The Need to Consider Context in the Evaluation of Anti-infectious and Immunomodulatory Effects of Vitamin A and its Derivatives

Author(s): Pedro Xavier-Elsas*, Bruno M. Vieira, Daniela Masid-de-Brito, Monica G. Barradas, Maria I.C. Gaspar-Elsas.

Journal Name: Current Drug Targets

Volume 20 , Issue 8 , 2019

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Graphical Abstract:


Vitamin A and its derivatives (retinoids) act as potent regulators in many aspects of mammalian reproduction, development, repair, and maintenance of differentiated tissue functioning. Unlike other vitamins, Vitamin A and retinoids, which have hormonal actions, present significant toxicity, which plays roles in clinically relevant situations, such as hypervitaminosis A and retinoic acid ("differentiation") syndrome. Although clinical presentation is conspicuous in states of insufficient or excessive Vitamin A and retinoid concentration, equally relevant effects on host resistance to specific infectious agents, and in the general maintenance of immune homeostasis, may go unnoticed, because their expression requires either pathogen exposure or the presence of inflammatory co-morbidities. There is a vast literature on the roles played by retinoids in the maintenance of a tolerogenic, noninflammatory environment in the gut mucosa, which is considered by many investigators representative of a general role played by retinoids as anti-inflammatory hormones elsewhere. However, in the gut mucosa itself, as well as in the bone marrow and inflammatory sites, context determines whether one observes an anti-inflammatory or proinflammatory action of retinoids. Both interactions between specialized cell populations, and interactions between retinoids and other classes of mediators/regulators, such as cytokines and glucocorticoid hormones, must be considered as important factors contributing to this overall context. We review evidence from recent studies on mucosal immunity, granulocyte biology and respiratory allergy models, highlighting the relevance of these variables as well as their possible contributions to the observed outcomes.

Keywords: Retinoid, immunomodulation, regulatory T cell, dendritic T cell, granulocyte, glucocorticoid hormones.

Mora JR, Iwata M, Von Andrian UH. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat Rev Immunol 2008; 8: 685-98.
Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annu Rev Nutr 2002; 22: 347-81.
Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients 2011; 3: 385-28.
Duester G. Retinoic acid synthesis and signaling during early organogenesis. Cell 2008; 134: 921-31.
Duester G. Retinoid signaling in control of progenitor cell differentiation during mouse development. Semin Cell Dev Biol 2013; 24: 694-700.
Das BC, Thapa P, Karki R, et al. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem 2014; 22: 673-83.
Gudas LJ. Emerging roles for retinoids in regeneration and differentiation in normal and disease states. Biochim Biophys Acta- Mol Cell Biol Lipids 2012. 1821: 213-21
Maden M. Retinoic acid in the development, regeneration, and maintenance of the nervous system. Nat Rev Neurosci 2007; 8: 755-65.
Lane MA, Bailey SJ. Role of retinoid signaling in the adult brain. Prog Neurobiol 2005; 75: 275-93.
Lara-Ramírez R, Zieger E, Schubert M. Retinoic acid signaling in spinal cord development. Int J Biochem Cell Biol 2013; 45: 1302-13.
Kolm PJ, Apekin V, Sive H. Xenopus hindbrain patterning requires retinoid signaling. Dev Biol 1997; 192: 1-16.
Addison M, Xu Q, Cayuso J, Wilkinson DG. Cell identity switching regulated by retinoic acid signaling maintains homogeneous segments in the hindbrain. Dev Cell 2018. 45: 606-620. e3.
Cvekl A, Wang WL. Retinoic acid signaling in mammalian eye development. Exp Eye Res 2009; 89(3): 280-91.
Stefanovic S, Zaffran S. Mechanisms of retinoic acid signaling during cardiogenesis. Mech Dev 2017; 143: 9-19.
Okano J, Lichti U, Mamiya S, et al. Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development. J Cell Sci 2012; 125: 1827-36.
Bohnsack BL, Lai L, Dolle P, Hirschi KK. Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferation. Genes Dev 2004; 18: 1345-58.
Chanda B, Ditadi A, Iscove NN, Keller G. Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. Cell 2013; 155: 215-27.
Ghiaur G, Yegnasubramanian S, Perkins B, et al. Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling. Proc Natl Acad Sci USA 2013; 110: 16121-6.
Makita T, Hernandez-Hoyos G, Chen T, et al. A developmental transition in definitive erythropoiesis: Erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes Dev 2001; 15: 889-901.
Biesalsk HK. Comparative assessment of the toxicology of vitamin A and retinoids in man. Toxicol 1989; 57: 117-61.
Patatanian E, Thompson DF. Retinoic acid syndrome: A review. J Clin Pharm Ther 2008; 33: 331-8.
Acin-Perez R, Hoyos B, Zhao F, et al. Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homeostasis. FASEB J 2010; 24: 627-36.
De Oliveira MR. Vitamin a and retinoids as mitochondrial toxicants. Oxid Med Cell Longev 2015; 2015: 140267.
Luesink M, Pennings JL, Wissink WM, et al. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: Triggering the differentiation syndrome. Blood 2009; 114: 5512-21.
Kumar S, Yedjou CG, Tchounwou PB, et al. Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. J Clin Exp Cancer Res 2014; 33: 42.
West KP Jr, Howard GR, Sommer A, et al. Vitamin A and infection: Public health implications. Annu Rev Nutr 1989; 9: 63-86.
Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr 2001; 21: 167-92.
Mawson AR. The pathogenesis of malaria: A new perspective. Pathog Glob Health 2013; 107: 122-9.
Wiedermann U, Tarkowski A, Bremell T, et al. Vitamin A deficiency predisposes to Staphylococcus aureus infection. Infect Immun 1996; 64: 209-14.
Coles CL, Rahmathullah L, Kanungo R, et al. Vitamin A supplementation at birth delays pneumococcal colonization in South Indian infants. J Nutr 2001; 131: 255-61.
Layton HW, Youmans GP. Effect of dietary factors upon the resistance of albino mice to experimental infection with Mycobacterium tuberculosis. J Bacteriol 1965; 90: 958-64.
Lassen HCA. Vitamin A deficiency and resistance against a specific infection. Preliminary report. J Hyg (Lond) 1930; 30: 300-10.
Schémann JF, Malvy D, Sacko D, Traore L. Trachoma and vitamin A deficiency. Lancet 2001; 357: 1676.
Bitetto D, Bortolotti N, Falleti E, et al. Vitamin A deficiency is associated with hepatitis C virus chronic infection and with unresponsiveness to interferon-based antiviral therapy. Hepatol 2013; 57: 925-33.
Benn CS, Balde A, George E, et al. Effect of vitamin A supplementation on measles-specific antibody levels in Guinea-Bissau. Lancet 2002; 359: 1313-4.
Castillo Y, Tachibana M, Nakatsu Y, et al. Combination of zinc and all-trans retinoic acid promotes protection against Listeria monocytogenes infection. PLoS One 2015; 10: e0137463.
Hof H, Emmerling P. Stimulation of cell-mediated resistance in mice to infection with Listeria monocytogenes by vitamin A. Annales d'Immunol (Paris) 1979; 130C: 587-94.
Semba RD. Vitamin A as anti-infective therapy, 1920 - 1940. J Nutr 1999; 129: 783-91.
Audouin-Chevallier I, Pallet V, Coustaut M, et al. Retinoids modulate the binding capacity of the glucocorticoid receptor and its translocation from cytosol to nucleus in liver cells. J Steroid Biochem Mol Biol 1995; 52: 321-8.
Hall JA, Grainger JR, Spencer SP, et al. The role of retinoic acid in tolerance and immunity. Immunity 2011; 35: 13-22.
Iwata M, Hirakiyama A, Eshima Y, et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 2004; 21: 527-38.
Manicassamy S, Pulendran B. Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages. Semin Immunol 2009; 21: 22-7.
Cassani B, Villablanca EJ, De Calisto J, et al. Vitamin A and immune regulation: Role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med 2012; 33: 63-76.
Agace WW, Persson EK. How vitamin A metabolizing dendritic cells are generated in the gut mucosa. Trends Immunol 2012; 33: 42-8.
Yokota A, Takeuchi H, Maeda N, et al. GM-CSF and IL-4 synergistically trigger dendritic cells to acquire RA-producing capacity. Int Immunol 2009; 21: 361-77.
Hall JA, Cannons JL, Grainger JR, et al. (2011) Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 2011; 34: 435-47.
Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007; 317: 256-60.
McGeachy MJ, Cua DJ. Th17 Cell differentiation: The long and winding road. Immunity 2008; 28: 445-53.
Wang C, Kang SG, Hogen Esch H, et al. Retinoic acid determines the precise tissue tropism of inflammatory th17 cells in the intestine. J Immunol 2010; 184: 5519-26.
Kang SG, Wang C, Matsumoto S, Kim CH. High and low vitamin a therapies induce distinct foxp3+ t-cell subsets and effectively control intestinal inflammation. Gastroenterol 2009; 137: 1391-1402. e1-6.
Van De Pavert SA, Ferreira M, Domingues RG, et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 2014; 508: 123-7.
Spencer SP, Wilhelm C, Yang Q, et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 2014; 343: 432-7.
Kugelberg E. Innate lymphoid cells: nutrients direct immune balance. Nat Rev Immunol 2014; 14: 137.
DePaolo RW, Abadie V, Tang F, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 2011; 471: 220-4.
Maynard CL, Weaver CT. Immunology: Context is key in the gut. Nature 2011; 471: 169-70.
Ertesvåg A, Naderi S, Blomhoff HK. Regulation of B cell proliferation and differentiation by retinoic acid. Semin Immunol 2009; 21: 36-41.
Chen X, Esplin BL, Garrett KP, et al. Retinoids accelerate B lineage lymphoid differentiation. J Immunol 2008; 180: 138-45.
Maruya M, Suzuki K, Fujimoto H, et al. Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells. Proc Natl Acad Sci USA 2011; 108: 722-7.
Roy B, Brennecke AM, Agarwal S, et al. An intrinsic propensity of murine peritoneal B1b cells to switch to IgA in presence of TGF-β and retinoic acid. PLoS One 2013; 8: e82121.
Mora JR, Iwata M, Eksteen B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006; 314: 1157-60.
Mora JR, von Andrian U. Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells. Semin Immunol 2009; 21: 28-35.
Hammerschmidt SI, Friedrichsen M, Boelter J, et al. Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice. J Clin Invest 2011; 121: 3051-61.
Tsuji M, Suzuki K, Kitamura H, et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 2008; 29: 261-71.
Tokuyama H, Tokuyama Y. Retinoic acid induces the expression of germ-line C alpha transcript mainly by a TGF-beta-independent mechanism. Cell Immunol 1997; 176: 14-21.
Seo GY, Jang YS, Kim HA, et al. Retinoic acid, acting as a highly specific IgA isotype switch factor, cooperates with TGF-β1 to enhance the overall IgA response. J Leukoc Biol 2013; 94: 325-35.
Watanabe K, Sugai M, Nambu Y, et al. Requirement for Runx proteins in IgA class switching acting downstream of TGF-beta 1 and retinoic acid signaling. J Immunol 2010; 184: 2785-92.
Massacand JC, Kaiser P, Ernst B, et al. Intestinal bacteria condition dendritic cells to promote IgA production. PLoS One 2008; 3: e2588.
Kim MS, Kim TS. IgA+ plasma cells in murine intestinal lamina propria as a positive regulator of Treg differentiation. J Leukoc Biol 2014; 95: 461-9.
Niess JH, Adler G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J Immunol 2010; 184: 2026-37.
Laffont S, Siddiqui KR, Powrie F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur J Immunol 2010; 40: 1877-83.
Paul CC, Mahrer S, Tolbert M, et al. Changing the differentiation program of hematopoietic cells: Retinoic acid-induced shift of eosinophil-committed cells to neutrophils. Blood 1995; 86: 3737-44.
Upham JW, Sehmi R, Hayes LM, et al. Retinoic acid modulates IL-5 receptor expression and selectively inhibits eosinophil-basophil differentiation of hemopoietic progenitor cells. J Allergy Clin Immunol 2002; 109: 307-13.
Ueki S, Mahemuti G, Oyamada H, et al. Retinoic acids are potent inhibitors of spontaneous human eosinophil apoptosis. J Immunol 2008; 181: 7689-98.
Leber BF, Denburg JA. Retinoic acid modulation of induced basophil differentiation. Allergy 1997; 52: 1201-6.
Xavier-Elsas P, Vieira BM, Masid-de-Brito D, et al. Novel lineage- and stage-selective effects of retinoic acid on mouse granulopoiesis: Blockade by dexamethasone or inducible NO synthase inactivation. Int Immunopharmacol 2017; 45: 79-89.
Jones C, Paula Neto HA, Assreuy J, et al. Prostaglandin E2 and Dexamethasone regulate eosinophil differentiation and survival through nitric oxide- CD95-Dependent pathway. Nitric Oxide: Biol Chem 2004; 11: 184-93.
Queto T, Xavier-Elsas P, Gardel MA, et al. Inducible nitric oxide synthase/cd95l-dependent suppression of pulmonary and bone marrow eosinophilia by diethylcarbamazine. Am J Respir Crit Care Med 2010; 181: 429-37.
Gaspar-Elsas MI, Queto T, Vasconcelos Z, et al. Evidence for a regulatory role of a4 integrins in the maturation of eosinophils generated from the bone-marrow in the presence of dexamethasone. Clin Exp Allergy 2009; 39: 1187-98.
Xavier Elsas P, Queto T, Mendonça-Sales SC, et al. Cysteinyl-leukotrienes mediate the enhancing effects of indomethacin and aspirin on murine bone-marrow culture. Br J Pharmacol 2008; 153: 528-35.
Gaspar-Elsas MI, Queto T, Masid-de-Brito D, et al. α-Galactosylceramide suppresses murine eosinophil production through interferon-γ-dependent induction of NO synthase and CD95. Br J Pharmacol 2015; 172: 3313-25.
Xavier-Elsas P, de Luca B, Queto T, et al. Blockage of eosinopoiesis by il-17a is prevented by cytokine and lipid mediators of allergic inflammation. Mediators Inflamm 2015; 968932.
Xavier-Elsas P, da Silva CL, Vieira BM, et al. The in vivo granulopoietic response to dexamethasone injection is abolished in perforin-deficient mutant mice and corrected by lymphocyte transfer from nonsensitized wild-type donors. Mediators Inflamm 2015; 495430.
Masid-de-Brito D, Queto T, Gaspar-Elsas MI, Xavier-Elsas P. Roles of 5-lipoxygenase and cysteinyl-leukotriene type 1 receptors in the hematological response to allergen challenge and its prevention by diethylcarbamazine in a murine model of asthma. Mediators Inflamm 2014; 2014: 403970.
Son H-L, Park H-R, Park Y-J, Kim S-W. Effect of retinoic acid in a mouse model of allergic rhinitis. Allergy Asthma Immunol Res 2015; 7: 590-8.
Maret MX, Ruffie C, Periquet B, et al. Liposomal retinoic acids modulate asthma manifestations in mice. J Nutr 2007; 137: 2730-6.
Gaspar-Elsas MI, Joseph D, Xavier-Elsas P, Vargaftig BB. Rapid increase in bone-marrow eosinophil production and responses to eosinopoietic interleukins triggered by intranasal allergen challenge. Am J Respir Cell Mol Biol 1997; 17: 404-13.
Inman MD. Bone marrow events in animal models of allergic inflammation and hyperresponsiveness. J Allergy Clin Immunol 2000; 106(5)(Suppl.): S235-41.
Matheu V, Berggård K, Barrios Y, et al. Impact on allergic immune response after treatment with vitamin A. Nutr Metab (Lond) 2009; 6: 44.

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Article Details

Year: 2019
Page: [871 - 878]
Pages: 8
DOI: 10.2174/1389450120666181217095323
Price: $58

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