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Vitamin D Therapy in Experimental Allergic Encephalomyelitis Could be Limited by Opposing Effects of Sphingosine 1-Phosphate and Gelsolin Dysregulation

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Abstract

Several studies support a protective effect of vitamin D on multiple sclerosis and experimental allergic encephalomyelitis (EAE), but the mechanisms of these favorable effects are unclear. Our study demonstrates that sphingosine 1-phosphate (S1P) is upregulated in the serum and spinal cords of EAE rats, but that vitamin D reverses the upregulation to alleviate inflammation. Vitamin D, however, cannot prevent the disease process, suggesting that other factors may be involved. To identify additional factors that might limit vitamin D efficacy, we assessed the effects of vitamin D on plasma gelsolin (pGSN), a regulator of S1P that is downregulated in the CSF of MS patients. Our results show that pGSN is downregulated in the serum of EAE rats, whereas its cellular form, cytoplasmic gelsolin (cGSN), is upregulated in the spinal cord of EAE rats. Importantly, vitamin D causes a downregulation of both pGSN and cGSN, which may counteract the positive effects of S1P decrease. Furthermore, 48 and 42 kDa caspase-3 cleavage products of cGSN are detected in EAE spinal cords, suggesting enhanced apoptotic activity, but these cleaved products undergo a similar decrease upon vitamin D treatment. To directly test the role of cGSN in the apoptotic process, we performed RNA interference in PC-12, a rat sympathetic nerve cell line. Results verify that cGSN suppresses apoptosis induced by TNF-α. Collectively, these results support a therapeutic effect of vitamin D that is derived from its ability to reduce S1P, but is limited by its simultaneous effect in reducing pGSN and cGSN. Based on these observations, we postulate that combined therapy with recombinant human pGSN and vitamin D may produce more beneficial effect in treating multiple sclerosis.

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Abbreviations

Caspase-3:

Cysteinyl aspartate-specific protease-3

cGSN:

Cytoplasmic gelsolin

CSF:

Cerebrospinal fluid

EAE:

Experimental allergic encephalomyelitis

GSN:

Gelsolin

MS:

Multiple sclerosis

OND:

Neurological disorder other than MS

pGSN:

Plasma gelsolin

S1P:

Sphingosine 1-phosphate

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Acknowledgments

This work was supported by National Natural Science Foundation of China Grant 81070952 and 81271319.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China

    Yanyan Zhu, Jifang Gao & Shilian Liu

  2. Laboratory of Systems Biology, Institutes of Biomedical Sciences, Fudan University, 138# Medical School Road, Shanghai, 200032, China

    Zhaoyu Qin

  3. Institutes of Biochemistry and Molecular Biology, School of Life Science, Shandong University, 27# Shanda Nan Road, Jinan, 250100, Shandong, China

    Mingchong Yang

  4. Department of Neurology, Qilu Hospital of Shandong University, 107# Wenhua Xi Road, Jinan, 250012, Shandong, China

    Yanjiang Qin

  5. School of Medicine and Life Science, University of Jinan, 106# Jiwei Road, Jinan, 250022, Shandong, China

    Ting Shen

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  1. Yanyan Zhu
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Correspondence to Shilian Liu.

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Yanyan Zhu and Zhaoyu Qin contributed equally to this work.

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Supplementary Fig. 1

Establishment of the EAE rat model. A, The weight of EAE rats decreases between days 9 and 14 after MBP injection and gradually increases after day15. However, the weight of control rats gradually and consistently increases. B, Disease symptoms were monitored over 25 days of EAE induction. The symptom emerged at approximately day10, peaked on the day 13, and disappeared at day19. C, Pathological section of inflammatory lesions stained with hematoxylin and eosin. No obvious inflammation was observed in the cerebrum of control (C-I) or acute stage EAE (C-II) rats; or in the spinal cord of control (C-III) or pre-stage (C-IV) rats. However, the spinal cord of EAE rats in the acute stage (C-V) developed serious lesions. (×400 magnification, scale bar 10 μm) (GIF 26 kb)

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Zhu, Y., Qin, Z., Gao, J. et al. Vitamin D Therapy in Experimental Allergic Encephalomyelitis Could be Limited by Opposing Effects of Sphingosine 1-Phosphate and Gelsolin Dysregulation. Mol Neurobiol 50, 733–743 (2014). https://doi.org/10.1007/s12035-014-8686-9

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