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Autophagy. 2018;14(12):2049-2064. doi: 10.1080/15548627.2018.1495681. Epub 2018 Sep 14.

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

Mylka V1,2,3, Deckers J1,2,3,4, Ratman D1,2,3, De Cauwer L1,2,3, Thommis J1,2,3, De Rycke R4,5,6,7, Impens F2,3,8, Libert C4,5, Tavernier J9,2,3, Vanden Berghe W10, Gevaert K2,3, De Bosscher K1,2,3.

Author information

1
a Receptor Research Laboratories, Nuclear Receptor Lab , Ghent University , Ghent , Belgium.
2
c Department of Biochemistry , VIB-UGent Center for Medical Biotechnology , Ghent , Belgium.
3
d Department of Biochemistry , Ghent University , Ghent , Belgium.
4
f Inflammation Research Center , VIB, Ghent University , Ghent , Belgium.
5
g Department of Biomedical Molecular Biology , Ghent University , Ghent , Belgium.
6
h Department of Plant Systems Biology , VIB , Ghent , Belgium.
7
i Department of Plant Biotechnology and Bioinformatics , Ghent University , Ghent , Belgium.
8
j VIB Proteomics Core , VIB , Ghent , Belgium.
9
b Receptor Research Laboratories, Cytokine Receptor Lab , Ghent University , Ghent , Belgium.
10
e PPES lab Protein Science, Proteomics & Epigenetic Signaling , Department Biomedical Sciences - University of Antwerp , Wilrijk , Belgium.

Abstract

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.

KEYWORDS:

Autophagy; CpdA; NFE2L2/NRF2; SQSTM1/p62; autophagy receptors; glucocorticoids; inflammation

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