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.

Sexual dimorphism in autoimmunity

“…Moreover, female but not male EAE-induced SJL mice treated with the S1PR2 antagonist JTE-013 exhibited decreased disease severity. In addition, increased levels of S1PR2 were also detected in the CNS of female patients with MS when compared with male patients or healthy controls (60).…”

“…Another recent study reports sex differences in the expression of sphingosine-1-phosphate receptor 2 (S1PR2) (60). S1PRs are GPCRs expressed in endothelium and other tissues that regulate cell survival, adherens junction assembly, migration, and barrier integrity (61)(62)(63).…”

“…Several studies have indicated their role in vascular biology (64)(65)(66). Using the EAE mouse model for human MS, Cruz-Orengo and colleagues recently suggested a role for S1PR2 in MS (60). SJL mice injected with a myelin oligodendrocyte G peptide develop EAE, and female mice are more susceptible to the disease than males.…”

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

“…MS has a much higher incidence in females than in males. S1P 2 has been determined to account for differences in the enhanced disease susceptibility of female SJL EAE mice by virtue of its sexually dimorphic expression pattern in brain regions relevant to disease (86). In female SJL EAE mice and in female patients with MS, S1P 2 was more highly expressed than in their male counterparts.…”

TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

“…The reasons for differences between females and males in autoimmune disease susceptibility remain an enigma. Sex hormones, the presence or absence of a second X chromosome, microbiota, and disruption at the bloodspinal cord and blood-brain barriers have been implicated as contributing factors (56)(57)(58). Although progress has been made in identifying the genetic determinants of autoimmunity (59), advances in identifying how sex hormones, microbiota, and their interactions with the immune system influence gender-bias autoimmunity remain limited.…”