Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling

Croker, Daniel E., Monk, Peter N., Halai, Reena, Kaeslin, Geraldine, Schofield, Zoe, Wu, Mike C. L., Clark, Richard J., Blaskovich, Mark A. T., Morikis, Dimitrios, Floudas, Christodoulos A., Cooper, Matthew and Woodruff, Trent M. (2016) Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunology and Cell Biology, 94 8: 787-795. doi:10.1038/icb.2016.43

Author Croker, Daniel E.
Monk, Peter N.
Halai, Reena
Kaeslin, Geraldine
Schofield, Zoe
Wu, Mike C. L.
Clark, Richard J.
Blaskovich, Mark A. T.
Morikis, Dimitrios
Floudas, Christodoulos A.
Cooper, Matthew
Woodruff, Trent M.
Title Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling
Journal name Immunology and Cell Biology   Check publisher's open access policy
ISSN 0818-9641
Publication date 2016-05-17
Year available 2016
Sub-type Article (original research)
DOI 10.1038/icb.2016.43
Open Access Status Not Open Access
Volume 94
Issue 8
Start page 787
End page 795
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted abstract
The complement cascade is comprised of a highly sophisticated network of innate immune proteins that are activated in response to invading pathogens or tissue injury. The complement activation peptide, C5a, binds two seven transmembrane receptors, namely the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2, or C5L2). C5aR2 is a non-G-protein-signalling receptor whose biological role remains controversial. Some of this controversy arises owing to the lack of selective ligands for C5aR2. In this study, a library of 61 peptides based on the C-terminus of C5a was assayed for the ability to selectively modulate C5aR2 function. Two ligands (P32 and P59) were identified as functionally selective C5aR2 ligands, exhibiting selective recruitment of β-arrestin 2 via C5aR2, partial inhibition of C5a-induced ERK1/2 activation and lipopolysaccharide-stimulated interleukin-6 release from human monocyte-derived macrophages. Importantly, neither ligand could induce ERK1/2 activation or inhibit C5a-induced ERK1/2 activation via C5aR1 directly. Finally, P32 inhibited C5a-mediated neutrophil mobilisation in wild-type, but not C5aR2−/− mice. These functionally selective ligands for C5aR2 are novel tools that can selectively modulate C5a activity in vitro and in vivo, and thus will be valuable tools to interrogate C5aR2 function.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 1 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 26 May 2016, 14:49:55 EST by Susan Allen on behalf of Institute for Molecular Bioscience