scholarly journals Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

2015 ◽  
Vol 95 (1) ◽  
pp. 125-148 ◽  
Author(s):  
Yanxia Guo ◽  
Chrysothemis Brown ◽  
Carla Ortiz ◽  
Randolph J. Noelle
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Immune Cell ◽  
Active Form ◽  
Cell Lineage ◽  
Vitamin A Metabolism ◽  
Immune Cell Subsets ◽  
Development And Differentiation ◽  
And Function ◽  
Leukocyte Homing

Although vitamin A was recognized as an “anti-infective vitamin” over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell- and humoral-mediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Amelie V. Bos ◽  
Martje N. Erkelens ◽  
Sebastiaan T.A. Koenders ◽  
Mario van der Stelt ◽  
Marjolein van Egmond ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
B Cells ◽  
Vitamin A ◽  
Immune Cells ◽  
Immune Cell ◽  
Human Monocyte ◽  
Valuable Insight ◽  
Vitamin A Metabolism ◽  
Cd38 Expression ◽  
Human Immune

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.

scholarly journals Normalization of enzyme expression and activity regulating vitamin A metabolism increases RAR-beta expression and reduces cellular migration and proliferation in diseases caused by tuberous sclerosis gene mutations

2020 ◽  
Author(s):  
ElHusseiny MM Abdelwahab ◽  
Judit Bovari-Biri ◽  
Gabor Smuk ◽  
Tunde Harko ◽  
Janos Fillinger ◽  
...  
Keyword(s):  
Cell Migration ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Tuberous Sclerosis ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Cellular Migration ◽  
Immunofluorescent Staining ◽  
Vitamin A Metabolism ◽  
Expression And Activity

Abstract Background Mutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters cellular including vitamin A metabolism and retinoic acid receptor beta (RARβ) expression. The goal of the present study was to investigate the molecular connection between vitamin A metabolism and TSC mutation. We also aimed to investigate the effect of the FDA approved drug rapamycin and the vitamin A metabolite retinoic acid (RA) in cell lines with TSC mutation. Methods Expression and activity of vitamin A associated metabolic enzymes and RARβ were assessed in human kidney angiomyolipoma derived cell lines, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines as well as RARβ protein levels were tested in primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining and western blotting were performed and analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch and a BrDU assay to assess cell migration and proliferation. Results Metabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cell lines and primary tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised ALDH and ADH expression and activity, restored RARβ expression and reduced cellular proliferation and migration. Conclusion Deregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit cell migration, but does not have a significant effect on proliferation. Based on our data, translational studies could confirm whether combination of RA with reduced dosage of rapamycin would have more beneficial effects to higher dosage of rapamycin monotherapy meanwhile reducing adverse effects of rapamycin for patients with TSC mutation.

scholarly journals Specific phenotype and function of CD56-expressing innate immune cell subsets in human thymus

2016 ◽  
Vol 100 (6) ◽  
pp. 1297-1310 ◽  
Author(s):  
Stephanie Gerstner ◽  
Wolfgang Köhler ◽  
Gordon Heidkamp ◽  
Ariawan Purbojo ◽  
Shizuka Uchida ◽  
...  
Keyword(s):  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Human Thymus ◽  
Immune Cell Subsets ◽  
And Function

scholarly journals RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism and retinoic acid synthesis

2011 ◽  
Vol 357 (2) ◽  
pp. 347-355 ◽  
Author(s):  
Krysten M. Farjo ◽  
Gennadiy Moiseyev ◽  
Olga Nikolaeva ◽  
Lisa L. Sandell ◽  
Paul A. Trainor ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Acid Synthesis ◽  
Vitamin A Metabolism

scholarly journals MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Tingting Liu ◽  
Jie Wang ◽  
Kalpana Subedi ◽  
Qijun Yi ◽  
Li Zhou ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
Loss Of Function ◽  
Mait Cells ◽  
Cellular Processes ◽  
Individual Mirnas ◽  
Maturation Stages ◽  
And Function ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

scholarly journals Regulatory T cells in inflammatory skin disease: from mice to humans

2019 ◽  
Vol 31 (7) ◽  
pp. 457-463 ◽  
Author(s):  
Lokesh A Kalekar ◽  
Michael D Rosenblum
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Critical Role ◽  
Cutaneous Lupus Erythematosus ◽  
The Body ◽  
Immune Cell Subsets ◽  
Organ Repair ◽  
And Function

Abstract The skin is the largest organ in the body and one of the primary barriers to the environment. In order to optimally protect the host, the skin is home to numerous immune cell subsets that interact with each other and other non-immune cells to maintain organ integrity and function. Regulatory T cells (Tregs) are one of the largest immune cell subsets in skin. They play a critical role in regulating inflammation and facilitating organ repair. In doing so, they adopt unique and specialized tissue-specific functions. In this review, we compare and contrast the role of Tregs in cutaneous immune disorders from mice and humans, with a specific focus on scleroderma, alopecia areata, atopic dermatitis, cutaneous lupus erythematosus and psoriasis.

Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency

2004 ◽  
Vol 286 (2) ◽  
pp. L437-L444 ◽  
Author(s):  
Stephen E. McGowan ◽  
Amey Jo Holmes ◽  
Jennifer Smith
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Airway Hyperresponsiveness ◽  
Vitamin A Deficiency ◽  
Elastic Fibers ◽  
Bronchial Wall ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Airway Caliber ◽  
And Function

Airway hyperresponsiveness (AHR) is influenced by structural components of the bronchial wall, including the smooth muscle and connective tissue elements and the neuromuscular function. AHR is also influenced by parenchymally derived tethering forces on the bronchial wall, which maintain airway caliber by producing outward radial traction. Our previous work has shown that vitamin A-deficient (VAD) rats exhibit cholinergic hyperresponsiveness and a decrease in the expression and function of the muscarinic-2 receptors (M2R). We hypothesized that if decreases in radial traction from airway or parenchymal structures contributed to the VAD-related increase in AHR, then the radial traction would normalize more slowly than VAD-related alterations in neurotransmitter signaling. Rats remained vitamin A sufficient (VAS) or were rendered VAD and then maintained on the VAD diet in the presence or absence of supplementation with all- trans retinoic acid (RA). VAD was associated with an approximately twofold increase in respiratory resistance and elastance compared with VAS rats. Exposure to RA for 12 days but not 4 days restored resistance and elastance to control (VAS) levels. In VAD rats, AHR was accompanied by decreases in bronchial M2R gene expression and function, which were restored after 12 days of RA supplementation. Subepithelial bronchial elastic fibers were decreased by ∼50% in VAD rats and were significantly restored by RA. The increase in AHR that is associated with VAD is accompanied by decreases in M2R expression and function that can be restored by RA and a reduction in airway elastic fibers that can be partially restored by RA.

IMMU-38. DEEP IMMUNOPROFILING OF HUMAN GLIOBLASTOMA (GBM) REVEALS DIFFERENCES IN THE TUMOR IMMUNE CELL INFILTRATE IN PATIENTS WITH HIGH VS. LOW PLASMA CELL-FREE DNA (CFDNA)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi100-vi101
Author(s):  
Stephen J Bagley ◽  
Cecile Alanio ◽  
Jacob Till ◽  
Aseel Abdalla ◽  
Zev Binder ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Cell Lineage ◽  
Predictive Biomarker ◽  
High Plasma ◽  
Lineage Differentiation ◽  
Tumor Infiltrate ◽  
Poor Outcomes ◽  
And Function ◽  
Immune Cell Infiltrates

Abstract BACKGROUND We have previously demonstrated that high baseline plasma cfDNA concentration is associated with poor survival in patients with newly diagnosed GBM. The mechanism of this association remains unknown. To explore whether differences in the immune landscape between high- vs. low-cfDNA patients may play a role in their divergent clinical outcomes, we phenotyped tumors from patients with high vs. low cfDNA using mass cytometry by time of flight (CyTOF). METHODS We performed CyTOF on frozen tumor infiltrate suspension from a pilot cohort of patients with previously untreated GBM with known baseline plasma cfDNA concentration (Bagley, Clin Cancer Res 2020). CyTOF was used to simultaneously measure expression of 39 molecules related to immune cell lineage, differentiation state, and function. Differences in immune cell infiltrates between high- and low-cfDNA patients were assessed using Mann-Whitney U tests. RESULTS Four patients with high cfDNA (median 57, range 33-90 ng/mL) were compared to six patients with low cfDNA (median 12, range 7-16 ng/mL). Immune cell infiltrates with increased adaptive cells (high monocytes and T cells, p=0.05) were present in high-cfDNA compared to low-cfDNA patients. While > 70% of the infiltrating T cells were exhausted in both groups, the pattern of exhaustion was significantly different in high- vs. low-cfDNA patients, with less CXCR5+CD69+ and more CXCR5-CD69- (p=0.008) progenitor exhausted T cells in cfDNA-high patients. CONCLUSIONS In this GBM pilot study, we demonstrated differences in the tumor immune infiltrate in patients with high vs. low baseline plasma cfDNA concentration. Preclinical studies will be needed to determine if this explains the association between high plasma cfDNA and poor outcomes previously observed in patients. Our results may have implications for the use of cfDNA concentration as a predictive biomarker for immunotherapy, as tumors with more intermediate progenitor (CXCR5-CD69-) exhausted T cells may respond better to PD-1 checkpoint blockade.

scholarly journals De Novo-Synthesized Retinoic Acid in Ovarian Antral Follicles Enhances FSH-Mediated Ovarian Follicular Cell Differentiation and Female Fertility

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 2160-2172 ◽  
Author(s):  
Tomoko Kawai ◽  
Noriyuki Yanaka ◽  
JoAnne S. Richards ◽  
Masayuki Shimada
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Chorionic Gonadotropin ◽  
Granulosa Cells ◽  
Human Chorionic Gonadotropin ◽  
De Novo ◽  
Active Form ◽  
Developmental Competence ◽  
Deficient Diet ◽  
Equine Chorionic Gonadotropin

Abstract Retinoic acid (RA) is the active form of vitamin A and is synthesized from retinol by two key enzymes, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). As the physiological precursor of RA, retinol impacts female reproductive functions and fertility. The expression of Adh1 and Adh5 as well as Aldh1a1 and Aldh1a7 are significantly increased in the ovaries of mice treated with equine chorionic gonadotropin/FSH. The RA receptor is expressed and localized in granulosa cells and is activated by endogenous RA as indicated by LacZ expression in granulosa cells of RA-responsive transgene-LacZ transgenic mice (RA reporter mice). Coinjection of the ADH inhibitor, 4-methylpyrazole, with equine chorionic gonadotropin significantly decreases the number and developmental competence of oocytes ovulated in response to human chorionic gonadotropin/LH as compared with controls. Injections of RA completely reverse the effects of the inhibitor of ovulation and oocyte development. When mice were fed a retinol-free, vitamin A-deficient diet that significantly reduced the serum levels of retinol, the expression of the LH receptor (Lhcgr) was significantly lower in the ovaries of the vitamin A-deficient mice, and injections of human chorionic gonadotropin failed to induce genes controlling ovulation. These results indicate that ovarian de novo biosynthesis of RA is required for the follicular expression of Lhcgr in granulosa cells and their ability to respond to the ovulatory LH surge.

scholarly journals Role and Mechanism of Vitamin A Metabolism in the Pathophysiology of Parkinson’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Anaıs Marie ◽  
Morgane Darricau ◽  
Katia Touyarot ◽  
Louise C. Parr-Brownlie ◽  
Clémentine Bosch-Bouju
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Dopaminergic Neurons ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Vitamin A Metabolism ◽  
Health And Wellbeing

Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson’s disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients.

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