Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Autoimmunity

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

  • Text
  • PDF
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

×

Figure 4

BBB expression of S1PR2 is increased in MS.

Options: View larger image (or click on image) Download as PowerPoint
BBB expression of S1PR2 is increased in MS.
(A) Endothelial cell (CD31, ...
(A) Endothelial cell (CD31, green) and (B) astrocyte (GFAP, green) localization of S1PR2 (red) in female and male cerebellar tissue obtained from patients with and without MS. Nuclei are counterstained with Topro3 (blue). (A) Control stains, in which sections were first blocked with immunogen (1 mg/ml) prior to detection of CD31 (green) and S1PR2 (red), are included. Scale bar: 25 μm. (C) Quantification of amounts of vessel-associated S1PR2 fluorescence in female (red circles) and male (blue circles) samples from patients with and without MS. Levels of S1PR2 fluorescence were determined by examining S1PR2 staining in venule ROIs in 10 images per patient (4–6 patients per group), normalized by area of CD31 staining to control for size and numbers of vessels. Note that the outlier in the male MS group also had a history of occipital head trauma. *P < 0.05. Horizontal bars represent geometric means.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts