Sphingosine 1-Phosphate Receptor 1 (S1P1) Upregulation and Amelioration of Experimental Autoimmune Encephalomyelitis by an S1P1 Antagonist

Sphingosine 1-phosphate receptor 1 (S1P1) is a G protein–coupled receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P1 are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P1 expressed on lymphocytes and S1P1 expressed within the central nervous system. Agonists to S1P1 and deficiency in S1P1 both cause lymphocyte sequestration in the lymph nodes. In the present study, we show that S1P1 antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P1 agonists while upregulating S1P1 on lymphocytes and endothelial cells. Additionally, we show that S1P1 antagonism reverses experimental autoimmune encephalomyelitis in mice without acting on S1P1 expressed within the central nervous system, demonstrating that lymphocyte sequestration via S1P1 antagonism is sufficient to alleviate autoimmune pathology.