Sphingosine 1-phosphate receptor type 1 as a novel target for the therapy of autoimmune diseases

Abstract

Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds 5 types of G protein-coupled S1P receptors. It has been well documented that S1P receptor type 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), because lymphocytes are unable to exit from SLO to periphery in mice lacking lymphocytic S1P1 conditionally. FTY720 (fingolimod) is an orally active first-in-class S1P receptor modulator and is highly effective in various experimental autoimmune disease models including encephalomyelitis, adjuvant- or collagen-induced arthritis, and lupus nephritis. FTY720 is a structural analogue of sphingosine and is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P binds to four types of S1P receptors (S1P1, S1P3, S1P4, and S1P5) except for S1P2 and acts as an agonist at these receptors. Particularly, FTY720-P strongly internalizes S1P1 from the cell surface, almost completely inhibits S1P responsiveness of lymphocytes in SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from SLO to decrease circulation of lymphocytes including autoreactive T cells and shows immunomodulating effects on autoimmune disease models. Recently, it has been reported that FTY720 has a superior efficacy in relapsing remitting multiple sclerosis patients compared to interferon-β. From these results, it is presumed that S1P1 is a novel target for the therapy of autoimmune diseases including multiple sclerosis.