Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome

Justyna Rzepecka, Miguel A. Pineda, Lamyaa Al-Riyami, David T. Rodgers, Judith K. Huggan, Felicity E. Lumb, Abedawn I. Khalaf, Paul J. Meakin, Marlene Corbet, Michael L. Ashford, Colin J. Suckling, Margaret M. Harnett (Lead / Corresponding author), William Harnett (Lead / Corresponding author)

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    46 Citations (Scopus)

    Abstract

    Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2(-/-) mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA.

    Original languageEnglish
    Pages (from-to)59-73
    Number of pages15
    JournalJournal of Autoimmunity
    Volume60
    DOIs
    Publication statusPublished - Jun 2015

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    Rzepecka, J., Pineda, M. A., Al-Riyami, L., Rodgers, D. T., Huggan, J. K., Lumb, F. E., Khalaf, A. I., Meakin, P. J., Corbet, M., Ashford, M. L., Suckling, C. J., Harnett, M. M., & Harnett, W. (2015). Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome. Journal of Autoimmunity, 60, 59-73. https://doi.org/10.1016/j.jaut.2015.04.005