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 1

S1PR2 exhibits sexually dimorphic gene expression within the CNS of naive SJL mice.

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S1PR2 exhibits sexually dimorphic gene expression within the CNS of naiv...
(A) Microarray analysis of S1PR2 and IL-20RB expression within cerebella (CB) (green) of female (red circles) and male (blue circles) littermates demonstrates significant alterations compared with frontal cortices (FCX) (purple). In box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate 10th and 90th percentiles. Data are expressed as fold change ± SEM and as individual values of Illumina probe levels. P < 0.05, ANOVA for sex- and region-specific gene expression (cerebella only). (B) QPCR evaluation of S1PR2 expression in cortices (CTX), cerebella, and spinal cords (SC) of same cohort. Data are expressed as mean S1PR2/GAPDH copies ± SEM for female (red bars) and male (blue bars) samples (n = 5). *P < 0.05, 2-way ANOVA. (C) Western blot analysis of S1PR2 in cortices, cerebella, and spinal cords in male (B6: light blue bars; SJL: blue bars) and female (B6: pink bars; SJL: red bars) C57BL/6 and SJL mice. Data are expressed as mean ± SEM densities normalized to male B6 (n = 5). *P < 0.05, 2-way ANOVA. (D) Male (light and dark blue bars) and female (pink and red bars) naive C57BL/6 and SJL mice were examined for BBB Na-Fluorescein permeability within cortices, cerebella, and spinal cords, normalized to sera values for individual mice (5–8 mice per group). Data are reported as arbitrary fluorescence values, normalized to mean ± SEM values for naive male C57BL/6 in each CNS region. **P < 0.01. (E) Immunohistochemical detection of albumen in cortices, cerebella, and spinal cords of naive female and male SJL mice. Scale bar: 25 μm. Images are representative of 3 images each from 2 to 3 mice per sex.