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Biochemical and functional study of the immunomodulatory capacity of the soluble form of human Toll-like receptor 2

Raby, Anne-Catherine 2008. Biochemical and functional study of the immunomodulatory capacity of the soluble form of human Toll-like receptor 2. PhD Thesis, Cardiff University.

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The Toll-like receptor (TLR) family plays a crucial role in innate immunity by mediating the recognition of, and response to a variety of microorganisms. Dysregulation of TLR-mediated inflammatory responses may, however, lead to a variety of acute and chronic inflammatory conditions. The description of a naturally occurring soluble form of TLR2 (sTLR2), and the observation that sTLR2-depleted serum renders leukocytes hypersensitive to TLR2-mediated stimulation, demanded a full assessment of sTLR2's regulatory capacity and an investigation of the underlying mechanism and therapeutic potential. The present study addressed these issues, and reports that cells overexpressing sTLR2, or stimulated in the presence of the sTLR2 protein, are TLR2 hyposensitive. Regulation was TLR2-specific, affected NF-kB activation, phagocytosis and superoxide production. Mice administered sTLR2 with Gram-positive bacteria-derived components showed lower levels of the neutrophil (PMN) chemoattractant, keratinocyte-derived chemokine lower PMN numbers and late apoptotic PMN. Mononuclear cell recruitment was not affected, and endogenous peritoneal sTLR2 levels increased. Notably, the anti-inflammatory effect of sTLR2 did not compromise the capacity of mice to clear a live infection. sTLR2 interfered with the mobilisation of TLR2 to lipid rafts, acted as a decoy receptor, and disrupted the receptor (TLR2)-co-receptor (CD 14) interaction by associating with CD 14. In order to identify the region(s) of sTLR2 involved in the interaction with CD 14, the leucine-rich repeats (LRRs) of TLR2 were mutated, and the ability of these mutants to affect CD 14- dependent signalling was evaluated. Peptides representing the LRR6 and LRR20 were found to specifically inhibit CD14-dependent TLR2 triggering, indicating that these LRRs are directly involved in the TLR2-CD14 interaction. This study defines sTLR2 as an efficient regulator of TLR2-mediated inflammatory responses. The capacity of sTLR2 and TLR2-derived peptides to exert regulatory effects by targeting CD 14 may inform the design of therapeutics against inflammatory conditions that will aim at disrupting the co-receptor's activity, thus blunting, but not abrogating, microbial recognition and host responses.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISBN: 9781303222689
Date of First Compliant Deposit: 30 March 2016
Last Modified: 16 Jul 2018 11:02

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