Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE

Abstract

AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA‐containing immune complex (DNA‐ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA‐ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA‐ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA‐ICs on RelB, IL‐10 and TNF‐α in mDCs. Further analysis indicated that DNA‐ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3‐mediated effects. Co‐culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA‐ICs, including proliferation, downregulation of IL‐10, TGF‐β and upregulation of TNF‐α. Moreover, VitD3 could also reverse the effects of DNA‐IC‐induced imbalance of CD4+ CD127− Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA‐ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA‐ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.