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1,25-Dihydroxyvitamin D3 Restrains CD4+ T Cell Priming Ability of CD11c+ Dendritic Cells by Upregulating Expression of CD31.

ABSTRACT: Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D modulates DC function remain poorly understood. We investigated the effects of vitamin D on murine CD11c+ bone marrow derived DC (BMDC) function by analyzing global gene expression in CD11c+ BMDC generated in the presence (VitD-CD11c+BMDC) or absence (Veh-CD11c+BMDC) of the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Seven genes were significantly increased in expression in both immature and LPS-matured VitD-CD11c+BMDC, one of which was CD31, a member of the immunoglobulin superfamily. Gene knockdown of CD31 enhanced the ability of VitD-CD11c+BMDC to prime naïve CD4+ T cells in vitro; conversely, increased expression of CD31 on vehicle treated CD11c+BMDC restrained their T cell priming abilities. Time-lapse imaging of BMDC and CD4+ T cells during in vitro priming revealed that CD31 reduced the BMDC-T cell interaction time. Finally, we confirmed a similar effect of 1,25(OH)2D3 on human CD34+ cell-derived CD11c+DC, whereby DC generated in the presence of 1,25(OH)2D3 had increased CD31 expression. In summary, we show that both mouse and human DC generated in the presence of 1,25(OH)2D3 upregulate CD31 expression, resulting in a reduced ability to prime CD4+ T cells by impairing a stable cell-cell contact.

SUBMITTER: Saul L

PROVIDER: S-EPMC6447667 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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1,25-Dihydroxyvitamin D3 Restrains CD4+ T Cell Priming Ability of CD11c+ Dendritic Cells by Upregulating Expression of CD31.

Saul Louise L Mair Iris I Ivens Alasdair A Brown Pamela P Samuel Kay K Campbell John D M JDM Soong Daniel Y DY Kamenjarin Nadine N Mellanby Richard J RJ

Frontiers in immunology 20190328

Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D ...[more]

PMID: 30984180

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Project description:The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3) inhibits the priming step required for NLRP3 inflammasome activation in immune cells. However, as activating the NLRP1 inflammasome in keratinocytes does not necessarily require a priming step, whether 1,25(OH)2VD3 inhibits NLRP1 activation in unprimed keratinocytes is currently unknown. In this study, we showed that 1,25(OH)2VD3 inhibits nigericin-induced NLRP1 inflammasome activation in unprimed keratinocytes. 1,25(OH)2VD3 suppressed nigericin-induced interleukin-1β (IL-1β) secretion and caspase-1 activation in human primary keratinocytes. In addition, 1,25(OH)2VD3 significantly inhibited the formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomers and specks, but not caspase-1 enzymatic activity, suggesting that 1,25(OH)2VD3 prevents NLRP1-ASC complex assembly in keratinocytes. Vitamin D receptor (VDR)-knockdown abolished the inhibitory effects of 1,25(OH)2VD3 on nigericin-induced ASC oligomerization and IL-1β secretion, suggesting that 1,25(OH)2VD3 suppresses inflammasome activation via VDR signaling. Furthermore, nigericin induced K+ efflux and cellular reactive oxygen species (ROS) production, and 1,25(OH)2VD3 pretreatment suppressed nigericin-induced ROS production. 1,25(OH)2VD3 increased the expression of both nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), whereas HO-1 inhibition or NRF2 and HO-1 knockdown abrogated the inhibitory effects of 1,25(OH)2VD3 on IL-1β secretion. Our results indicate that 1,25(OH)2VD3 inhibits nigericin-induced activation step of NLRP1 inflammasome activation in unprimed keratinocytes. Our findings reveal the mechanism underlying the inhibitory effect of 1,25(OH)2VD3, which involves NRF2-HO-1 pathway activation through the VDR, providing further insight into the potential function of 1,25(OH)2VD3 as a therapeutic agent for inflammasome-related skin diseases.

Project description:Fibroblast growth factor 23 (FGF23), a hormone, mainly produced by osteocytes, regulates phosphate and vitamin D metabolism. By contrast, 1,25-dihydroxyvitamin D3, the active form of vitamin D, has been shown to enhance FGF23 production. While it is likely that osteocytes are heterogenous in terms of gene expression profiles, specific subpopulations of Fgf23-expressing osteocytes have not been identified. Single-cell RNA sequencing (scRNA-seq) technology can characterize the transcriptome of an individual cell. Recently, scRNA-seq has been used for bone tissue analysis. However, owing to technical difficulties associated with isolation of osteocytes, studies using scRNA-seq analysis to characterize FGF23-producing osteocytes are lacking. In this study, we characterized osteocytes secreting FGF23 from murine femurs in response to calcitriol (1,25-dihydroxyvitamin D3) using scRNA-seq. We first detected Dmp1, Mepe, and Phex expression in murine osteocytes by in situ hybridization and used these as marker genes of osteocytes. After decalcification, enzyme digestion, and removal of CD45+ cells, femoral bone cells were subjected to scRNA-seq. We identified cell clusters containing osteocytes using marker gene expression. While Fgf23 expression was observed in some osteocytes isolated from femurs of calcitriol-injected mice, no Fgf23 expression was detected in untreated mice. In addition, the expression of several genes which are known to be changed after 1,25-dihydroxyvitamin D3 treatment such as Ccnd2, Fn1, Igfbp7, Pdgfa, and Timp1 was also affected by calcitriol treatment in Fgf23-expressing osteocytes, but not in those lacking Fgf23 expression, even after calcitriol administration. Furthermore, box-and-whisker plots indicated that Fgf23 expression was observed in osteocytes with higher expression levels of the Fam20c, Dmp1, and Phex genes, whose inactivating mutations have been shown to cause FGF23-related hypophosphatemic diseases. These results indicate that osteocytes are heterogeneous with respect to their responsiveness to 1,25-dihydroxyvitamin D3, and sensitivity to 1,25-dihydroxyvitamin D3 is one of the characteristics of osteocytes with Fgf23 expression. It is likely that there is a subpopulation of osteocytes expressing several genes, including Fgf23, involved in phosphate metabolism.

Dataset Information

1,25-Dihydroxyvitamin D3 Restrains CD4+ T Cell Priming Ability of CD11c+ Dendritic Cells by Upregulating Expression of CD31.

Publications

1,25-Dihydroxyvitamin D<sub>3</sub> Restrains CD4<sup>+</sup> T Cell Priming Ability of CD11c<sup>+</sup> Dendritic Cells by Upregulating Expression of CD31.

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