title: 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.forename: Lillian
authors.initials: L
authors.lastname: Cruz-Orengo
authors.forename: Brian P
authors.initials: BP
authors.lastname: Daniels
authors.forename: Denise
authors.initials: D
authors.lastname: Dorsey
authors.forename: Sarah Alison
authors.initials: SA
authors.lastname: Basak
authors.forename: José G
authors.initials: JG
authors.lastname: Grajales-Reyes
authors.forename: Erin E
authors.initials: EE
authors.lastname: McCandless
authors.forename: Laura
authors.initials: L
authors.lastname: Piccio
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Anne H
authors.initials: AH
authors.lastname: Cross
authors.forename: Seth D
authors.initials: SD
authors.lastname: Crosby
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012727:Sex Characteristics; D013045:Species Specificity; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse