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Title: Study of the capacity of Toll-like receptors to modulate pro-inflammatory responses mediated by receptors for the complement anaphylatoxin C5a
Author: Holst, Benjamin
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2013
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Toll-like receptors (TLRs) and the complement system play a crucial role in the innate immune response by mediating the initial recognition of, and prompt response to a variety of microorganisms. The concerted activation of TLRs and complement ensures efficient clearance of infection. Previous studies have documented synergism between TLRs and the receptor for the pro-inflammatory 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. This study tested the hypothesis that a genuine, bi-directional signalling crosstalk between TLRs and C5a receptors exists, involving not only modulation of TLR-mediated responses by C5a receptor activation, but also modulation by TLR activation of the extent and/or quality of cellular responses to C5a. The experiments described in this thesis confirmed this hypothesis by demonstrating a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identifying underlying mechanistic targets. Pre-exposure of peripheral blood mononuclear cells 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 up-regulation or modulation of C5a-induced calcium mobilization. Rather, TLRs targeted the second C5a receptor, C5L2 (acting as a negative modulator of C5aR) by reducing C5L2 expression and 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. Expression of the key adaptor molecule β-arrestin 1, which mediates the inhibitory effects of C5L2 on C5aR, was also found to be negatively regulated by TLR activation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defence at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR180 Immunology ; R Medicine (General)