IL-10 Signaling Is Essential for 1,25-Dihydroxyvitamin D3-Mediated Inhibition of Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis (MS) results from an aberrant, neuroantigen-specific, T cell-mediated autoimmune response. Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports vitamin D3 synthesis, we proposed that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) may protect against MS. In support of this hypothesis, 1,25-(OH)2D3 strongly inhibited experimental autoimmune encephalomyelitis (EAE). This inhibition required lymphocytes other than the encephalitogenic T cells. In this study, we tested the hypothesis that 1,25-(OH)2D3 might inhibit EAE through the action of IL-10-producing regulatory lymphocytes. We report that vitamin D3 and 1,25-(OH)2D3 strongly inhibited myelin oligodendrocyte peptide (MOG35–55)-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene. Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)2D3 to inhibit EAE. The 1,25-(OH)2D3 also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa. Thus, 1,25-(OH)2D3 may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro-protective functions of sunlight and vitamin D3. In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D3 insufficiency, to increase MS risk and severity.

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

“…Similarly, 1,25-(OH) 2 D 3 -treated Wt male mice had a 7-d delay in EAE onset, 50% reduced EAE incidence, 73% decreased peak severity score, and 90% less cumulative disability than placebo-treated males. These results confirmed our previous results (11,31,32,39).…”

“…However, male and female Wt mice ingesting 1,25-(OH) 2 D 3 had moderate hypercalcemia and weight loss (17 and 25%, respectively). Moderate hypercalcemia and weight loss have not been observed previously at these 1,25-(OH) 2 D 3 doses in Wt mice (32,39,43); we have no explanation as to why they were observed in these experiments. Weight loss (22%) was also observed in female GKO mice ingesting 100 ng/d 1,25-(OH) 2 D 3 ; this was expected because of previous reports of hypercalcemia in Wt mice given this dose (43).…”

“…research, hypercalcemia was neither necessary nor sufficient to inhibit EAE (29,39,49), so hypercalcemia cannot explain EAE inhibition in these experiments. In MS patients, daily 1,25-(OH) 2 D 3 treatments reduced relapses and slowed disease progression, but two patients who did not adhere to dietary calcium restrictions developed hypercalcemia (50).…”

“…Vdr transcript abundance was very low in Foxp3-expressing regulatory T cells (Tregs) (11). Because Vdr low-expressing Treg cells are a minority (,1%) of the infiltrating cells and are fewer in GKO mice than Wt mice at EAE stage 3, and most infiltrating cells are Vdr high-expressing Th1 cells, Th17 cells, and macrophages (32,39,46,47), the reduced Vdr expression in GKO mice is unlikely to be explained by the composition of the cellular infiltrate.…”

1,25‐dihydroxyvitamin D3 promotes IL‐10 production in human B cells

“…At the molecular level, a link between vitamin D and IL-10 is evident. Human serum levels of pro-vitamin D correlate with those of IL-10 [13] and intact IL-10 signaling is essential for the vitamin D-mediated protection in murine experimental autoimmune encephalomyelitis [43].…”