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Primer: Toll-like receptor signaling pathways—what do rheumatologists need to know?

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From Nature Clinical Practice Rheumatology

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Abstract

Toll-like receptors (TLRs) have caught the attention of rheumatologists searching for additional therapeutic targets for diseases such as rheumatoid arthritis and systemic lupus erythematosus. Signaling from these molecules can induce the expression of cytokines such as tumor necrosis factor and interferon α. Strategies that target TLRs and their co-receptors (such as MD2 for TLR4 or CD36 for TLR2) might be a more-selective approach than inhibition of global signals such as nuclear factor κB or p38 mitogen-activated protein kinase. TLR signaling requires adaptor proteins, including MyD88, Mal, TRIF and TRAM, which are recruited to specific receptors: Mal is used only by TLR2 and TLR4, TRIF is used by TLR3 and TLR4, and TRAM is recruited by TLR4 alone. Mal and TRAM are subject to complex biochemical regulation. Inhibition of Mal or MyD88 blocks the production of inflammatory mediators in synovial tissue. Another possible intracellular target is Unc93b, a protein involved in signaling from TLR3, TLR7 and TLR9. 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.

Key Points

  • Toll-like receptors (TLRs) are important innate immune receptors that trigger inflammatory signaling pathways in response to microbial products or the products of inflamed tissues

  • TLRs are expressed in inflamed joints and are strong inducers of inflammatory cytokines

  • Inhibition of certain TLRs has resulted in anti-inflammatory and joint-protective effects in animal models of arthritis

  • TLRs activate complex signaling pathways that include specific adaptor proteins

  • Highly complex biochemical and genetic regulation of the adaptor proteins has been uncovered, and thereby presents possible new targets for use in the effort to limit the inflammatory effects of TLRs

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Figure 1: TLRs and chronic inflammation.
Figure 2: TLR signaling pathways.
Figure 3: Regulation of Mal and TRAM.

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Acknowledgements

The author would like to thank the Science Foundation Ireland and the Irish Health Research Board for research funding.

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Author notes

  1. School of Biochemistry and Immunology, Trinity College Dublin, Ireland laoneill@tcd.ie

Authors and Affiliations

  1. L AJ O'Neill holds the Chair of Biochemistry and is Head of the School of Biochemistry and Immunology at Trinity College Dublin, Ireland.,

    Luke AJ O'Neill

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O'Neill, L. Primer: Toll-like receptor signaling pathways—what do rheumatologists need to know?. Nat Rev Rheumatol 4, 319–327 (2008). https://doi.org/10.1038/ncprheum0802

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  • DOI: https://doi.org/10.1038/ncprheum0802

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