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. Epub 2015 May 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acanthocheilonema / metabolism
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / prevention & control
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / prevention & control
  • Collagen
  • Gerbillinae
  • Helminth Proteins / pharmacology*
  • Inflammasomes / immunology
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Interleukin-1beta / biosynthesis*
  • Joints / immunology
  • Joints / pathology
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / immunology

Substances

  • Anti-Inflammatory Agents
  • ES-62 protein, Acanthocheilonema viteae
  • Helminth Proteins
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Collagen