Targeting the S1P receptor signaling pathways as a promising approach for treatment of autoimmune and inflammatory diseases

Abstract

The past two decades of intense research have revealed a key role of the sphingolipid molecule sphingosine 1-phosphate (S1P) in regulating multiple physiological and pathophysiological processes including cell proliferation and survival, cell migration, inflammatory mediator synthesis and tissue remodeling. S1P mainly acts through five high-affinity G protein-coupled S1P receptors, which are ubiquitously expressed and mediate a complex network of signaling in a cell type dependent manner. S1P receptors have become an attractive pharmacological target to interfere with S1P-mediated cellular responses, which contribute to various autoimmune and inflammatory diseases. Pioneering in this field was the synthesis of FTY720 (fingolimod, Gilenya®) from myriocin, one of the metabolites of the fungus Isaria sinclairii known from traditional Chinese medicine for its antibacterial and energy boosting effect. Fingolimod turned out as a very potent immunomodulatory agent that subsequently passed all clinical trials successfully and is now approved for the treatment of relapsing-remitting multiple sclerosis. Pharmacologically, fingolimod was characterized as a non-selective agonist of all of the S1P receptors (S1PR), with the exception of S1P₂, and in addition, as a selective S1P₁ functional antagonist by induction of irreversible S1P₁ internalization and degradation. Since proper lymphocyte trafficking depends on the expression of S1P₁ on lymphocytes, the degradation of S1P₁ leads to trapping and accumulation of lymphocytes in secondary lymphoid tissue, and consequently to a depletion of lymphocytes from the blood. Novel S1PR modulators are now being developed with a more selective receptor activation profile and improved pharmacokinetic characteristics. In this review, we will summarize the state-of-the-art approaches that target directly or indirectly S1P signaling and may be useful as novel strategies to treat autoimmune and inflammatory diseases.

Keywords: Autoimmune diseases; Fingolimod; Inflammation; S1P receptor modulators.