C5L2 is a functional receptor for acylation stimulating protein. J. Biol. Chem. 280, 23936–23944 (2005)
Riedemann, N. C. et al. Regulation by C5a of neutrophil activation during sepsis. Immunity 19, 193–202 (2003)
Riedemann, N. C. et al. Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J. 18, 370–372 (2004)
Perianayagam, M. C., Balakrishnan, V. S., King, A. J., Pereira, B. J. & Jaber, B. L. C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway. Kidney Int. 61, 456–463 (2002)
Hawlisch, H. et al. C5a negatively regulates Toll-like receptor 4-induced immune responses. Immunity 22, 415–426 (2005)
Guo, R. F., Riedemann, N. C. & Ward, P. A. Role of C5a–C5aR interaction in sepsis. Shock 21, 1–7 (2004)
Gavrilyuk, V. et al. Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. J. Neurochem. 92, 1140–1149 (2005)
Gao, H. et al. Evidence for a functional role of the second C5a receptor C5L2. FASEB J. 19, 1003–1005 (2005)
White, J. H. et al. Heterodimerization is required for the formation of a functional GABAB receptor. Nature 396, 679–682 (1998)
Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040–1046 (2000)
Duncan, G. S. et al. Genetic evidence for functional redundancy of Platelet/Endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J. Immunol. 162, 3022–3030 (1999)
Acknowledgements
We thank D. Katz and Y. Zhu for technical assistance and members of the Yeh laboratory for discussion. We also thank C. Gerard for C5aR-deficient mice. This work is supported in part by Canadian Institutes of Health Research and by the Canadian Cancer Society.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Figures S1-S8 with Legends and Supplementary Methods. (PDF 2473 kb)
Rights and permissions
About this article
Cite this article
Chen, NJ., Mirtsos, C., Suh, D. et al. C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 446, 203–207 (2007). https://doi.org/10.1038/nature05559
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature05559
This article is cited by
-
Complement System: a Neglected Pathway in Immunotherapy
Clinical Reviews in Allergy & Immunology (2020)
-
Complement receptors C5aR1 and C5aR2 act differentially during the early immune response after bone fracture but are similarly involved in bone repair
Scientific Reports (2017)
-
Complement in ANCA-associated vasculitis: mechanisms and implications for management
Nature Reviews Nephrology (2017)
-
Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling
Immunology & Cell Biology (2016)
-
Anaphylatoxin C5a modulates hepatic stellate cell migration
Fibrogenesis & Tissue Repair (2014)
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.