LRH-1/NR5a2 in regulation of the immune system

Abstract

The orphan nuclear receptor Liver receptor homolog-1 (LRH-1/NR5a2) is involved in the regulation of development, lipid metabolism and proliferation, and is predominantly expressed in epithelial tissues. However, its expression in immune cells and its function in immune regulation is currently poorly understood. Here, LRH-1 expression in primary and secondary lymphatic tissues, as well as in mature CD4+ and CD8+ T cells, was examined. Based on in silico analysis, potential LRH-1 binding sites within the promoter of CD95/Fas ligand (FasL), an apoptosis-inducing ligand and regulator of immune cell homeostasis and cytotoxicity, were identified. LRH-1 directly binds to its binding sites in the FASLG promoter and thereby drives FASLG transcription. Furthermore, mutations in the LRH-1 binding sites reduce FASLG promoter activity. Pharmacological inhibition of LRH-1 decreased activation-induced FasL mRNA expression, as well as FasL-mediated activation-induced T cell apoptosis and cytotoxicity. Moreover, in a mouse model of Concanavalin A-induced and FasL-mediated hepatitis, pharmacological inhibition of LRH-1 resulted in decreased hepatic FasL expression and a significant reduction of associated liver damage. Also in cells of the innate immune system, i.e. macrophages, pharmacological LRH-1 inhibition illustrated a regulatory function on the toll-like receptor-induced expression of pro-inflammatory cytokines, such as TNFα, IL-6, and IL-1 and the respiratory capacity. In summary, these data describe different regulatory roles of LRH-1 in T cells and macrophages, and reveal important insights into the potential of pharmacological intervention of LRH-1 in immunopathologies.