Cruz-Orengo L, Daniels BP, Dorsey D, Basak SA, Grajales-Reyes JG, McCandless EE, Piccio L, Schmidt RE, Cross AH, Crosby SD, Klein RS. Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest. 2014 May 8. pii: 73408
Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described.
We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.
Sphingosine-1-phosphate receptor binds to the sphingosine-1-phosphate receptors. Gilenya works because it modulates sphingosine-1-phosphate one (and others but not really S1P2 receptor). In this study it is suggested that a reason why females may get more autoimmunity is because they have more S1P2 receptor in their blood brain barrier (but it would have to be every where as the enhanced autoimmunity in females is common to all adult onset autoimmunities). This affects the processes that control the (actin) cytoskeleton of the cell, which influence the cell shape and the ability of the blood vessel to allow a cell can migrate through it to get into the brain and also influences the position of a cell attractant called a chemokine called CXCL12. This may be seen as a flag telling white blood cells to enter into the tissue as shown in other studies. Blockade of S1P2 was used to control EAE.
The manufacturers of the many Gilenya me-toos, in the pipeline will be checking to see if their compounds block S1P2, to give it a sales boost.