Exploring the Expanding Role of Nuclear Receptor LRH-1/NR5A2 in Cell Biology and Immunity

LRH-1/NR5A2 is a member of the NR5A subfamily of nuclear receptors, acting as a crucial transcription factor involved in diverse biological processes. Although LRH-1 has been extensively studied in vitro and in vivo, in relation to its role in embryonic development and differentiation and in adult tissue processes, such as cholesterol, glucose, and ethanol metabolism, current knowledge about its function in immunity is very limited. This review, therefore, presents the most recent knowledge regarding NR5A2 regulation and LRH-1 function, including the wide spectrum of its target genes. In addition to LRH-1 regulating steroidogenesis in tissues such as the ovaries, testes, pancreas, and breast adipocytes, it is also key in driving glucocorticoid production in intestine, where its immunomodulatory activity is undoubtedly important in maintaining gut homeostasis and countering inflammation. Likewise, LRH-1 also appears to be crucial to the enterohepatic circulation, regulating hepatic bile acid synthesis and secretion, and intestinal transport/reabsorption. Our review also highlights fundamental roles for LRH-1 in macrophage polarization and in T cell homeostasis, revealing a major role in Th2 immune responses. Although no studies to date have explored the association of LRH-1 with respect to B-lymphocyte biology, we highlight the need for understanding its wider role in the immune system and its interplay with tissues and organs in health and disease.