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.
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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.
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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
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DOI: https://doi.org/10.1038/nature05559
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