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The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages

Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1...

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Autores principales: Mylka, Viacheslav, Deckers, Julie, Ratman, Dariusz, De Cauwer, Lode, Thommis, Jonathan, De Rycke, Riet, Impens, Francis, Libert, Claude, Tavernier, Jan, Vanden Berghe, Wim, Gevaert, Kris, De Bosscher, Karolien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984772/
https://www.ncbi.nlm.nih.gov/pubmed/30215534
http://dx.doi.org/10.1080/15548627.2018.1495681
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author Mylka, Viacheslav
Deckers, Julie
Ratman, Dariusz
De Cauwer, Lode
Thommis, Jonathan
De Rycke, Riet
Impens, Francis
Libert, Claude
Tavernier, Jan
Vanden Berghe, Wim
Gevaert, Kris
De Bosscher, Karolien
author_facet Mylka, Viacheslav
Deckers, Julie
Ratman, Dariusz
De Cauwer, Lode
Thommis, Jonathan
De Rycke, Riet
Impens, Francis
Libert, Claude
Tavernier, Jan
Vanden Berghe, Wim
Gevaert, Kris
De Bosscher, Karolien
author_sort Mylka, Viacheslav
collection PubMed
description Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.
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spelling pubmed-69847722020-02-10 The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages Mylka, Viacheslav Deckers, Julie Ratman, Dariusz De Cauwer, Lode Thommis, Jonathan De Rycke, Riet Impens, Francis Libert, Claude Tavernier, Jan Vanden Berghe, Wim Gevaert, Kris De Bosscher, Karolien Autophagy Research Paper - Basic Science Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy. Taylor & Francis 2018-09-14 /pmc/articles/PMC6984772/ /pubmed/30215534 http://dx.doi.org/10.1080/15548627.2018.1495681 Text en © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Research Paper - Basic Science
Mylka, Viacheslav
Deckers, Julie
Ratman, Dariusz
De Cauwer, Lode
Thommis, Jonathan
De Rycke, Riet
Impens, Francis
Libert, Claude
Tavernier, Jan
Vanden Berghe, Wim
Gevaert, Kris
De Bosscher, Karolien
The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
title The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
title_full The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
title_fullStr The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
title_full_unstemmed The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
title_short The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
title_sort autophagy receptor sqstm1/p62 mediates anti-inflammatory actions of the selective nr3c1/glucocorticoid receptor modulator compound a (cpda) in macrophages
topic Research Paper - Basic Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984772/
https://www.ncbi.nlm.nih.gov/pubmed/30215534
http://dx.doi.org/10.1080/15548627.2018.1495681
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