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

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.

Overexpression of GSN could decrease inflammation and apoptosis in EAE and may enhance vitamin D therapy on EAE/MS

“…An epidemiological survey has found that there is a close correlation between the incidence of MS and light 34 , and since light is the catalyst of vitamin D synthesis in body, people presume that light affects the levels of vitamin D and thus, affects the incidence of MS 35 . Subsequent experiments present that 25- (OH) 2 D 3 level in MS patients is significantly lower than normal 36, 37 , and animal experiments in EAE prove that dietary supplement of vitamin D during the acute stage of EAE can effectively delay the onset time and alleviate the symptoms, but cannot prevent the development of EAE completely 38 (our previous animal experiments also got the same results 39, 22 ).…”

“…Our previous research proved that increasing the GSN level in rats might have a therapeutic effect on EAE 22 . To determine the effects of GSN in the animal model, we established the EAE model in our laboratory.…”

“…In our former study we demonstrated that vitamin D could delay the onset of EAE, but could not prevent disease, and this limitation might be associated with the decrease of GSN by vitamin D 22 . In order to determine whether a combined therapy of GSN and vitamin D might produce a more beneficial effect in treating MS/EAE, we treated rats with or without vitamin D supplementation during LV-GSN or control lentivirus injection.…”

“…In our previously study, we have found that the therapeutic effect of vitamin D on EAE is derived from its ability to reduce S1P, but on the other hand is limited by its simultaneous effect in reducing pGSN and cGSN 22 . In the current research, we sought to examine the therapeutic effect of GSN on EAE and the relationship between GSN and vitamin D, and finally, to find out whether overexpressed GSN could enhance vitamin D therapy in EAE.…”

“…It is reported that the full-length gelsolin and its C-terminal half mostly have an anti-apoptotic function; in contrast, the N-terminal half of gelsolin potentially plays a pro-apoptotic role 21 ; however, the relationship between cGSN and MS has not yet been reported. Our previous research first suggested that cGSN might play a protective role against apoptosis in the MS process 22 .…”