Role of S1P Signaling in Physiology and Disease

The recognition is that lymphocyte S1PR1 is essential for T and B lymphocyte recirculation and autoreactive adaptive immune cell trafficking has been firmly established with the launch of the first S1PR-targeted drug in 2010 for multiple sclerosis. However, given that S1P receptors play fundamental roles in vascular system, better understanding of S1P functions are needed.

In the adult arterial vasculature, S1PR1 signaling is activated by disturbed flow, which injures the vascular endothelium. The figure  shows that S1PR1 signal in the GFP signaling mouse developed by Proia and co-workers is highly active in endothelial cells at the aortic branch points, which are known to be subjected to disturbed shear forces (Red- VE-Cadherin, Green- S1PR1 signal, Blue- nuclei).  Lack of S1PR1 in the endothelium leads to exaggerated inflammation and injury and exaggerated vascular disease (Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlbäck B,  Kono M, Proia RL, Smith JD, Hla T. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal. 2015 Aug 11;8(389):ra79). The role of other S1P receptors in vascular homeostasis and disease is being investigated using genetic mouse models.

While the role of S1PR1 in adaptive immune cell trafficking is appreciated, we do not know what S1P signaling does to innate immune cells such as neutrophils and monocyte/ macrophages.  We are also studying S1PR function in innate immune response and innate-adpative immune cell cross talk.