O'Neill, L.A. & Bowie, A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353-364

School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
Nature reviews. Immunology (Impact Factor: 34.99). 06/2007; 7(5):353-64. DOI: 10.1038/nri2079
Source: PubMed

ABSTRACT Signalling by Toll-like receptors (TLRs) involves five adaptor proteins known as MyD88, MAL, TRIF, TRAM and SARM. Recent insights have revealed additional functions for MyD88 apart from NF-kappaB activation, including activation of the transcription factors IRF1, IRF5 and IRF7, and also a role outside the TLRs in interferon-gamma signalling. Biochemical information on MAL and TRAM has shown that both act as bridging adaptors, with MAL recruiting MyD88 to TLR2 and TLR4, and TRAM recruiting TRIF to TLR4 to allow for IRF3 activation. Finally, the function of the fifth adaptor, SARM, has been revealed, which negatively regulates TRIF. These new insights allow for a detailed description of the function of the five TIR-domain-containing adaptors in the initiation of TLR signalling.

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    • ". In other words, also mussel TLRs might recognize pathogens both in the extracellular and intracellular space. Besides TLRs, other TIR domain-containing proteins are involved in immune signaling, since this domain is often used for homophilic interactions [101]. Interestingly, the TIR domain appears to be widespread in bivalves, with over 100 TIR domain-containing proteins predicted in the oyster genome. "
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    ABSTRACT: Non-self recognition with the consequent tolerance or immune reaction is a crucial process to succeed as living organisms. At the same time the interactions between host species and their microbiome, including potential pathogens and parasites, significantly contribute to animal life diversity. Marine filter-feeding bivalves, mussels in particular, can survive also in heavily anthropized coastal waters despite being constantly surrounded by microorganisms. Based on the first outline of the Mytilus galloprovincialis immunome dated 2011, the continuously growing transcript data and the recent release of a draft mussel genome, we explored the available sequence data and scientific literature to reinforce our knowledge on the main gene-encoded elements of the mussel immune responses, from the pathogen recognition to its clearance. We carefully investigated molecules specialized in the sensing and targeting of potential aggressors, expected to show greater molecular diversification, and outlined, whenever relevant, the interconnected cascades of the intracellular signal transduction. Aiming to explore the diversity of extracellular, membrane-bound and intracellular pattern recognition receptors in mussel, we updated a highly complex immune system, comprising molecules which are described here in detail for the first time (e.g. NOD-like receptors) or which had only been partially characterized in bivalves (e.g. RIG-like receptors). Overall, our comparative sequence analysis supported the identification of over 70 novel full-length immunity-related transcripts in M. galloprovincialis. Nevertheless, the multiplicity of gene functions relevant to immunity, the involvement of part of them in other vital processes, and also the lack of a refined mussel genome make this work still not-exhaustive and support the development of more specific studies
    Fish &amp Shellfish Immunology 02/2015; 46(1). DOI:10.1016/j.fsi.2015.02.013 · 2.67 Impact Factor
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    • "Lipopolysaccharide (LPS), an endotoxin, is well known to interact with toll-like receptor 4 (TLR4), leading to the expression of several proinflammatory cytokines, as well as other inflammatory mediators such as NO and prostaglandin-E2 (PGE2) (Miguel et al., 2007). TLR4 mediates cell activation via engagement of the myeloid differentiation primary response gene-88 (MyD88) and/ or TIR domain-containing, adaptor-inducing, interferon-β (TRIF)dependent signaling pathways (O'Neill and Bowie, 2007). The MyD88- dependent pathway mediates the activation of a number of intracellular signaling proteins, including mitogen-activated protein kinase (MAPK) (Akira and Takeda, 2004). "
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    ABSTRACT: Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signalling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. Copyright © 2015. Published by Elsevier Inc.
    Toxicology and Applied Pharmacology 02/2015; 284(2). DOI:10.1016/j.taap.2015.02.006 · 3.71 Impact Factor
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    • "MyD88-dependent signaling typically requires the adaptor proteins TIRAP (TIR domain containing adaptor protein) and MyD88 to initiate the rapid production of proinflammatory cytokines, chemokines and their receptors TNF, IL-1a, IL-1b, IL-1ra, IL-6, IL-8, IL-10, IL-12p40, IL- 23, macrophage inflammatory protein (MIP)-1a, and MIP-1b [47]. These factors facilitate the inflammatory response by increasing vascular permeability, directing dendritic cells and initiating macrophage migration from the periphery [48]. In contrast, the independent signaling pathway is reliant on Toll-like receptor adaptor molecule (TICAM)-1, -2, the TIR-domain-containing adaptor inducing interferon-b (TRIF) or TRIF-related adaptor molecule (TRAM) resulting in the production of interferon-b and chemokines. "
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    ABSTRACT: Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll-like receptor (TLR) 4 pathway as a common component of their pathobiology. Given the global observation of toxicity clusters, identification of a common initiating factor provides an excellent opportunity to simultaneously target multiple side effects of anticancer treatment. Furthermore, identification of common biological underpinnings could perhaps reduce polypharmacy and have pharmacoeconomic benefits. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 12/2014; 41(2). DOI:10.1016/j.ctrv.2014.11.005 · 7.59 Impact Factor
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