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Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions

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Abstract

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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Funding

This study was supported in part by 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 grants (to L.N.N.).

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Authors and Affiliations

  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

    Zafrul Hasan, Toan Q. Nguyen, Jovi Hui Xin Wong, Caleb Cheng Yi Wong, Clarissa Kai Hui Tan & Long N. Nguyen

  2. Department of Pharmacology, Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, Singapore

    Brenda Wan Shing Lam

  3. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

    Jiabo Yu, Chung Hwee Thiam, Yongliang Zhang & Veronique Angeli

  4. Life Sciences Institute, Singapore Lipidomics Incubator (SLING), National University of Singapore, Singapore, 117456, Singapore

    Long N. Nguyen

  5. Cardiovascular Disease Research (CVD) Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore

    Long N. Nguyen

  6. Life Sciences Institute, Immunology Program, National University of Singapore, Singapore, 117456, Singapore

    Jiabo Yu, Chung Hwee Thiam, Yongliang Zhang, Veronique Angeli & Long N. Nguyen

  7. Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore

    Jiabo Yu, Chung Hwee Thiam, Yongliang Zhang, Veronique Angeli & Long N. Nguyen

  8. Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh

    Zafrul Hasan

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Contributions

ZH designed and performed in vivo experiments and ex vivo experiments. TQN performed lipidomic analysis and in vivo experiments. BWSL and JW performed IF staining. CKHT assisted with Evans blue leakage. CCYW assisted with H&E staining. CHT collected lymph. JY helped with EAE experiments. VA supervised CHT. YZ supervised JY. LNN conceived and designed the study and performed confocal imaging. LNN and ZH prepared the figures and wrote the paper. We thank other NNL lab members for kind assistance with experiments in this project.

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Correspondence to Long N. Nguyen.

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Hasan, Z., Nguyen, T.Q., Lam, B.W.S. et al. Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions. Cell. Mol. Life Sci. 79, 541 (2022). https://doi.org/10.1007/s00018-022-04573-y

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