C5L2 is a recently identified receptor for C5a/C5adesArg, C3a and C3adesArg (ASP). C5a/C5adesArg bind with high affinity, with no identified activation. By contrast, some studies demonstrate C3a/ASP binding/activation to C5L2; others do not. Our aim is to critically evaluate ASP/C3adesArg-C5L2 binding and bioactivity. Cell-associated fluorescent-ASP (FI-ASP) binding to C5L2 increased from transiently transfected < stably transfected
C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a
NATURE
Authors: Chen, Nien-Jung; Mirtsos, Christine; Suh, Daniel; Lu, Yong-Chen; Lin, Wen-Jye; McKerlie, Colin; Lee, Taeweon; Baribault, Helene; Tian, Hui; Yeh, Wen-Chen
Abstract
Complement-derived anaphylatoxins regulate immune and inflammatory responses through G-protein-coupled receptor ( GPCR)mediated signalling(1-4). 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 evidence(5-7). 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) signalling(4,8,9), C5L2-deficient mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, show reduced ovalbumin (OVA)-induced airway hyperresponsiveness 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.