Croker, D.E., Halai, R., Kaeslin, G. et al. (5 more authors) (2014) C5a2 can modulate ERK1/2 signaling in macrophages via heteromer formation with C5a1 and beta-arrestin recruitment. Immunology and Cell Biology, 92 (7). pp. 631-639. ISSN 0818-9641
Abstract
The complement system is a major component of our innate immune system, in which the complement proteins C5a and C5a-des Arg bind to two G-protein-coupled receptors: namely, the C5a receptor (C5a1) and C5a receptor like-2 receptor (C5a2, formerly called C5L2). Recently, it has been demonstrated that C5a, but not C5a-des Arg, upregulates heteromer formation between C5a1 and C5a2, leading to an increase in IL-10 release from human monocyte-derived macrophages (HMDMs). A bioluminescence resonance energy transfer (BRET) assay was used to assess the recruitment of β-arrestins by C5a and C5a-des Arg at the C5a1 and C5a2 receptors. C5a demonstrated elevated β-arrestin 2 recruitment levels in comparison with C5a-des Arg, whereas no significant difference was observed at C5a2. A constitutive complex that formed between β-arrestin 2 and C5a2 accounted for half of the BRET signal observed. Interestingly, both C5a and C5a-des Arg exhibited higher potency for β-arrestin 2 recruitment via C5a2, indicating preference for C5a2 over C5a1. When C5a was tested in a functional ERK1/2 assay in HMDMs, inhibition of ERK1/2 was observed only at concentrations at or above the EC50 for heteromer formation. This suggested that increased recruitment of the β-arrestin-C5a2 complex at these C5a concentrations might have an inhibitory role on C5a1 signaling through ERK1/2. An improved understanding of C5a2 modulation of signaling in acute inflammation could be of benefit in the development of ligands for conditions such as sepsis.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2014 Nature Publishing Group: Open Access Hybrid Model Option B. 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: |
|
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: | 23 May 2016 15:22 |
Last Modified: | 23 May 2016 22:37 |
Published Version: | http://dx.doi.org/10.1038/icb.2014.32 |
Status: | Published |
Publisher: | Nature Publishing Group: Open Access Hybrid Model Option B |
Refereed: | Yes |
Identification Number: | 10.1038/icb.2014.32 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:99940 |