期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 6, 页码 2571-2584出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73408
关键词
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资金
- NIH/National Institute of Neurological Disorders and Stroke [R01 NS052632, P01 NS059560]
- Multiple Sclerosis Society
- National Science Foundation Graduate Research Fellowship [DGE-1143954]
- Ruth L. Kirschstein Postdoctoral National Research Service Award [1F32NS0748424]
- National Cancer Institute Cancer Center Support [P30 CA91842]
- Institute of Clinical and Translational Sciences/Clinical and Translational Science Award from National Center for Research Resources (NCRR) [UL1 TR000448]
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.
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