Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions

Schwaderer, Juliane; Gaiser, Ann-Kathrin; Phan, Truong San; Delgado, M. Eugenia; Brunner, Thomas

doi:10.1038/cddis.2017.173

Cited by 20 publications

(43 citation statements)

References 39 publications

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“…Of interest, LRH-1 expression was not completely absent, suggesting that the remaining LRH-1 expression is derived from a different cellular source, e.g. as previously shown by us for T cells [32] and others for macrophages [33]. While the inଏammation-driven induction of the steroidogenic enzymes Cyp11b1, Cyp11a1 and Cyp21 was evident in control animals, epithelial-speciଏc deletion of LRH-1 resulted in a signiଏcant reduction of the expression of these enzymes ( Fig.…”

Section: Lrh-1-dependent Expression Of Steroidogenic Enzymes In the Cmentioning

confidence: 52%

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

et al. 2019

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Inଏammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis are devastating chronic immunopathologies of the intestinal mucosa, which are frequently treated by immunosuppressive glucocorticoids. Endogenous glucocorticoids are not only produced by the adrenal glands, but also by the intestinal epithelium. Local glucocorticoid synthesis critically contributes to the immune homeostasis of the intestinal mucosa. As defective intestinal glucocorticoid synthesis has been associated with the development of IBD, we investigated the expression of steroidogenic enzymes and the key transcriptional regulator Liver Receptor Homolog-1 (LRH-1/NR5A2) in ileal and colonic biopsies human pediatric IBD and control patients. Furthermore, the induction of steroidogenic enzymes and their transcriptional regulation by LRH-1 was investigated in a mouse model of experimental colitis. These analyses revealed that colitis-induced expression of steroidogenic enzymes in the murine colon is dependent on the presence of LRH-1, as intestinal deletion of LRH-1 strongly reduced their colitis-induced expression. Similarly, a strong correlation between the expression of LRH-1 and different steroidogenic enzymes was seen in intestinal biopsies of human pediatric patients. Importantly, reduced expression of hydroxysteroid dehydrogenase 11B1 (HSD11B1) was observed in IBD patients compared to control patients, suggesting that defective local reactivation of glucocorticoids could contribute to the pathogenesis of IBD.

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Section: Lrh-1-dependent Expression Of Steroidogenic Enzymes In the Cmentioning

confidence: 52%

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

et al. 2019

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“…More recently expression of LRH-1/NR5A2 was also reported in T lymphocytes, albeit at much lower levels compared to the liver. In these cells, LRH-1/NR5A2 transcriptionally activates the FASLG gene, the product of which binds to the FAS death receptor (CD95) thereby activating the cell-extrinsic apoptosis pathway [103]. The Fas/FasL pathway is a crucial checkpoint to terminate antigen-specific immunity from effector T-cells a function highlighted by the fact that mutations in either FASLG or FAS genes lead to AIDs [104,105].…”

Section: Immune Cellsmentioning

confidence: 99%

“…The Fas/FasL pathway is a crucial checkpoint to terminate antigen-specific immunity from effector T-cells a function highlighted by the fact that mutations in either FASLG or FAS genes lead to AIDs [104,105]. Accordingly, inhibition of LRH-1/NR5A2 blunts FasL expression and abates re-stimulation-mediated suicide of activated murine T-cells, a process contingent on the extrinsic apoptosis pathway [103,106]. Contextually relevant, islet autoreactive CD8+ cytotoxic T-lymphocytes isolated from T1DM patients displayed persistent proliferation with a concomitant reduction in apoptosis susceptibility upon repeated antigen stimulation, an effect mediated by reduced Fas expression levels [107].…”

Section: Immune Cellsmentioning

confidence: 99%

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier

Gauthier

2020

Metabolism

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets the destruction of islet beta-cells resulting in insulin deficiency, hyperglycemia and death if untreated. Despite advances in medical devices and longer-acting insulin, there is still no robust therapy to substitute and protect beta-cells that are lost in T1DM. Attempts to refrain from the autoimmune attack have failed to achieve glycemic control in patients highlighting the necessity for a paradigm shift in T1DM treatment. Paradoxically, beta-cells are present in T1DM patients indicating a disturbed equilibrium between the immune attack and beta-cell regeneration reminiscent of unresolved wound healing that under normal circumstances progression towards an anti-inflammatory milieu promotes regeneration. Thus, the ultimate T1DM therapy should concomitantly restore immune self-tolerance and replenish the beta-cell mass similar to wound healing. Recently the agonistic activation of the nuclear receptor LRH-1/ NR5A2 was shown to induce immune self-tolerance, increase beta-cell survival and promote regeneration through a mechanism of alpha-to-beta cell phenotypic switch. This trans-regeneration process appears to be facilitated by a pancreatic anti-inflammatory environment induced by LRH-1/NR5A2 activation. Herein, we review the literature on the role of LRH1/NR5A2 in immunity and islet physiology and propose that a cross-talk between these cellular compartments is mandatory to achieve therapeutic benefits.

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“…Although the role of LRH-1 in cells from hematopoietic cells is mostly unexplored, its expression appears not to be restricted to the macrophage lineage. We previously have shown that immature and mature T cells express LRH-1, which is further induced upon T cell activation 12 . A more recent publication highlights the critical role of LRH-1 in T cell maturation and functions 13 .…”

Section: Introductionmentioning

confidence: 98%

“…Specific depletion of LRH-1 in T cells strongly reduced their activation-induced proliferation, resulting in the impaired induction of T cell-regulated immune responses 13 . Importantly, we identified the tumor necrosis factor (TNF) family member Fas ligand (FasL, CD95L) as an LRH-1-regulated target gene 12 . Pharmacological inhibition of LRH-1 not only resulted in reduced activationinduced FasL transcription and protein expression but also in attenuated FasL-mediated effector functions in T cells, such as cell-mediated cytotoxicity and activationinduced cell death.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

et al. 2020

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Liver receptor homolog-1 (LRH-1, Nr5a2) is an orphan nuclear receptor mainly expressed in tissues of endodermal origin, where its physiological role has been extensively studied. LRH-1 has been implicated in liver cell differentiation and proliferation, as well as glucose, lipid, and bile acid metabolism. In addition, increasing evidence highlights its role in immunoregulatory processes via glucocorticoid synthesis in the intestinal epithelium. Although the direct function of LRH-1 in immune cells is fairly elucidated, a role of LRH-1 in the regulation of macrophage differentiation has been recently reported. In this study, we aimed to investigate the role of LRH-1 in the regulation of pro-inflammatory cytokine production in macrophages. Our data demonstrate that pharmacological inhibition, along with LRH-1 knockdown, significantly reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in the macrophage line RAW 264.7 cells, as well as in primary murine macrophages. This inhibitory effect was found to be independent of defects of LRH-1-regulated cell proliferation or toxic effects of the LRH-1 inhibitors. In contrast, LRH-1 inhibition reduced the mitochondrial ATP production and metabolism of macrophages through downregulation of the LRH-1 targets glucokinase and glutminase-2, and thus impairing the LPS-induced macrophage activation. Interestingly, in vivo pharmacological inhibition of LRH-1 also resulted in reduced tumor necrosis factor (TNF) production and associated decreased liver damage in a macrophage-and TNF-dependent mouse model of hepatitis. Noteworthy, despite hepatocytes expressing high levels of LRH-1, pharmacological inhibition of LRH-1 per se did not cause any obvious liver damage. Therefore, this study proposes LRH-1 as an emerging therapeutic target in the treatment of inflammatory disorders, especially where macrophages and cytokines critically decide the extent of inflammation.

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Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions

Cited by 20 publications

References 39 publications

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

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