Abstract
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.
Highlights
The liver receptor homolog-1 (LRH-1/Nr5a2) belongs to the Ftz-F1 subfamily of nuclear receptors and is predominantly expressed in enterohepatic tissues of both, Official journal of the Cell Death Differentiation AssociationSchwaderer et al Cell Death and Disease (2020)11:154 the regulation of the local immune homeostasis[8,9]
Given that activated macrophages are a rich source of cytokines implicated in the initiation of inflammatory responses, we aimed to investigate the effect of pharmacological inhibition of LRH-1 in the activation-induced production of proinflammatory cytokines
RAW 264.7 cells showed a clear endogenous LRH-1 transcriptional activity as measured by an LRH-1 activity luciferase reporter[14], which was significantly reduced by the LRH-1 inhibitor 3d2 (Fig. 1b). 3d2 is a small inhibitor identified in a chemical screen and has been shown to directly bind to the ligandbinding domain of this nuclear receptor, stabilizing its inactive conformation and selectively preventing its transcriptional activity[15]
Summary
The liver receptor homolog-1 (LRH-1/Nr5a2) belongs to the Ftz-F1 subfamily of nuclear receptors and is predominantly expressed in enterohepatic tissues of both, Official journal of the Cell Death Differentiation AssociationSchwaderer et al Cell Death and Disease (2020)11:154 the regulation of the local immune homeostasis[8,9]. Pharmacological inhibition of LRH-1 resulted in reduced activationinduced FasL transcription and protein expression and in attenuated FasL-mediated effector functions in T cells, such as cell-mediated cytotoxicity and activationinduced cell death. Pharmacological inhibition of LRH-1 decreased the concanavalin A-induced FasL expression in vivo, resulting in a strong protection from FasL-mediated liver cell apoptosis and associated hepatitis[12]. These studies demonstrate the presence and relevance of LRH-1 in the immune cell activation and effector function of hematopoietic cells but they suggest this nuclear receptor as an interesting therapeutic target in the treatment of immunopathological diseases
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