Retinoic Acid and Immunity

Abstract

Vitamin A and its active metabolite retinoic acid (RA) are key players in the regulation of the immune response, especially at the mucosal borders, where RA is particularly abundant. Retinoic acid receptors (RARs), via their transcriptional activity, modulate the expression of many genes in many types of immune cells, such as T cells, B cells, macrophages or dendritic cells. Among the pleiotropic effects on immune cells, the ability of RA and RARs to confer gut tropism and to promote the generation of regulatory T cells (Tregs) are undoubtedly the most prominent. However, depending on the physiopathological context, RA can also promote inflammation. These multiple and sometimes paradoxical properties of RA reflect the importance of this nutrient‐derived molecule in the fine‐tuning of the immune system.

Key Concepts

  • Retinoic acid is the active metabolite of Vitamin A, a nutrient essential for many biological processes.
  • Retinoic acid receptors act as transcription factors to regulate the expression of several genes.
  • Retinoic acid induces the expression of gut homing receptors on several immune cells.
  • Retinoic acid induces the generation of regulatory T cells that control the immune and inflammatory response.
  • In certain physiopathological contexts, retinoic acid can act as an adjuvant to promote inflammation.

Keywords: retinoic acid; immunity; gut homing; vitamin A; retinoic acid receptor

Figure 1. Vitamin A transport and metabolism. Vitamin A is obtained from the diet and absorbed in the small intestine, where it can be further processed or transported to the liver for storage. From there it can be exported to the general circulation, where it is combined with a transport protein, RBP (retinol binding protein), that facilitates its uptake by cells through the receptor STRA6 (stimulated by retinoic acid gene 6). Once in the cell, vitamin A can be converted to retinaldehyde (retinal) through the action of ADH (alcohol dehydrogenase). The additional step required to form the active metabolite retinoic acid (RA) is performed via the irreversible activity of RALDH (retinaldehyde dehydrogenase). In the cell, RA can enter the nucleus to activate transcription via ligation with the RARs (retinoic acid receptors). RA is carried within the cell by transporters from the CRABP (cellular RA binding protein) family. While CRABP1 is involved in RA catabolism, CRABP2 transports RA to the nucleus, allowing its transfer to RARs. RA can also be delivered to PPARβ/γ receptors by FABP5 (fatty‐acid binding protein 5). Excess RA is catabolised by further oxidation by CYP26, a cytochrome P450 family member.
Figure 2. Mechanisms of action of retinoic acid and its receptors (a) Retinoic acid (RA) mediates its canonical function through binding to retinoic acid receptor (RAR)‐α, ‐β or ‐γ, which form heterodimers with retinoid X receptors (RXR)‐α, ‐β or ‐γ. RAR–RXR heterodimers act as ligand‐dependent transcription factors that bind to RA responsive elements (RAREs) in the gene promoter region. In the absence of ligand, RAR–RXR heterodimers are bound to DNA and recruit corepressors that serve as adaptor molecules to recruit factors such as histone deacetylases (HDACs), which make promoter regions unavailable for transcriptional activation. Upon RA ligation, RARs release the corepressors and recruit coactivators, such as histone acetyl transferases (HATs), allowing the stimulation of gene transcription. (b) Phosphorylation of RARs by MSK1 (mitogen‐ and stress‐activated protein kinase 1) or CDK7 (cyclin‐dependent kinase 7) modulates their transcriptional activity. (c) RAR–RXR can interfere with the activity of the transcription factor AP‐1 independently of RAR transcriptional activity. (d) Cytoplasmic RARs can modulate the activity of several signalling molecules such as PKC (protein kinase C), PI3K (phosphoinositide‐3‐kinase), Src or the MAPKs (mitogen‐activated protein kinases) ERK and p38.
Figure 3. Cellular sources of retinoic acid in the gut. In the gut, immune cells (CD103 expressing dendritic cells and macrophages) and nonimmune cells (epithelial cells and stromal cells) are able to produce RA from vitamin A. Their ability to produce RA is due to the expression of RALDH, which is tightly regulated by several factors, such as RA itself, TLR (toll‐like receptor) ligands, interleukins, the TNF (tumour necrosis factor) ligand 4‐1BB or prostaglandin E2, and controlled notably by the Wnt/β‐catenin and the p38α signalling pathways. GM‐CSF (Granulocyte‐macrophage colony‐stimulating factor), a key factor in this process, is produced notably by stromal cells and type 3 innate lymphoid cells (ILC3).
Figure 4. Main effects of retinoic acid on immune cells. Retinoic acid influences the differentiation of CD4 and CD8 T cells, dendritic cells, B cells and ILCs (innate lymphoid cells), and plays an important role in gut tropism and the embryonic development of secondary lymphoid organs (SLOs).
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Larange, Alexandre(Aug 2017) Retinoic Acid and Immunity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027294]