Emerging roles of a chemoattractant receptor GPR15 and ligands in pathophysiology

Chemokine receptors play a central role in the maintenance of immune homeostasis and development of inflammation by directing leukocyte migration to tissues. GPR15 is a G protein-coupled receptor (GPCR) that was initially known as a co-receptor for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), with structural similarity to other members of the chemoattractant receptor family. Since the discovery of its novel function as a colon-homing receptor of T cells in mice a decade ago, GPR15 has been rapidly gaining attention for its involvement in a variety of inflammatory and immune disorders. The recent identification of its natural ligand C10orf99, a chemokine-like polypeptide strongly expressed in gastrointestinal tissues, has established that GPR15-C10orf99 is a novel signaling axis that controls intestinal homeostasis and inflammation through the migration of immune cells. In addition, it has been demonstrated that C10orf99-independent functions of GPR15 and GPR15-independent activities of C10orf99 also play significant roles in the pathophysiology. Therefore, GPR15 and its ligands are potential therapeutic targets. To provide a basis for the future development of GPR15- or GPR15 ligand-targeted therapeutics, we have summarized the latest advances in the role of GPR15 and its ligands in human diseases as well as the molecular mechanisms that regulate GPR15 expression and functions.