Abstract
Sphingosine 1-phosphate receptor 1 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 both on S1P1 expressed on lymphocytes and on S1P1 expressed within the central nervous system. Agonists to S1P1 or deficiency in S1P1 both cause lymphocyte sequestration in the lymph nodes. Here 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.
- Received October 12, 2012.
- Revision received November 30, 2012.
- Accepted November 30, 2012.
- The American Society for Pharmacology and Experimental Therapeutics