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, William Harnett

Research output: Contribution to journalArticle

46 Citations (Scopus)
2275 Downloads (Pure)

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-1b 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
Early online date11 May 2015
DOIs
Publication statusPublished - Jun 2015

Keywords

  • arthritis
  • ES-62
  • IL-1β
  • inflammasome
  • NRF2
  • parasitic worm

Cite this