Sphingosine-1-Phosphate Signaling in the Inflamed Brain

Lay Summary

Imaging may reveal potential new targets for Multiple Sclerosis therapies

Investigators anticipate that cellular imaging techniques in a multiple sclerosis mouse model will enable them to identify the signaling that drives immune cell infiltration and inflammation in autoimmune multiple sclerosis (MS) and assess whether this signaling can be disrupted.

MS is an autoimmune disease in which the body’s immune cells mistake nerve cells in the brain and spinal cord (the central nervous system, CNS) as foreign and attack them. The immune cells produce inflammation that destroys myelin, which is the fatty sheath that insulates nerve cell axons (the cells’ communication cables) and interrupts messages traveling from one nerve cell to another. Researchers have found that a molecule called “S1P” drives this inflammatory process in MS. The molecule signals immune cells to travel to the CNS and attack. A drug called Gilenya that blocks S1P signaling was recently approved by the federal Food and Drug Administration to treat MS. While Gilenya is extremely effective in treating MS by targeting the S1P molecule, it is not the drug of choice because it can cause devastating—and sometimes fatal—side-effects. For, not only does the S1P molecule drive the inflammatory process in MS; it also maintains normal heart rate and blood pressure.

The researchers hypothesize that there are specific enzymes that generate development of the S1P molecule within cells in the CNS, and specific “transporters” that move the molecule out of the cells and into spaces in the CNS where the molecules can send signals beckoning immune cells to infiltrate the CNS. They plan to manipulate these enzymes and transporters to change the distribution of the S1P molecules in the CNS and will use confocal microscopy imaging to assess how effective these changes are in disrupting the S1P molecule’s activities. Additionally, they hypothesize that S1P draws immune cells deep into brain tissue where they produce inflammation.

They will use cellular two-photon imaging to see if this is the case. If these hypotheses are correct, the investigators anticipate that: 1) the enzymes and transporters—rather than the S1P molecule—could become targets for MS therapies, thereby avoiding disruption of the molecule’s important roles in maintaining heart rate and blood pressure; and 2) that therapies also could be developed to block S1P from beckoning immune cells deep into the brain. Such therapies could then undergo development for clinical testing following the grant period.

Significance: The research may identify targets for developing improved MS therapies that prevent inflammation without producing potentially hazardous side-effects.

Abstract

Sphingosine-1-phosphate signaling in the inflamed brain

The signaling lipid sphingosine 1-phosphate (S1P) plays a central role in pathogenesis of the autoimmune disease multiple sclerosis (MS). FTY720, a drug that targets 4 of 5 S1P receptors, was approved by the US FDA in 2010 for treatment of relapsing MS; it also has been shown to reduce inflammation in animal models of cerebral ischemia and traumatic injury. Many explanations have been proposed for FTY720’s efficacy. T cells are first activated in the lymph nodes that drain the central nervous system (CNS), and must leave the lymph nodes to travel to the CNS and cause damage. A gradient of S1P guides T cells out of the lymph nodes into circulation; by inhibiting S1P receptor 1 (S1PR1) signaling in T cells, FTY720 blocks T cell exit from lymph nodes and limits disease. However, recent evidence suggests that inhibition of pro-inflammatory S1PR1 signaling in CNS-resident immune cells, particularly astrocytes, is FTY720’s key action. Deletion of S1PR1 in astrocytes substantially reduces the severity of EAE, and in the absence of S1PR1 on astrocytes FTY720 has no measurable effect on disease. Despite its efficacy, FTY720 is prescribed only as a second-line drug because it also modulates S1P signaling in the vasculature and heart, with sometimes fatal side-effects. FTY720’s global effects on immune cell trafficking may further leave patients vulnerable to infection. The goal of the next generation of therapies is to target pro-inflammatory S1P signaling specifically in the CNS. We will (1) delineate where in the CNS S1P is acting, (2) determine what is the source of S1P in the CNS, and (3) ask how blocking S1P signaling in astrocytes limits CNS inflammation.