The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Hübner, Sabine; Dejager, Lien; Libert, Claude; Tuckermann, Jan

doi:10.1515/hsz-2015-0106

Cited by 49 publications

(38 citation statements)

References 65 publications

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“…In addition to suppressing numerous inflammation-associated genes, GR transcriptionally activates many genes which encode negative regulators of inflammatory factors (Hubner et al, 2015). Among the highly Dex-induced genes from our RNA-seq analysis were such examples as Nfkbia (encoding IκBα), Tnfaip3 (encoding A20), Dusp1 and Dusp6 (encoding dual specificity phosphatases, DUSPs), Tsd22d3 (encoding glucocorticoid-induced leucine zipper, GILZ).…”

Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action

et al. 2017

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Summary Despite the widespread use of glucocorticoids (GCs), their anti-inflammatory effects are not understood mechanistically. Numerous investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinical situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we profiled macrophage transcriptional and chromatinscapes with Dexamethasone (Dex) treatment before or after stimulation by lipopolysaccharide (LPS). The late activation of GR had a similar gene expression profile as from GR pre-activation, while ameliorating the disruption of metabolic genes. Chromatin occupancy of GR was not predictive of Dex-regulated gene expression, contradicting the ‘trans-repression by tethering’ model. Rather, GR activation resulted in genome-wide blockade of NF-κB interaction with chromatin and directly induced inhibitors of NF-κB and AP-1. Our investigation using GC treatments with clinically relevant timing highlights mechanisms underlying GR actions for modulating the ‘inflamed epigenome’.

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Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action

et al. 2017

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“…S5 B, b and f). Thus, the administration of CpdX in vivo could possibly inhibit the induction of the (+)GRE antiinflammatory genes DUSP1 and GILZ by physiological GCs (1,27). This possibility is, however, unlikely as Dex-induced expression of DUSP1 and GILZ is not affected by CpdX addition to A549 cells…”

Section: Which Mechanisms Allow a Single Gr To Exert Three Main Functmentioning

confidence: 99%

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

Hua

Ganti

Chambon

2015

Proc. Natl. Acad. Sci. U.S.A.

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Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GCinduced tethered indirect transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression functions, while still exerting a tethered indirect transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.glucocorticoid receptor | SUMOylation | NF-κB/AP1-mediated GC-induced tethered repression

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“…Glucocorticoids exert profound regulatory effects on components of immunity via different and complex mechanisms and by interfering with several signaling pathways (8). Cell- and tissue-specific and stress-dependent transcriptional responses to glucocorticoids are mediated by the glucocorticoid receptor (GR) (9–11). …”

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confidence: 99%

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

et al. 2017

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Cell- and tissue-specific actions of glucocorticoids are mediated by the glucocorticoid receptor. Here, we demonstrate that the glucocorticoid receptor (GR) in macrophages is essential for cardiac healing after myocardial infarction. Compared with GRflox (wild-type controls), GRLysMCre mice that lacked GR in myeloid cells showed increased acute mortality as a result of cardiac rupture. Seven days after left coronary artery ligation, GRLysMCre mice exhibited worse cardiac function and adverse remodeling associated with impaired scar formation and angiogenic response to ischemic injury. Inactivation of GR altered the functional differentiation/maturation of monocyte-derived macrophages in the infarcted myocardium. Mechanistically, CD45+/CD11b+/Ly6G−/F4/80+ macrophages isolated from GRLysMCre infarcts showed deregulation of factors that control inflammation, neovascularization, collagen degradation, and scar tissue formation. Moreover, we demonstrate that cardiac fibroblasts sorted from the ischemic myocardium of GRLysMCre mice compared with cells isolated from injured GRflox hearts displayed higher matrix metalloproteinase 2 expression, and we provide evidence that the macrophage GR regulates myofibroblast differentiation in the infarct microenvironment during the early phase of wound healing. In summary, GR signaling in macrophages, playing a crucial role in tissue-repairing mechanisms, could be a potential therapeutic target during wound healing after ischemic myocardial injury.—Galuppo, P., Vettorazzi, S., Hövelmann, J., Scholz, C.-J., Tuckermann, J. P., Bauersachs, J., Fraccarollo, D. The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

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The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Cited by 49 publications

References 65 publications

Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action

Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

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