Sphingosine-1-phosphate and the art of multi-tasking 
The lipid sphingosine-1-phosphate (S1P) plays critical roles in the immune system and in blood vessel development. 

• Mice that cannot produce S1P die at mid-gestation due to a failure of vascular development.

• S1P is an indispensable guidance cue for lymphocyte migration, and thus a novel target for immunosuppressive therapies.  T and B cells continually circulate among lymphoid organs (including lymph nodes, Peyer's patches, and the spleen) situated all over the body, each of which presents pathogens from the local tissue it drains.  Although much is known about how lymphocytes enter lymphoid organs, little is known about how they leave.  Three observations suggest that S1P controls the exit step: (1) lymphocytes require the S1P receptor S1P1 to leave lymphoid organs into circulation (blood or lymph), (2) the concentration of S1P is higher in circulation than in the lymphoid organs, and (3) disrupting S1P compartmentalization by increasing lymphoid organ S1P or decreasing circulatory S1P blocks exit.  These findings suggest a simple model of egress in which the S1P1 receptor guides lymphocytes towards the high S1P concentration in circulation.  Exit-blocking drugs are being developed to interfere with the action of S1P, and one of these drugs, FTY720, is in Phase III clinical trials to treat multiple sclerosis.  Current immune suppressants act by causing a global shutdown in the immune response, leaving patients vulnerable to infection.  Exit-blocking drugs, by contrast, protect the transplanted organ or the organ subject to autoimmune attack by preventing T cells from leaving the lymphoid organs.  Within the lymphoid organs, however, T cells can still respond to some systemic infections.

  Model of lymphocyte egress. Lymphocytes (blue circles) express surface S1P1 when inside the lymphoid tissue, and expression of this receptor is required for exit.  S1P (purple crosses) is maintained at low concentrations in the lymphoid environment in comparison to the high concentration in circulation, and this concentration difference is also required for exit. These findings suggest a simple model of egress is in which the S1P1 receptor guides lymphocytes towards the high S1P concentration in circulation.

• S1P has been implicated in angiogenesis, enabling tumor growth, and in inflammation.  Our research will focus initially on how S1P affects the inflammatory response.

Sphingosine-1-phosphate: Just the right amount
Despite the critical roles of S1P in mammalian biology, we understand little about how its production and distribution are regulated.  Controlling S1P levels is particularly challenging because S1P plays a dual role as an intercellular signaling molecule and as an intracellular metabolic intermediate: all cells are thought to be able to generate S1P in the process of normal sphingolipid turnover.  

A surprising result in our recent work was the finding that lymph S1P is independent of plasma S1P.  Albumin and high density lipoproteins, major S1P carriers, are thought to be supplied to lymph from transudated plasma and are present in lymph at concentrations within a few fold of those in plasma, yet S1P is not carried along.  Hence we will investigate how plasma S1P is removed from tissues.  We previously found that red blood cells are a major source of plasma S1P, but the source of lymph S1P is unknown. We will ask what cells re-supply S1P to lymph.  A third critical unanswered question is how S1P is exported from cells: as a polar lipid, it is predicted not to cross the plasma membrane unassisted. 

Addressing these questions will enhance our understanding of the basic question of how cell signaling molecules are distributed, and give further insight into the biological roles of S1P.