TLR TOLERANCE

Investigation of the Regulation of Toll-like Receptor Mediated Transcription

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 Obiettivo del progetto (Objective)

'Toll-like receptors (TLRs) are key microbial sensors essential for the development of innate immunity to pathogens[1]. TLR activation induces the expression of inflammatory cytokines, antimicrobial proteins, and regeneration factors. Uncontrolled activation of TLRs leads to the development of fatal inflammatory diseases. TLR activation is tightly controlled to ensure that repeated activation does not lead to sustained activation of target genes - a phenomenon termed TLR-tolerance. Lipopolysaccharide-(LPS)-tolerance applies primarily to inflammatory cytokines but not antimicrobial proteins. Selective inactivation of inflammatory genes, but not antimicrobial genes ensures the host’s ability to continuously build up antimicrobial defences without causing fatal inflammatory responses. I recently discovered that Bcl-3 mediates LPS-tolerance by inhibiting the activity of NF-kappaB, a major LPS-activated transcription factor. In the absence of Bcl-3, an inhibitory NF-kappaB complex is degraded, the inflammatory response exacerbated and LPS-tolerance abolished. NF-kappaB-binding sites are significantly enriched among tolerisable (inflammatory) genes. I hypothesise that the NF-kappaB binding site of a promoter dictates sensitivity to TLR-tolerance and that Bcl-3-mediated suppression of TLR signaling applies to inflammatory but not antimicrobial genes. The proposed research will test these hypotheses and investigate the underlying molecular mechanisms of Bcl-3-and NF-kappaB-mediated tolerance.'

Introduzione (Teaser)

Inflammation could be detrimental to our health, sometimes leading to inflammatory diseases. Delineating the molecular mechanisms that link microbial recognition with the onset of inflammation could provide a therapeutic solution for such diseases.

Descrizione progetto (Article)

Central to immune responses is the recognition of pathogens through specialised sensors known as Toll-like receptors (TLRs). TLRs get activated through binding of different bacterial components such as glycolipids, lipopolysaccharides (LPS) or RNA. This induces a downstream signalling of events which culminates in expression of inflammatory genes.

Despite the importance of TLR activation, uncontrolled or prolonged activation can lead to devastating consequences such as inflammatory diseases. Different negative regulators prohibit such sustained receptor activation and tightly regulate the process of TLR activation. This phenomenon is known as TLR tolerance and was the subject of investigation of the EU-funded 'Investigation of the regulation of toll-like receptor mediated transcription' (TLR TOLERANCE) project.

Emerging evidence indicates that TLR tolerance is a gene-specific phenomenon with only certain genes being sensitive to LPS tolerance. The selective inactivation of inflammatory but not antimicrobial genes ensures that the host can build up its immunity against microbes whilst avoiding the emergence of inflammatory disease.

Researchers on the TLR TOLERANCE project investigated the mechanism underlying this selective gene targeting. They found that B cell leukaemia-3 (bcl3) inactivated the transcription factor called nuclear factor (NF)-kb to induce tolerance. This transcription factor is normally activated by LPS.

Additionally, scientists performed bioinformatics analysis of many LPS target genes and identified that NF-kb can only bind on genes that are LPS tolerised. By delineating the mechanisms of NF-kb inactivation, they were able to elucidate its interaction with bcl3 and precisely identify the binding sites. These findings led to the design of peptides with potential therapeutic utility that were able to reduce the inflammatory cytokine IL-23 in cells.

Overall, the work by the TLR TOLERANCE project sets the basis for unravelling the transcriptional regulation of inflammation. Further investigation of the modulating activity of the generated peptides could lead to novel therapeutic interventions for inflammatory diseases.