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 signalling. 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 evidence. 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) signalling, 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 gamma-irradiation. Our data indicate that C5L2 can function as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses.
Chen
Nien-Jung
NJ
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Mirtsos
Christine
C
Suh
Daniel
D
Lu
Yong-Chen
YC
Lin
Wen-Jye
WJ
McKerlie
Colin
C
Lee
Taeweon
T
Baribault
Helene
H
Tian
Hui
H
Yeh
Wen-Chen
WC
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003167:Complement Activation; D015926:Complement C3a / Q000276:immunology / Q000378:metabolism*; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000166:cytology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000199:Actins; C000594938:C5ar2 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D015926:Complement C3a; D015936:Complement C5a