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.
Identifieur interne : 001505 ( Main/Exploration ); précédent : 001504; suivant : 001506Prophylactic 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.
Auteurs : Justyna Rzepecka [Royaume-Uni] ; Miguel A. Pineda [Royaume-Uni] ; Lamyaa Al-Riyami [Royaume-Uni] ; David T. Rodgers [Royaume-Uni] ; Judith K. Huggan [Royaume-Uni] ; Felicity E. Lumb [Royaume-Uni] ; Abedawn I. Khalaf [Royaume-Uni] ; Paul J. Meakin [Royaume-Uni] ; Marlene Corbet [Royaume-Uni] ; Michael L. Ashford [Royaume-Uni] ; Colin J. Suckling [Royaume-Uni] ; Margaret M. Harnett [Royaume-Uni] ; William Harnett [Royaume-Uni]Source :
- Journal of autoimmunity [ 1095-9157 ] ; 2015.
Descripteurs français
- KwdFr :
- Acanthocheilonema (métabolisme), Animaux (MeSH), Anti-inflammatoires (pharmacologie), Arthrite expérimentale (prévention et contrôle), Arthrite expérimentale (traitement médicamenteux), Articulations (anatomopathologie), Articulations (immunologie), Collagène (MeSH), Facteur-2 apparenté à NF-E2 (génétique), Facteur-2 apparenté à NF-E2 (immunologie), Gerbillinae (MeSH), Inflammasomes (immunologie), Inflammation (immunologie), Inflammation (traitement médicamenteux), Interleukine-1 bêta (biosynthèse), Macrophages (immunologie), Mâle (MeSH), Polyarthrite rhumatoïde (prévention et contrôle), Polyarthrite rhumatoïde (traitement médicamenteux), Protéines d'helminthes (pharmacologie), Souris (MeSH), Souris de lignée BALB C (MeSH), Souris de lignée C57BL (MeSH), Souris knockout (MeSH).
- MESH :
- anatomopathologie : Articulations.
- biosynthèse : Interleukine-1 bêta.
- génétique : Facteur-2 apparenté à NF-E2.
- immunologie : Articulations, Facteur-2 apparenté à NF-E2, Inflammasomes, Inflammation, Macrophages.
- métabolisme : Acanthocheilonema.
- pharmacologie : Anti-inflammatoires, Protéines d'helminthes.
- prévention et contrôle : Arthrite expérimentale, Polyarthrite rhumatoïde.
- traitement médicamenteux : Arthrite expérimentale, Inflammation, Polyarthrite rhumatoïde.
- Animaux, Collagène, Gerbillinae, Mâle, Souris, Souris de lignée BALB C, Souris de lignée C57BL, Souris knockout.
English descriptors
- KwdEn :
- Acanthocheilonema (metabolism), Animals (MeSH), Anti-Inflammatory Agents (pharmacology), Arthritis, Experimental (drug therapy), Arthritis, Experimental (prevention & control), Arthritis, Rheumatoid (drug therapy), Arthritis, Rheumatoid (prevention & control), Collagen (MeSH), Gerbillinae (MeSH), Helminth Proteins (pharmacology), Inflammasomes (immunology), Inflammation (drug therapy), Inflammation (immunology), Interleukin-1beta (biosynthesis), Joints (immunology), Joints (pathology), Macrophages (immunology), Male (MeSH), Mice (MeSH), Mice, Inbred BALB C (MeSH), Mice, Inbred C57BL (MeSH), Mice, Knockout (MeSH), NF-E2-Related Factor 2 (genetics), NF-E2-Related Factor 2 (immunology).
- MESH :
- chemical , biosynthesis : Interleukin-1beta.
- chemical , genetics : NF-E2-Related Factor 2.
- chemical , immunology : Inflammasomes, NF-E2-Related Factor 2.
- chemical , pharmacology : Anti-Inflammatory Agents, Helminth Proteins.
- drug therapy : Arthritis, Experimental, Arthritis, Rheumatoid, Inflammation.
- immunology : Inflammation, Joints, Macrophages.
- metabolism : Acanthocheilonema.
- pathology : Joints.
- prevention & control : Arthritis, Experimental, Arthritis, Rheumatoid.
- Animals, Collagen, Gerbillinae, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout.
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.
DOI: 10.1016/j.jaut.2015.04.005
PubMed: 25975491
PubMed Central: PMC4459730
Affiliations:
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Le document en format XML
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Electronic address: abedawn.khalaf@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl</wicri:regionArea><wicri:noRegion>Glasgow G1 1Xl</wicri:noRegion></affiliation></author><author><name sortKey="Meakin, Paul J" sort="Meakin, Paul J" uniqKey="Meakin P" first="Paul J" last="Meakin">Paul J. Meakin</name><affiliation wicri:level="1"><nlm:affiliation>Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 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Electronic address: c.j.suckling@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl</wicri:regionArea><wicri:noRegion>Glasgow G1 1Xl</wicri:noRegion></affiliation></author><author><name sortKey="Harnett, Margaret M" sort="Harnett, Margaret M" uniqKey="Harnett M" first="Margaret M" last="Harnett">Margaret M. Harnett</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Margaret.Harnett@glasgow.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Harnett, William" sort="Harnett, William" uniqKey="Harnett W" first="William" last="Harnett">William Harnett</name><affiliation wicri:level="1"><nlm:affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: w.harnett@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25975491</idno><idno type="pmid">25975491</idno><idno type="doi">10.1016/j.jaut.2015.04.005</idno><idno type="pmc">PMC4459730</idno><idno type="wicri:Area/Main/Corpus">001554</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">001554</idno><idno type="wicri:Area/Main/Curation">001554</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">001554</idno><idno type="wicri:Area/Main/Exploration">001554</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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.</title><author><name sortKey="Rzepecka, Justyna" sort="Rzepecka, Justyna" uniqKey="Rzepecka J" first="Justyna" last="Rzepecka">Justyna Rzepecka</name><affiliation wicri:level="1"><nlm:affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: justyna.rzepecka@aquila-bm.com.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation></author><author><name sortKey="Pineda, Miguel A" sort="Pineda, Miguel A" uniqKey="Pineda M" first="Miguel A" last="Pineda">Miguel A. Pineda</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Miguel.Pineda@glasgow.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Al Riyami, Lamyaa" sort="Al Riyami, Lamyaa" uniqKey="Al Riyami L" first="Lamyaa" last="Al-Riyami">Lamyaa Al-Riyami</name><affiliation wicri:level="1"><nlm:affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: Lamyaa.alriyami@gmail.com.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation></author><author><name sortKey="Rodgers, David T" sort="Rodgers, David T" uniqKey="Rodgers D" first="David T" last="Rodgers">David T. Rodgers</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: david.t.rodgers@googlemail.com.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Huggan, Judith K" sort="Huggan, Judith K" uniqKey="Huggan J" first="Judith K" last="Huggan">Judith K. Huggan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: j.huggan@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl</wicri:regionArea><wicri:noRegion>Glasgow G1 1Xl</wicri:noRegion></affiliation></author><author><name sortKey="Lumb, Felicity E" sort="Lumb, Felicity E" uniqKey="Lumb F" first="Felicity E" last="Lumb">Felicity E. Lumb</name><affiliation wicri:level="1"><nlm:affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: felicity.lumb@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation></author><author><name sortKey="Khalaf, Abedawn I" sort="Khalaf, Abedawn I" uniqKey="Khalaf A" first="Abedawn I" last="Khalaf">Abedawn I. Khalaf</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: abedawn.khalaf@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl</wicri:regionArea><wicri:noRegion>Glasgow G1 1Xl</wicri:noRegion></affiliation></author><author><name sortKey="Meakin, Paul J" sort="Meakin, Paul J" uniqKey="Meakin P" first="Paul J" last="Meakin">Paul J. Meakin</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY</wicri:regionArea><wicri:noRegion>Dundee DD1 9SY</wicri:noRegion></affiliation></author><author><name sortKey="Corbet, Marlene" sort="Corbet, Marlene" uniqKey="Corbet M" first="Marlene" last="Corbet">Marlene Corbet</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: m.corbet.1@research.gla.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Ashford, Michael L" sort="Ashford, Michael L" uniqKey="Ashford M" first="Michael L" last="Ashford">Michael L. Ashford</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY</wicri:regionArea><wicri:noRegion>Dundee DD1 9SY</wicri:noRegion></affiliation></author><author><name sortKey="Suckling, Colin J" sort="Suckling, Colin J" uniqKey="Suckling C" first="Colin J" last="Suckling">Colin J. Suckling</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: c.j.suckling@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl</wicri:regionArea><wicri:noRegion>Glasgow G1 1Xl</wicri:noRegion></affiliation></author><author><name sortKey="Harnett, Margaret M" sort="Harnett, Margaret M" uniqKey="Harnett M" first="Margaret M" last="Harnett">Margaret M. Harnett</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Margaret.Harnett@glasgow.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Harnett, William" sort="Harnett, William" uniqKey="Harnett W" first="William" last="Harnett">William Harnett</name><affiliation wicri:level="1"><nlm:affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: w.harnett@strath.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of autoimmunity</title><idno type="eISSN">1095-9157</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acanthocheilonema (metabolism)</term><term>Animals (MeSH)</term><term>Anti-Inflammatory Agents (pharmacology)</term><term>Arthritis, Experimental (drug therapy)</term><term>Arthritis, Experimental (prevention & control)</term><term>Arthritis, Rheumatoid (drug therapy)</term><term>Arthritis, Rheumatoid (prevention & control)</term><term>Collagen (MeSH)</term><term>Gerbillinae (MeSH)</term><term>Helminth Proteins (pharmacology)</term><term>Inflammasomes (immunology)</term><term>Inflammation (drug therapy)</term><term>Inflammation (immunology)</term><term>Interleukin-1beta (biosynthesis)</term><term>Joints (immunology)</term><term>Joints (pathology)</term><term>Macrophages (immunology)</term><term>Male (MeSH)</term><term>Mice (MeSH)</term><term>Mice, Inbred BALB C (MeSH)</term><term>Mice, Inbred C57BL (MeSH)</term><term>Mice, Knockout (MeSH)</term><term>NF-E2-Related Factor 2 (genetics)</term><term>NF-E2-Related Factor 2 (immunology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acanthocheilonema (métabolisme)</term><term>Animaux (MeSH)</term><term>Anti-inflammatoires (pharmacologie)</term><term>Arthrite expérimentale (prévention et contrôle)</term><term>Arthrite expérimentale (traitement médicamenteux)</term><term>Articulations (anatomopathologie)</term><term>Articulations (immunologie)</term><term>Collagène (MeSH)</term><term>Facteur-2 apparenté à NF-E2 (génétique)</term><term>Facteur-2 apparenté à NF-E2 (immunologie)</term><term>Gerbillinae (MeSH)</term><term>Inflammasomes (immunologie)</term><term>Inflammation (immunologie)</term><term>Inflammation (traitement médicamenteux)</term><term>Interleukine-1 bêta (biosynthèse)</term><term>Macrophages (immunologie)</term><term>Mâle (MeSH)</term><term>Polyarthrite rhumatoïde (prévention et contrôle)</term><term>Polyarthrite rhumatoïde (traitement médicamenteux)</term><term>Protéines d'helminthes (pharmacologie)</term><term>Souris (MeSH)</term><term>Souris de lignée BALB C (MeSH)</term><term>Souris de lignée C57BL (MeSH)</term><term>Souris knockout (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Interleukin-1beta</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>NF-E2-Related Factor 2</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Inflammasomes</term><term>NF-E2-Related Factor 2</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-Inflammatory Agents</term><term>Helminth Proteins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Articulations</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Interleukine-1 bêta</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Arthritis, Experimental</term><term>Arthritis, Rheumatoid</term><term>Inflammation</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur-2 apparenté à NF-E2</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Articulations</term><term>Facteur-2 apparenté à NF-E2</term><term>Inflammasomes</term><term>Inflammation</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Inflammation</term><term>Joints</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Acanthocheilonema</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Acanthocheilonema</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Joints</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Anti-inflammatoires</term><term>Protéines d'helminthes</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Arthritis, Experimental</term><term>Arthritis, Rheumatoid</term></keywords><keywords scheme="MESH" qualifier="prévention et contrôle" xml:lang="fr"><term>Arthrite expérimentale</term><term>Polyarthrite rhumatoïde</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Arthrite expérimentale</term><term>Inflammation</term><term>Polyarthrite rhumatoïde</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Collagen</term><term>Gerbillinae</term><term>Male</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Collagène</term><term>Gerbillinae</term><term>Mâle</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris de lignée C57BL</term><term>Souris knockout</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25975491</PMID><DateCompleted><Year>2016</Year><Month>03</Month><Day>24</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-9157</ISSN><JournalIssue CitedMedium="Internet"><Volume>60</Volume><PubDate><Year>2015</Year><Month>Jun</Month></PubDate></JournalIssue><Title>Journal of autoimmunity</Title><ISOAbbreviation>J Autoimmun</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>59-73</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.jaut.2015.04.005</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0896-8411(15)00058-X</ELocationID><Abstract><AbstractText>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. </AbstractText><CopyrightInformation>Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rzepecka</LastName><ForeName>Justyna</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: justyna.rzepecka@aquila-bm.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pineda</LastName><ForeName>Miguel A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Miguel.Pineda@glasgow.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Al-Riyami</LastName><ForeName>Lamyaa</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: Lamyaa.alriyami@gmail.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodgers</LastName><ForeName>David T</ForeName><Initials>DT</Initials><AffiliationInfo><Affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: david.t.rodgers@googlemail.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huggan</LastName><ForeName>Judith K</ForeName><Initials>JK</Initials><AffiliationInfo><Affiliation>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: j.huggan@strath.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lumb</LastName><ForeName>Felicity E</ForeName><Initials>FE</Initials><AffiliationInfo><Affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: felicity.lumb@strath.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Khalaf</LastName><ForeName>Abedawn I</ForeName><Initials>AI</Initials><AffiliationInfo><Affiliation>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: abedawn.khalaf@strath.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Meakin</LastName><ForeName>Paul J</ForeName><Initials>PJ</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Corbet</LastName><ForeName>Marlene</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: m.corbet.1@research.gla.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ashford</LastName><ForeName>Michael L</ForeName><Initials>ML</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Suckling</LastName><ForeName>Colin J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1Xl, UK. Electronic address: c.j.suckling@strath.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Harnett</LastName><ForeName>Margaret M</ForeName><Initials>MM</Initials><AffiliationInfo><Affiliation>Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: Margaret.Harnett@glasgow.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Harnett</LastName><ForeName>William</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address: w.harnett@strath.ac.uk.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>086852</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>E013929</GrantID><Agency>Biotechnology and Biological Sciences Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>18413</GrantID><Agency>Arthritis Research UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>12/0004458</GrantID><Agency>Diabetes UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MC_PC_13063</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>05</Month><Day>11</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Autoimmun</MedlineTA><NlmUniqueID>8812164</NlmUniqueID><ISSNLinking>0896-8411</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000893">Anti-Inflammatory Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C435884">ES-62 protein, Acanthocheilonema viteae</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015801">Helminth Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C587672">IL1B protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D058847">Inflammasomes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D053583">Interleukin-1beta</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051267">NF-E2-Related Factor 2</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C495636">Nfe2l2 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>9007-34-5</RegistryNumber><NameOfSubstance UI="D003094">Collagen</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D063486" MajorTopicYN="N">Acanthocheilonema</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000893" MajorTopicYN="N">Anti-Inflammatory Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001169" MajorTopicYN="N">Arthritis, Experimental</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000517" MajorTopicYN="N">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001172" MajorTopicYN="N">Arthritis, Rheumatoid</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000517" MajorTopicYN="N">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003094" MajorTopicYN="N">Collagen</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005849" MajorTopicYN="N">Gerbillinae</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015801" MajorTopicYN="N">Helminth Proteins</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058847" MajorTopicYN="N">Inflammasomes</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007249" MajorTopicYN="N">Inflammation</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D053583" MajorTopicYN="N">Interleukin-1beta</DescriptorName><QualifierName UI="Q000096" MajorTopicYN="Y">biosynthesis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007596" MajorTopicYN="N">Joints</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008264" MajorTopicYN="N">Macrophages</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018345" MajorTopicYN="N">Mice, Knockout</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051267" MajorTopicYN="N">NF-E2-Related Factor 2</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Arthritis</Keyword><Keyword MajorTopicYN="N">ES-62</Keyword><Keyword MajorTopicYN="N">IL-1β</Keyword><Keyword MajorTopicYN="N">Inflammasome</Keyword><Keyword MajorTopicYN="N">NRF2</Keyword><Keyword MajorTopicYN="N">Parasitic worm</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>03</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2015</Year><Month>04</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>04</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>3</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25975491</ArticleId><ArticleId IdType="pii">S0896-8411(15)00058-X</ArticleId><ArticleId 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IdType="pubmed">19344451</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></pubmed><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Écosse</li></region><settlement><li>Glasgow</li></settlement><orgName><li>Université de Glasgow</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Rzepecka, Justyna" sort="Rzepecka, Justyna" uniqKey="Rzepecka J" first="Justyna" last="Rzepecka">Justyna Rzepecka</name></noRegion><name sortKey="Al Riyami, Lamyaa" sort="Al Riyami, Lamyaa" uniqKey="Al Riyami L" first="Lamyaa" last="Al-Riyami">Lamyaa Al-Riyami</name><name sortKey="Ashford, Michael L" sort="Ashford, Michael L" uniqKey="Ashford M" first="Michael L" last="Ashford">Michael L. Ashford</name><name sortKey="Corbet, Marlene" sort="Corbet, Marlene" uniqKey="Corbet M" first="Marlene" last="Corbet">Marlene Corbet</name><name sortKey="Harnett, Margaret M" sort="Harnett, Margaret M" uniqKey="Harnett M" first="Margaret M" last="Harnett">Margaret M. Harnett</name><name sortKey="Harnett, William" sort="Harnett, William" uniqKey="Harnett W" first="William" last="Harnett">William Harnett</name><name sortKey="Huggan, Judith K" sort="Huggan, Judith K" uniqKey="Huggan J" first="Judith K" last="Huggan">Judith K. Huggan</name><name sortKey="Khalaf, Abedawn I" sort="Khalaf, Abedawn I" uniqKey="Khalaf A" first="Abedawn I" last="Khalaf">Abedawn I. Khalaf</name><name sortKey="Lumb, Felicity E" sort="Lumb, Felicity E" uniqKey="Lumb F" first="Felicity E" last="Lumb">Felicity E. Lumb</name><name sortKey="Meakin, Paul J" sort="Meakin, Paul J" uniqKey="Meakin P" first="Paul J" last="Meakin">Paul J. Meakin</name><name sortKey="Pineda, Miguel A" sort="Pineda, Miguel A" uniqKey="Pineda M" first="Miguel A" last="Pineda">Miguel A. Pineda</name><name sortKey="Rodgers, David T" sort="Rodgers, David T" uniqKey="Rodgers D" first="David T" last="Rodgers">David T. Rodgers</name><name sortKey="Suckling, Colin J" sort="Suckling, Colin J" uniqKey="Suckling C" first="Colin J" last="Suckling">Colin J. Suckling</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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