title: 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.
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.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: justyna.rzepecka@aquila-bm.com.
authors.forename: Justyna
authors.initials: J
authors.lastname: Rzepecka
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Miguel.Pineda@glasgow.ac.uk.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pineda
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: Lamyaa.alriyami@gmail.com.
authors.forename: Lamyaa
authors.initials: L
authors.lastname: Al-Riyami
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: david.t.rodgers@googlemail.com.
authors.forename: David T
authors.initials: DT
authors.lastname: Rodgers
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: j.huggan@strath.ac.uk.
authors.forename: Judith K
authors.initials: JK
authors.lastname: Huggan
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: felicity.lumb@strath.ac.uk.
authors.forename: Felicity E
authors.initials: FE
authors.lastname: Lumb
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: abedawn.khalaf@strath.ac.uk.
authors.forename: Abedawn I
authors.initials: AI
authors.lastname: Khalaf
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Electronic address: p.j.meakin@dundee.ac.uk.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Meakin
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: m.corbet.1@research.gla.ac.uk.
authors.forename: Marlene
authors.initials: M
authors.lastname: Corbet
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Electronic address: m.l.j.ashford@dundee.ac.uk.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Ashford
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: c.j.suckling@strath.ac.uk.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Margaret.Harnett@glasgow.ac.uk.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Harnett
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: w.harnett@strath.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Harnett
mesh_terms: D063486:Acanthocheilonema / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000517:prevention & control; D003094:Collagen; D005849:Gerbillinae; D015801:Helminth Proteins / Q000494:pharmacology*; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D007596:Joints / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D003094:Collagen
keywords: Arthritis; ES-62; IL-1β; Inflammasome; NRF2; Parasitic worm