Croker, D.E., Monk, P.N. orcid.org/0000-0003-4637-3059, Halai, R. et al. (9 more authors) (2016) Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunology and Cell Biology, 94 (8). pp. 787-795. ISSN 0818-9641
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.Immunology and Cell Biology advance online publication, 17 May 2016; doi:10.1038/icb.2016.43.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 The authors. This is an author produced version of a paper subsequently published in Immunology and Cell Biology. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Funding Information: | Funder Grant number BRITISH HEART FOUNDATION PG/09/018 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 20 May 2016 11:38 |
Last Modified: | 30 Nov 2016 23:43 |
Published Version: | https://dx.doi.org/10.1038/icb.2016.43 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/icb.2016.43 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:99923 |