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

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

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2571-2584
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014
Externally publishedYes

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Lysosphingolipid Receptors
Autoimmunity
Multiple Sclerosis
Adherens Junctions
Central Nervous System Diseases
Caveolins
Disease Susceptibility
Endocytosis
Permeability
Pharmacology
Incidence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cruz-Orengo, L., Daniels, B. P., Dorsey, D., Basak, S. A., Grajales-Reyes, J. G., McCandless, E. E., ... Klein, R. S. (2014). Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. Journal of Clinical Investigation, 124(6), 2571-2584. https://doi.org/10.1172/JCI73408

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. / Cruz-Orengo, Lillian; Daniels, Brian P.; Dorsey, Denise; Basak, Sarah Alison; Grajales-Reyes, José G.; McCandless, Erin E.; Piccio, Laura; Schmidt, Robert E.; Cross, Anne H.; Crosby, Seth D.; Klein, Robyn S.

In: Journal of Clinical Investigation, Vol. 124, No. 6, 02.06.2014, p. 2571-2584.

Research output: Contribution to journalArticle

Cruz-Orengo, L, Daniels, BP, Dorsey, D, Basak, SA, Grajales-Reyes, JG, McCandless, EE, Piccio, L, Schmidt, RE, Cross, AH, Crosby, SD & Klein, RS 2014, 'Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility', Journal of Clinical Investigation, vol. 124, no. 6, pp. 2571-2584. https://doi.org/10.1172/JCI73408
Cruz-Orengo, Lillian ; Daniels, Brian P. ; Dorsey, Denise ; Basak, Sarah Alison ; Grajales-Reyes, José G. ; McCandless, Erin E. ; Piccio, Laura ; Schmidt, Robert E. ; Cross, Anne H. ; Crosby, Seth D. ; Klein, Robyn S. / Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 6. pp. 2571-2584.
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