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Review
. 2018 Aug 9;2018:3067126.
doi: 10.1155/2018/3067126. eCollection 2018.

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

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Free PMC article
Review

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

Luana de Mendonça Oliveira et al. Mediators Inflamm. .
Free PMC article

Abstract

Vitamin A metabolite retinoic acid (RA) plays important roles in cell growth, differentiation, organogenesis, and reproduction and a key role in mucosal immune responses. RA promotes dendritic cells to express CD103 and to produce RA, enhances the differentiation of Foxp3+ inducible regulatory T cells, and induces gut-homing specificity in T cells. Although vitamin A is crucial for maintaining homeostasis at the intestinal barrier and equilibrating immunity and tolerance, including gut dysbiosis, retinoids perform a wide variety of functions in many settings, such as the central nervous system, skin aging, allergic airway diseases, cancer prevention and therapy, and metabolic diseases. The mechanism of RA is interesting to explore as both a mucosal adjuvant and a combination therapy with other effective agents. Here, we review the effect of RA on innate and adaptive immunity with a special emphasis on inflammatory status.

Figures

Figure 1
Figure 1
RA metabolism and signaling. (A) Vitamin A and its precursors (β-carotene) obtained from diet are absorbed by intestinal epithelium cells and esterified in retinyl esters by the enzyme lecithin retinol acyltransferase (LRAT). (B) Retinyl esters are packed with chylomicrons and enter general circulation where they are captured by hepatocytes and stored as retinol. (C) The retinol binds to retinol binding protein (RBP) in the liver and is carried through the bloodstream. This complex is recognized via the stimulated by retinoic acid 6 (STRA6) receptor, which mediates the absorption of extracellular retinol to cytosol. (D) After uptake, RA is generated from retinol by two sequential reactions. First, retinol is oxidized into retinal by enzyme alcohol dehydrogenase (ADH). Subsequently, in CD103+ DCs, retinal is oxidized by the enzyme retinal dehydrogenase (RALDH) to generate RA. (E) Intestinal epithelium cells can also metabolize vitamin A after absorption into retinal and RA, which can be directly released into the intestinal mucosa. (F) RA interacts with nuclear receptors, such as the retinoic acid receptor (RAR) and retinoid receptor X (RXR), to regulate the transcription of several target genes by binding the retinoic acid-responsive elements (RAREs) in DNA. (G) Control of the RA concentration in tissues is performed by a group of enzymes that belong to the cytochrome P450 family 26 (CYP26), which catalyzes RA present in the cytosol to generate the oxidized forms.
Figure 2
Figure 2
Role of RA in immune cells. RA can act on different cells of both the innate and adaptive immune systems exerting local action at mucosal sites and systemic action, which simultaneously, depending on where the RA-producing cells, mainly CD103+ DCs, are located when it releases the RA. (A) However, in an inflammatory environment (red box), PGE2 released during the inflammatory response inhibits the RALDH enzyme that is required for RA synthesis. When RA is released, it acts as follows: (B) RA together with proinflammatory cytokines contributes to the activation of DCs and the generation of effector T cells; (C) RA promotes macrophage modulation, inhibiting inflammatory mediators and the release of TNF and NO; (D) RA also activates ILC3, especially LTi cells, which are required for the formation of lymphoid tissue, including during fetal development; (E) RA induces expression of the molecules α4β7 and CCR9 in lymphocytes and ILCs and the homing of these cells into the intestine and promotes the balance of Th17/Treg cells in the GALT, assuring tolerance, but is also able to induce Th17 in the presence of infection and inflammation; and (F) RA promotes the activation of B cells and their differentiation into Ab-secreting plasma cells.
Figure 3
Figure 3
Potential anti-inflammatory effects of RA. RA can decrease inflammatory processes, promoting homeostasis and attenuating harmful inflammatory responses in mucosa and tissues. RA shows immunosuppressive effect on Th1/Th17 cells in multiple sclerosis (MS) and induces Apo E in microglia, protecting from the neurotoxic effects mediated by amyloid β (Aβ) in Alzheimer disease (AD), contributing to neuronal homeostasis. RA is crucial for intestinal tolerance, by inducing Treg, cytokines IL-10 and IL-22, and antimicrobial peptide (AMP) synthesis, which may lead to Th17 inhibition. RA modulates inflammatory airway diseases (asthma and rhinitis) by inhibiting Th2/Th17 response and enhancing Treg cells. Retinoids increases type I collagen and TGF-β, reducing matrix metalloproteinase (MMPs) in photoaging (AGE), and reduces IL-1 family cytokines (IL-17 and TNF-α), IL-33, and epidermal hyperplasia in psoriatic (PSO) lesions. RA also has effects in adipocytes, promoting white adipose tissue (WAT) browning by differentiation into beige cells (antiobesity) instead of white cells (proobesity). The formation of brown adipocytes within WAT enhances energy expenditure and reduces obesity. In addition, RA can repress the expression of inflammatory chemokines and cytokines, inhibiting inflammatory responses triggered by obesity.

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