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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Research Article Autoimmunity

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 8

In vivo S1PR2 inactivation preserves BBB polarity during EAE.

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In vivo S1PR2 inactivation preserves BBB polarity during EAE. Detection ...
Detection of CD31 (green) and CXCL12 (red) within cortices, cerebella, and spinal cords of (A and B) female SJL mice treated with vehicle or JTE-013 (1.5 mg/kg) or (C and D) wild-type and S1pr2–/– mice, all at peak of EAE. (A and C) Nuclei have been stained with Topro3 (blue). Scale bar: 10 μm. Data are representative of approximately 30 images each from 3 to 5 mice per treatment group. Quantification of fluorescence intensity during confocal microscopy for CXCL12 (red lines) and CD31 (green lines) is shown below microphotographs. Arrows indicate location transected in line plot depictions. (B and D) Quantitative analysis of location of CXCL12 expression on CD31+ venules within CNS tissues of (B) vehicle- and JTE-013–treated and (D) wild-type and S1pr2–/– mice at peak of EAE. Data are derived from venules analyzed within 30 images per brain region for 3 to 5 mice per treatment group and are expressed as (mean ± SEM) percentages of vessels with abluminal, lumenal, or absent CXCL12 signal. *P < 0.05; **P < 0.01; ***P < 0.001 for χ2 comparisons between CXCL12 locations within each brain region.