TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2

Raby, Anne-Catherine ORCID: https://orcid.org/0000-0002-5354-5835, Holst, Benjamin, Davies, James Anthony ORCID: https://orcid.org/0000-0003-3569-4500, Colmont, Chantal Sophie, Laumonnier, Yves, Coles, Barbara, Shah, Sanjoy, Hall, Judith Elizabeth ORCID: https://orcid.org/0000-0002-6770-7372, Topley, Nicholas, Köhl, Jörg, Morgan, Bryan Paul ORCID: https://orcid.org/0000-0003-4075-7676 and Labeta, Mario Oscar ORCID: https://orcid.org/0000-0001-5750-6983 2011. TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2. European Journal of Immunology 41 (9) , pp. 2741-2752. 10.1002/eji.201041350

Preview

PDF - Published Version Download (357kB) | Preview

Abstract

TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca2+ mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Complement ; Inflammation ; Innate immunity ; TLR
Publisher:	John Wiley & Sons
ISSN:	0014-2980
Date of First Compliant Deposit:	30 March 2016
Last Modified:	23 May 2024 01:06
URI:	https://orca.cardiff.ac.uk/id/eprint/22556

Citation Data

Cited 54 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item