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Toll-like receptors and chronic inflammation in rheumatic diseases: new developments

Nature Reviews Rheumatology volume 12, pages 344–357 (2016)Cite this article

Subjects

Key Points

  • Toll-like receptors (TLRs) have an important role in chronic inflammation in rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, gout and Lyme disease

  • The Toll–IL-1 receptor (TIR) domain triggers biological responses to IL-1 molecules and to TLR ligands

  • Both microbial (such as lipopolysaccharide and DNA) and endogenous ligands have a role in chronic inflammation in rheumatic diseases

  • Novel strategies to inhibit TLR signalling to treat chronic inflammation in rheumatic diseases include antibodies and small molecules that target TLR receptors and TLR signalling

Abstract

In the past few years, new developments have been reported on the role of Toll-like receptors (TLRs) in chronic inflammation in rheumatic diseases. The inhibitory function of TLR10 has been demonstrated. Receptors that enhance the function of TLRs, and several TLR inhibitors, have been identified. In addition, the role of the microbiome and TLRs in the onset of rheumatic diseases has been reported. We review novel insights on the role of TLRs in several inflammatory joint diseases, including rheumatoid arthritis, systemic lupus erythematosus, gout and Lyme arthritis, with a focus on the signalling mechanisms mediated by the Toll–IL-1 receptor (TIR) domain, the exogenous and endogenous ligands of TLRs, and the current and future therapeutic strategies to target TLR signalling in rheumatic diseases.

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Figure 1: Localization, signalling pathways and regulation of human Toll-like receptors (TLRs).
Figure 2: Toll–IL-1-receptor (TIR) domains.
Figure 3: Self-sustaining chronic inflammatory loop maintained through Toll-like receptor (TLR) activation.
Figure 4: Therapeutic targeting of Toll-like receptors (TLRs) or TLR signalling pathways.

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Acknowledgements

S.A.-R. is supported by grants 15-A0-00-004310-01 from the Arthritis National Research Foundation (ANRF), VENI grant 916.12.039 from the Netherlands Organization for Scientific Research and AFS 14-1-291 grant from the Dutch Arthritis Foundation.

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Authors and Affiliations

  1. Department of Internal Medicine, Radboud University Medical Centre, Geert Grooteplein Zuid 8, Nijmegen, 6525 GA, Netherlands

    Leo A. B. Joosten, Charles A. Dinarello & Mihai G. Netea

  2. Radboud Center for Infectious diseases (RCI), Radboud University Medical Centre, Geert Grooteplein Zuid 8, Nijmegen, 6525 GA, Netherlands

    Leo A. B. Joosten & Mihai G. Netea

  3. Department of Rheumatology, Radboud University Medical Centre, Geert Grooteplein 28, Nijmegen, 6525 GA, Netherlands

    Shahla Abdollahi-Roodsaz

  4. Division of Rheumatology, Department of Medicine, New York University School of Medicine, 550 1st Avenue, New York, 11016, New York, USA

    Shahla Abdollahi-Roodsaz

  5. Department of Medicine, University of Colorado Denver, 13001 E 17th Place Aurora, Colorado, 80045, USA

    Charles A. Dinarello

  6. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152–160 Pearse Street, Dublin, 2, Ireland

    Luke O'Neill

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Joosten, L., Abdollahi-Roodsaz, S., Dinarello, C. et al. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol 12, 344–357 (2016). https://doi.org/10.1038/nrrheum.2016.61

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