Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility
Lillian Cruz-Orengo, … , Seth D. Crosby, Robyn S. Klein
Lillian Cruz-Orengo, … , Seth D. Crosby, Robyn S. Klein
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2571-2584. https://doi.org/10.1172/JCI73408.
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Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

Abstract

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.

Authors

Lillian Cruz-Orengo, Brian P. Daniels, Denise Dorsey, Sarah Alison Basak, José G. Grajales-Reyes, Erin E. McCandless, Laura Piccio, Robert E. Schmidt, Anne H. Cross, Seth D. Crosby, Robyn S. Klein

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Figure 5

S1PR2 inactivation ameliorates EAE and alterations in BBB permeability.

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S1PR2 inactivation ameliorates EAE and alterations in BBB permeability. ...
(A and B) Female SJL mice immunized with PLP139–151 were treated with vehicle or JTE-013 (JTE; 1.5 mg/kg) when mice reached a clinical score of 2. (A) Clinical scores of mice treated for 10 (top) or 30 (bottom) consecutive days ± SEM. Insets show means of cumulative scores (MCS) and of highest severity scores (MHSS) ± SEM for 10 to 15 mice per group. (B) H&E-stained (left panels) and LFB-stained (right panels) sections from spinal cords and cerebella of vehicle- and JTE-treated mice at peak of EAE (top) or remission (bottom). Bar graphs depict mean numbers of white matter lesions (WML) within both CNS regions for either peak or remission ± SEM for 5 to 6 mice per treatment group. Arrows highlight inflammatory foci. Scale bar: 25 μm. (C) Relative BBB permeability of cortex, cerebellum, and spinal cord tissues from vehicle- and JTE-treated mice at peak of EAE or remission. Data are depicted as mean fluorescence intensity, normalized against sera values for individual mice ± SEM for 6 mice per treatment group, with means normalized against mean values for untreated, naive controls. *P < 0.05; **P < 0.01; ***P < 0.001.