An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2.
C5L2 is an enigmatic serpentine receptor that is co-expressed with the C5a receptor on many cells including polymorphonuclear neutrophils. The apparent absence of coupling of C5L2 with G proteins suggests that this receptor may modulate the biological activity of C5a, perhaps by acting as a decoy receptor. Alternatively, C5L2 may affect C5a function through formation of a heteromeric complex with the C5aR, or it may utilize a G protein-independent signaling pathway. Here we show that in mice bearing a targeted deletion of C5L2, the biological activity of C5a/C5a(desArg) is enhanced both in vivo and in vitro. The biological role of C5L2 thus appears to be limiting to the pro-inflammatory response to the anaphylatoxin. Accordingly, up-regulation of C5L2 may be of benefit in inflammatory states driven by C5a, including sepsis, asthma, cystic fibrosis, and chronic obstructive lung disease.
Gerard
Norma P
NP
Pulmonary Division, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lu
Bao
B
Liu
Pixu
P
Craig
Stewart
S
Fujiwara
Yuko
Y
Okinaga
Shoji
S
Gerard
Craig
C
D000706:Anaphylatoxins / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism; D002633:Chemotaxis; D003001:Cloning, Molecular; D015936:Complement C5a / Q000737:chemistry*; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009504:Neutrophils / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D000706:Anaphylatoxins; D000893:Anti-Inflammatory Agents; C000594938:C5ar2 protein, mouse; D018076:DNA, Complementary; D015850:Interleukin-6; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D019204:GTP-Binding Proteins