Emerging roles of orphan nuclear receptors in regulation of innate immunity

Innate immunity constitutes the first line of defense against pathogenic and dangerous insults. However, it is a double-edged sword, as it functions in both clearance of infection and inflammatory damage. It is therefore important that innate immune responses are tightly controlled to prevent harmful excessive inflammation. Nuclear receptors (NRs) are a family of transcription factors that play critical roles in various physiological responses. Orphan NRs are a subset of NRs for which the ligands and functions are unclear. Accumulating evidence has revealed that orphan NRs play essential roles in innate immune responses to prevent pathogenic inflammatory responses and to enhance antimicrobial host defenses. In this review, we describe current knowledge on the roles and mechanisms of orphan NRs in the regulation of innate immune responses. Discovery of new functions of orphan NRs would facilitate development of novel preventive and therapeutic strategies against human inflammatory diseases.