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

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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-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

Fingerprint

Inflammasomes
Experimental Arthritis
Helminths
Interleukin-1
Rheumatoid Arthritis
Macrophages
Genes
Biological Therapy
Therapeutics
Oxidants
Transcription Factors
Joints
Pharmaceutical Preparations

Keywords

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

Cite this

Rzepecka, Justyna ; Pineda, Miguel A. ; Al-Riyami, Lamyaa ; Rodgers, David T. ; Huggan, Judith K. ; Lumb, Felicity E. ; Khalaf, Abedawn I. ; Meakin, Paul J. ; Corbet, Marlene ; Ashford, Michael L. ; Suckling, Colin J. ; Harnett, Margaret M. ; Harnett, William. / 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. In: Journal of Autoimmunity. 2015 ; Vol. 60. pp. 59-73.
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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-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.",
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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, Justyna; Pineda, Miguel A.; Al-Riyami, Lamyaa; Rodgers, David T.; Huggan, Judith K.; Lumb, Felicity E.; Khalaf, Abedawn I.; Meakin, Paul J.; Corbet, Marlene; Ashford, Michael L.; Suckling, Colin J.; Harnett, Margaret M.; Harnett, William.

In: Journal of Autoimmunity, Vol. 60, 06.2015, p. 59-73.

Research output: Contribution to journalArticle

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AU - Rzepecka, Justyna

AU - Pineda, Miguel A.

AU - Al-Riyami, Lamyaa

AU - Rodgers, David T.

AU - Huggan, Judith K.

AU - Lumb, Felicity E.

AU - Khalaf, Abedawn I.

AU - Meakin, Paul J.

AU - Corbet, Marlene

AU - Ashford, Michael L.

AU - Suckling, Colin J.

AU - Harnett, Margaret M.

AU - Harnett, William

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N2 - 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.

AB - 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.

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