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Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells.

ABSTRACT: The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.

SUBMITTER: Bos AV

PROVIDER: S-EPMC8298001 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Vitamin A and immune function: retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells.

Project description:Vitamin A and its active metabolite, all-trans retinoic acid (RA), regulate the antibody response in vivo, although the underlying mechanisms are not well understood. We have investigated the regulation by RA of B cell population dynamics and Ig gene expression in purified splenic mouse B cells stimulated through the B cell antigen receptor (BCR) and/or CD38, a BCR coreceptor. After ligation of the BCR and/or CD38, B cells became more heterogeneous in size. RA substantially restrained this change, concomitant with inhibition of cell proliferation. To examine B cell heterogeneity more closely, we categorized stimulated B cells by size (forward angle light scatter) and determined cell division dynamics, germ-line Ig heavy chain gene transcription and surface IgG1 (sIgG1) expression. Flow cytometric analysis of carboxyfluorescein diacetate succinimidyl ester-labeled B cells costained for sIgG1 showed that the more proliferative groups of B cells were smaller, whereas cells expressing more sIgG1 were larger. RA enriched the latter population, whereas cell division frequency in general and the number of smaller B cells that had undergone division cycles were reduced. Although RA significantly inhibited Ig germ-line transcript levels in the total B cell population, CD19(-)IgG1(+) B cells, which represent a more differentiated phenotype, were enriched. Furthermore, pax-5 mRNA was decreased and activation-induced cytidine deaminase mRNA was increased in RA-treated stimulated B cells. Thus, RA regulated factors known to be required for Ig class switch recombination and modulated the population dynamics of ligation-stimulated B cells, while promoting the progression of a fraction of B cells into differentiated sIgG-expressing cells.

| S-EPMC1242304 | biostudies-literature

Vitamin effects on the immune system: vitamins A and D take centre stage.

Project description:Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.

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Synergistic effect of retinoic acid and vitamin D analog EB1089-induced apoptosis of hepatocellular cancer cells.

Project description:Previous report showed that leukemia cells' differentiation could be induced by retinoic acid (RA), and prostate cancer cells' proliferation could be inhibited by Vitamin D or its analog. This study aimed to examine whether RA and vitamin D analog EB1089 have synergistic effect on hepatocellular cancer cells' apoptosis. The hepatocellular cancer cell lines' viability was determined by MTT method after treating by RA and EB1089 alone or in combination, cell cycle of SSMC-7721 cell analyzed by FACS, mitochondrial membrane potential of SSMC-7721 under different treatments were detected using MitoTracker Red CMXRos. TUNEL analysis was also used for cell apoptosis detection. Real time-PCR and Western Blot assay were used to detect the expression of Bcl-2 and Bax. Moreover, hepatocellular cancer model was developed by subcutaneously (S.C.) challenging H22 cells to nude mice. In the combination group (10 ?mol/L RA, 10 nmol/L EB1089), the viability of hepatocellular cancer cells decreased significantly compared with drugs used alone (P < 0.05). From the TUNEL analysis, SSMC-7721 cells have a higher apoptotic ratio in the combined drug group than in the groups for which the drugs were used separately. In a hepatocellular cancer model, the tumor weight of H22 tumor bearing mice was more reduced in the combined drug treated group when compared to the groups for which the drugs were used alone (P < 0.05), in addition, significantly prolonged survival was observed. Combination of RA and EB1089 exert synergistic growth inhibition and apoptosis induction on hepatocellular cancers cells.

| S-EPMC3597171 | biostudies-literature

Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells.

Project description:Despite the high prevalence of chronic gastritis caused by Helicobacter pylori, the gastric mucosa has received little investigative attention as a unique immune environment. Here, we analyzed whether retinoic acid (RA), an important homeostatic factor in the small intestinal mucosa, also contributes to gastric immune regulation. We report that human gastric tissue contains high levels of the RA precursor molecule retinol (ROL), and that gastric epithelial cells express both RA biosynthesis genes and RA response genes, indicative of active RA biosynthesis. Moreover, primary gastric epithelial cells cultured in the presence of ROL synthesized RA in vitro and induced RA biosynthesis in co-cultured monocytes through an RA-dependent mechanism, suggesting that gastric epithelial cells may also confer the ability to generate RA on gastric dendritic cells (DCs). Indeed, DCs purified from gastric mucosa had similar levels of aldehyde dehydrogenase activity and RA biosynthesis gene expression as small intestinal DCs, although gastric DCs lacked CD103. In H. pylori-infected gastric mucosa, gastric RA biosynthesis gene expression was severely disrupted, which may lead to reduced RA signaling and thus contribute to disease progression. Collectively, our results support a critical role for RA in human gastric immune regulation.

| S-EPMC4372513 | biostudies-literature

Retinoic Acid: A New Old Friend of IL-17A in the Immune Pathogeny of Liver Fibrosis.

Project description:Despite all the medical advances mortality due to cirrhosis and hepatocellular carcinoma, the end stages of fibrosis, continuously increases. Recent data suggest that liver fibrosis is guided by type 3 inflammation with IL-17A at the top of the line. The storage of vitamin A and its active metabolites, as well as genetics, can influence the development and progression of liver fibrosis and inflammation. Retinoic acid (active metabolite of vitamin A) is able to regulate the differentiation of IL-17A+/IL-22-producing cells as well as the expression of profibrotic markers. IL-17A and its pro-fibrotic role in the liver is the most studied, while the interaction and communication between IL-17A, IL-22, and vitamin A-active metabolites has not been investigated. We aim to update what is known about IL-17A, IL-22, and retinoic acid in the pathobiology of liver diseases.

| S-EPMC8239722 | biostudies-literature

Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian Cancer.

Project description:Vitamin D and its derivatives, acting via the vitamin D receptor (VDR) and retinoic acid-related orphan receptors γ and α (RORγ and RORα), show anticancer properties. Since pathological conditions are characterized by disturbances in the expression of these receptors, in this study, we investigated their expression in ovarian cancers (OCs), as well as explored the phenotypic effects of vitamin D hydroxyderivatives and RORγ/α agonists on OC cells. The VDR and RORγ showed both a nuclear and a cytoplasmic location, and their expression levels were found to be reduced in the primary and metastatic OCs in comparison to normal ovarian epithelium, as well as correlated to the tumor grade. This reduction in VDR and RORγ expression correlated with a shorter overall disease-free survival. VDR, RORγ, and RORα were also detected in SKOV-3 and OVCAR-3 cell lines with increased expression in the latter line. 20-Hydroxy-lumisterol3 (20(OH)L3) and synthetic RORα/RORγ agonist SR1078 inhibited proliferation only in the OVCAR-3 line, while 20-hydroxyvitamin-D3 (20(OH)D3) only inhibited SKOV-3 cell proliferation. 1,25(OH)2D3, 20(OH)L3, and SR1078, but not 20(OH)D3, inhibited spheroid formation in SKOV-3 cells. In summary, decreases in VDR, RORγ, and RORα expression correlated with an unfavorable outcome for OC, and compounds targeting these receptors had a context-dependent anti-tumor activity in vitro. We conclude that VDR and RORγ expression can be used in the diagnosis and prognosis of OC and suggest their ligands as potential candidates for OC therapy.

| S-EPMC7699234 | biostudies-literature

Vitamin A receptors. Retinoic acid binding in ocular tissues.

Project description:Analysis of the sucrose-density-gradient patterns of the 110 000g supernatant fractions of adult and foetal retina and pigment epithelium showed them to contain a limited number of highly specific binding sites ('receptors') for [3H]retinoic acid that sediment at approx. 2S. Binding in pigment epithelium is higher than in any tissue yet reported. A 5S binding component is also observed and is probably due to serum contamination. Fractionation studies indicate that [3H]retinoic acid binding in the retina is lower in the photoreceptor units than in the retinal inner layers. This is in contrast with previous results that show greater [3H]retinol binding in photoreceptors. Studies with dystrophic human and rat retinas, which lack the photoreceptor layers, confirm that [3H]retinoic acid binding is greater in the non-photoreceptor layers of the retina. No specific [3H]retinoic acid binding is found in corneal epithelium, although endothelium and the conjunctiva demonstrate specific 2S binding. Such differences in retinol and retinoic acid binding may indicate different roles for the two compounds in ocular tissues.

| S-EPMC1184197 | biostudies-other

Exit from HSC dormancy is controlled via vitamin A/retinoic acid

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-05-15 | GSE87814 | GEO

A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid.

Project description:The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-γ production, and generation of regulatory T cells (Tregs) by aqueous humor (AH) and identified TGF-β as a critical factor. However, T cell subsets including Foxp3(+) Treg and Th17 were unknown at that time, as was the role of retinoic acid (RA) in Treg induction. Consequently, the effect of the ocular microenvironment on T cell lineage commitment and function, and the role of RA in this process, had not been explored. We now use gene-manipulated mice and highly purified T cell populations to demonstrate that AH suppresses lineage commitment and acquisition of Th1 and Th17 effector function of naive T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted its massive conversion to Foxp3(+) Tregs that expressed CD25, GITR, CTLA-4, and CD103 and were functionally suppressive. TGF-β and RA were both needed and synergized for Treg conversion by AH, with TGF-β-enhancing T cell expression of RA receptor α. Newly converted Foxp3(+) Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-aza-2'-deoxycytidine. In contrast, T cells already committed to effector function were resistant to the suppressive and Treg-inducing effects of AH. We conclude that RA in the eye plays a dual role: in vision and in immune privilege. Nevertheless, primed effector T cells are relatively insensitive to AH, helping to explain their ability to induce uveitis despite an inhibitory ocular microenvironment.

| S-EPMC3186879 | biostudies-literature

Retinoic Acid Mediated Clearance of <i>Citrobacter rodentium</i> in Vitamin A Deficient Mice Requires CD11b+ and T Cells.

Project description:Vitamin A deficiency affects over 250 million preschool-age children worldwide and is associated with increased childhood mortality and risk of developing enteric infections. Vitamin A deficient (A-) mice developed chronic Citrobacter rodentium infection. A single oral dose of retinoic acid (RA) at d7 post-infection was sufficient to induce clearance of the pathogen in A- mice. RA treatment of A- mice induced il17 expression in the colon. In A- mice, colonic IL-17 was primarily produced by CD11b+ cells; however, in A+ mice, the major source of colonic IL-17 was CD4+ T cells. To determine the cellular targets of vitamin A required for host resistance to C. rodentium, mice that express a dominant negative (dn) retinoic acid receptor (RAR) in T cells (T-dnRAR) or macrophage/neutrophils (LysM-dnRAR) were used. T-dnRAR mice had T cells that produced a robust intestinal IL-17 response and for 40% of the mice was enough to clear the infection. The remainder of the T-dnRAR mice developed a chronic infection. A- LysM-dnRAR mice developed early lethal infections with surviving mice becoming chronically infected. RA treatment of A- LysM-dnRAR mice was ineffective for inducing colonic IL-17 or clearing C. rodentium. Retinoid signaling is required in T cells and CD11b+ cells for complete elimination of enteric pathogens.

| S-EPMC6331472 | biostudies-literature

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