757 publications from this institution
The past 10 years have seen the description of families of receptors that drive proinflammatory cytokine production in infection and tissue injury. Two major classes have been examined in the context of inflammatory joint disease - the Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs such as TLR2 and TLR4 are being implicated in the pathology of rheumatoid arthritis, ankylosing spondylitis, lyme arthritis and osteoarthritis. Nalp3 has been identified as a key NLR for IL-1β production and has been shown to have a particular role in gout. These findings present new therapeutic opportunities, possibly allowing for the replacement of biologics with small molecule inhibitors.
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No abstract is provided for this article.
The IL-1R/TLR superfamily was first defined in detail 10 years ago. Since then, there has been remarkable progress in our understanding of both branches of the superfamily. Ligands have been described for most receptors. Within the IL-1R subfamily, notable examples include IL33 for ST2 and IL-1F6 for IL-1Rrp2. The role of TLRs in the sensing of microbial products has led to a renaissance of interest in innate immune mechanisms. For investigators interested in signal transduction, the area has proved very fruitful in terms of the discovery of new signalling pathways and processes. MyD88 is the universal adapter for the superfamily and its central role in inflammation, host defence and even in certain cancers, has been confirmed from studies in knockout mice. We now have a good understanding of the major components activated by TLRs, notably the TIR domain- containing adapters that initiate signalling following recruitment to TIR domains within the TLRs themselves, the IRAK family of protein kinases that are then recruited, and a series of ubiquitination and phosphorylation reactions that ultimately lead to the activation of transcription factors such as NF-κB and IRF family members. The structural basis for signalling is still poorly understood however, and we have no appreciation of the kinetics involved in the pathways. Additional components and regulatory cross-talk from multiple signals also continue to be discovered. Genetic variation in signalling components such as in IRAK4, Mal and Unc93b however highlight the importance of these pathways in human health and disease. I will discuss our recent findings of a novel component in TLR4 signalling, what genetic variation in Mal tells us about the evolution of host defence to pathogens and also the molecular basis to how Mal signals, and the emerging role of miRNAs as key regulators of TLR signalling events.
Interleukin-1 (IL-1) belongs to a family of cell activators termed cytokines. These are proteins which mediate the activation, differentiation or maturation of cells involved in immune and inflammatory responses [reviewed in 1]. The advent of cytokines has allowed elaborate networks to be established between a wide variety of cell types. This has greatly improved our understanding of the molecular and cellular events which occur during inflammation.
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<b>Introduction:</b> Dysregulated immune responses are a key feature of severe coronavirus disease 2019 (COVID-19) pathophysiology. Despite common symptoms there is disparity in patients' recovery, driving research into targeted therapies. <b>Aim:</b> To characterize the biological mechanisms in COVID-19 recovery. <b>Methods:</b> Serum proteomics (Olink platform) was carried out on 350 patients within the placebo and otilimab arms of OSCAR Part 1 (Otilimab in Severe COVID-19-Related Disease; NCT04376684). Patients were stratified by clinical response or mortality at Day 28, baseline severity, age (70y) and comorbidity status. Differentially expressed proteins (DEPs) at baseline were characterized. <b>Results:</b> Each stratification revealed 300+ DEPs that were assessed for enrichment of biological pathways. The tumor necrosis factor receptor 2 non-canonical NF-κB pathway was enriched in all groups, as was a cluster of pathways associated with dysfunctional protein metabolism and post‑translational modification. The size of this latter cluster was highly variable between groups. A distinct cluster of pathways linked to programmed cell death was associated with the fatal and ≥70y groups, but not observed in the severity or response analyses. Unique to the ≥70y group was a cluster of fibroblast growth factor-related and phospholipase C signaling pathways, potentially indicative of enhanced immune cell activation. <b>Conclusion:</b> These analyses reinforce the need for personalized treatment of severe COVID-19 and build rationale for poor outcomes in specific patient groups including older age. <b>Funded by GSK:</b> medical writing support provided by Fishawack Indicia Ltd, funded by GSK.
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No abstract is provided for this article.
Significant advances in our understanding of innate immunity have been made following the identification of three families of pathogen sensors: Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). Members of the TLR family recognize bacteria, viruses, fungi and protozoa; NLRs with known functions detect bacteria, and RLRs are anti-viral. It is likely that interplay between these families ensures the efficient co-ordination of innate immune responses, through either synergistic or co-operative signalling. Important interactions occur between TLRs and certain NLRs for inducing the pro-inflammatory cytokine interleukin (IL)-1β. TLRs induce pro-IL-1β production and prime NLR-containing multi-protein complexes, termed ‘inflammasomes’, to respond to bacterial products and products of damaged cells. This results in caspase-1 activation and the subsequent processing of pro-IL-1β to its active form. In this article, we hypothesize that during the first phase of the host response to infection, an important interplay occurs between these families, providing a substantial combinatorial repertoire in innate immunity.
No abstract is provided for this article.
Signaling by the toll-like receptor (TLR) and interleukin-1 receptor superfamily requires the adapter protein myeloid differentiation primary response protein 88 (MyD88). The recent determination of the structure of the so-called Myddosome provides us with new insights into the structural basis for innate immune signaling. Other information on the biochemistry and genetics of MyD88 and other adapters, such as MyDD adapter-like and TRIF-related adapter molecule, allows us to describe in some detail the signaling process activated by TLRs and provides new insights into the role these important proteins play in innate immunity.
