Luke A O'Neill

..Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation...

..A surprising link between innate immunity and nuclear reprogramming is reported by Lee et al.; this discovery may boost the efficiency of stem cell production...

..The aim of this study was to examine the effect of blocking Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA) synovial cells...

..These findings present new therapeutic opportunities, possibly allowing for the replacement of biologics with small molecule inhibitors...

..Here we review these recent advances and speculate about whether manipulating TLRs is likely to be successful in fighting off different diseases...

..This area has therefore proved very fruitful in terms of improving our knowledge of the molecular basis for innate immunity and inflammation, and we can anticipate further discoveries in the coming years...

..As we learn more about TLR signal transduction, more options are presenting themselves for pharmacological targeting...

..These recent findings emphasize the importance of considering TLR signaling in the context of other signaling pathways, as is likely to occur in vivo during infection and inflammation...

..Inhibition of TLR4, TLR7 and TLR9 has produced intriguing results, which indicate that TLRs and their signaling pathways might indeed have great potential as novel targets for the treatment of inflammatory joint disease...

..Recent work has identified that NLRX1, a member of another class of innate immune receptors, sequesters MAVS away from RIG-I and thereby prevents mitochondrial anti-viral immunity...

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..Chiu et al. (2009) now implicate cytosolic DNA-dependent RNA polymerase III as the DNA sensor linking DNA release by pathogenic bacteria and viruses in the host cell cytosol to IFN-beta production and innate immunity...

..In this issue of Immunity, Shaked et al. (2009) describe how miR-132 mediates an anti-inflammatory effect via the targeting of acetylcholinesterase, leading to an increase in the neurotransmitter acetylcholine...

..Furthermore, new complexities in the signaling pathways activated by these receptors continue to be revealed. Together, these new insights are leading to therapeutically useful information in the fight against viruses...

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..miRNAs are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammatory diseases...

..This somewhat unexpected role for citrate in LPS action adds to a growing literature on the role for metabolism in the regulation of signalling in inflammation...

..2011) and Luo et al. (2011) reveal the structure of RIG-I, and in combination with functional analyses, they show how RIG-I recognizes viral RNA to initiate signaling and a type I interferon response...

..2007) uncover a complex negative feedback mechanism to limit TLR signaling involving the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases, which induce expression of the inhibitory proteins SOCS1 and SOCS3...

..These new insights allow for a detailed description of the function of the five TIR-domain-containing adaptors in the initiation of TLR signalling...

..This receptor superfamily therefore appears to play a central role in inflammation and host defence against infection, pointing to the TIR domain as a critical molecular player in the innate immune response...

..However, signals that separate Mal from MyD88 have yet to emerge, although biochemical differences between the two proteins imply that each will have a specific function...

..It is probable that differential use of adaptors will help explain the distinct pathways activated by TLRs during host defence...

..Future studies on TLR signalling may reveal hitherto unsuspected specificities in the innate immune response to infection...

..Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection...

..These findings may ultimately explain how dendritic cells control specific T-cell responses...

..The signaling proteins activated are also conserved across species. This receptor superfamily therefore represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses...

..Selective targeting of pathways by anti-inflammatory glucocorticoids also indicates the potential for modulating TLR signalling therapeutically...

..The challenge is to place a value on one target relative to another, and to devise strategies to modulate them...

..Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence...

..Importantly, their dysregualtion may be important for chronic inflammation, which in turn can lead to autoimmunity and cancer, as discussed in this Viewpoint...

..Overall, we demonstrate for the first time disruption of a specific TLR signaling pathway by a short virally derived peptide...

..Secondly, TLRs trigger anti-viral signalling pathways leading to the induction of the interferon response. Thirdly, viral immune strategies employed against TLRs have been identified...

..These findings identify vaccinia virus proteins as possible therapeutic agents for the manifestations of several inflammatory lung diseases...

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..Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-kappaB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-kappaB activation...

..This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain...

..If this process is impaired, disease, such as T2D, might persist. This review aims to discuss a possible link between the molecular phenomena of obesity and inflammation and the role that miR-107 may contribute to these processes...

..This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFkappaB...

..In this review, we focus in on a trio of miRNA which have proven to be key in many immune and inflammatory pathways; miR-155, miR-21 and miR-146...

..Another novel mechanism of viral DNA recognition unveiled, leading to proinflammatory cytokine production, involves the PYHIN family member AIM2...

..Furthermore, N1L inhibited IRF3 signaling, which is also regulated by TBK1. These studies define a role for N1L as an immunomodulator of innate immunity by targeting components of NF-kappaB and IRF3 signaling pathways...

..In this study we used predicted miRNA-gene interactions to analyse mRNA gene expression microarray data to predict miRNAs associated with particular diseases or conditions...

..In this chapter we outline the signalling pathways that respond to viral infection and the various methods that viruses utilize to evade detection and modulate the innate immune response to favour their survival...

..Thus, the fifth mammalian TIR adaptor SARM is a negative regulator of Toll-like receptor signaling...

..pylori LPS. Thus, modulation of TRIB3 by H. pylori and/or its products may be an important mechanism during H. pylori-associated pathogenesis...

..Therefore, this study shows for the first time the involvement of a DEAD box helicase in TBK1/IKKepsilon-mediated IRF activation and Ifnb promoter induction...

..IFI16 (p204) is the first PYHIN protein to our knowledge shown to be involved in IFN-β induction. Thus, the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors we call 'AIM2-like receptors' (ALRs)...

..Here, modulation of apoptotic and NF-kappaB signal transduction pathways are examined as examples of common pathways appropriated in contrasting ways by herpesviruses and poxviruses...

..This further emphasises the importance of DDX3 in anti-viral immunity, and is consistent with the idea that viruses target DDX3 for immune evasion...

..Further, IRAK-2 loss-of-function mutants, which could not activate NFkappaB, were incapable of promoting TRAF6 ubiquitination. Thus we propose that IRAK-2 plays a more central role than IRAK-1 in TLR signaling to NFkappaB...

..A52R-mediated enhancement of TLR-induced IL-10 may be important to virulence, given the role of IL-10 in immunoregulation...

..Also, recent research concerning the expression profile of TLR3, its evasion by viruses and a potential role in crosspriming is addressed, which reveals a clearer appreciation of the contribution of TLR3 to antiviral immunity...

..Further, the viral proteins themselves or derivatives of them may be of use therapeutically to curtail inflammation and autoimmunity...

..Again, complexes recovered from the beads are analysed by Western blotting...