Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 11, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-022-04573-y
Keywords
Sphingosine-1-phosphate; S1P transporters; S1P signaling; Neuroinflammation; Multiple sclerosis; Lymphocyte egress
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Funding
- Singapore Ministry of Health's National Research Council [NMRC/OFIRG/0066/20]
- Ministry of Education [MOE2018-T2-1-126, NUHSRO/2022/067/T1, T2EP30221-0012]
- NUSMED-FOS Joint Research Programme on Healthy Brain Aging
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The protein Spns2 is involved in regulating lymphocyte movement and has been shown to have potential as a drug target in autoimmune diseases. This study examined mice with a genetic deletion of Spns2 and found that it affected lymphocyte levels, S1P secretion, and lymph node vasculature. Additionally, these mice were resistant to multiple sclerosis, suggesting that targeting Spns2 could be a promising therapeutic approach for neuroinflammation.
Protein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 (Spns2(-/-)) has been shown to reduce disease severity in several autoimmune disease models. To examine whether Spns2 could be exploited as a drug target, we generated and characterized the mice with postnatal knockout of Spns2 (Spns2-Mx1Cre). Our results showed that Spns2-Mx1Cre mice had significantly low number of lymphocytes in blood and lymphoid organs similar to Spns2(-/-) mice. Lymph but not plasma S1P levels were significantly reduced in both groups of knockout mice. Our lipidomic results also showed that Spns2 releases different S1P species into lymph. Interestingly, lymphatic vessels in the lymph nodes (LNs) of Spns2(-/-) and Spns2-Mx1Cre mice exhibited morphological defects. The structures of high endothelial venules (HEV) in the LNs of Spns2-Mx1Cre mice were disorganized. These results indicate that lack of Spns2 affects both S1P secretion and LN vasculatures. Nevertheless, blood vasculature of these Spns2 deficient mice was not different to controls under homeostasis and vascular insults. Importantly, Spns2-Mx1Cre mice were resistant to multiple sclerosis in experimental autoimmune encephalomyelitis (EAE) models with significant reduction of pathogenic Th17 cells in the central nervous system (CNS). This study suggests that pharmacological inhibition of Spns2 may be exploited for therapeutic applications in treatment of neuroinflammation.
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