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

  • J Autoimmun. 2015 Jun:60:59-73. doi: 10.1016/j.jaut.2015.04.005.
Justyna Rzepecka  1 ,  Miguel A Pineda  2 ,  Lamyaa Al-Riyami  3 ,  David T Rodgers  4 ,  Judith K Huggan  5 ,  Felicity E Lumb  6 ,  Abedawn I Khalaf  7 ,  Paul J Meakin  8 ,  Marlene Corbet  9 ,  Michael L Ashford  10 ,  Colin J Suckling  11 ,  Margaret M Harnett  12 ,  William Harnett  13
Affiliations
  • 1. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: [email protected].
  • 2. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: [email protected].
  • 3. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: [email protected].
  • 4. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: [email protected].
  • 5. Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: [email protected].
  • 6. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: [email protected].
  • 7. Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: [email protected].
  • 8. Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Electronic address: [email protected].
  • 9. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: [email protected].
  • 10. Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Electronic address: [email protected].
  • 11. Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: [email protected].
  • 12. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: [email protected].
  • 13. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: [email protected].
PMID: 25975491 DOI: 10.1016/j.jaut.2015.04.005
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.

Keywords
Arthritis; ES-62; IL-1β; Inflammasome; NRF2; Parasitic worm.
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