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

Rzepecka, J. et al. (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, pp. 59-73. (doi:10.1016/j.jaut.2015.04.005) (PMID:25975491) (PMCID:PMC4459730)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Pineda, Dr Miguel
Authors: 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., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Autoimmunity
Publisher:Elsevier
ISSN:0896-8411
ISSN (Online):1095-9157
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Journal of Autoimmunity 60:59-73
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOME)086852/Z/08/ZIII -IMMUNOLOGY
455802Small molecule analogues (SMAs) of an immunomodulatory helminth product provide a novel approach to dissecting macrophage signalsMargaret HarnettBiotechnology and Biological Sciences Research Council (BBSRC)BB/E013929/1III -IMMUNOLOGY
484131Exploiting the host-parasite relationship to develop novel safe anti-inflammatory therapiesMargaret HarnettArthritis Research UK (ARC)MP/18413III -IMMUNOLOGY