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C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a


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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Figure 1: C5L2 expression and C5a activation in c5l2 -/- neutrophils.
Figure 2: Reduced C5a-induced downstream signalling in c5l2 -/- cells.
Figure 3: Reduced C3a-induced signalling and F-actin formation in c5l2 -/- neutrophils.
Figure 4: Defective in vivo inflammatory responses and haematopoietic cell regeneration in c5l2 -/- mice.
Figure 5: Overexpression of C5L2 in lung fibroblasts and RAW cells.

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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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Correspondence to Wen-Chen Yeh.

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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).

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