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Review
. 2017 Jan 13;9(1):68.
doi: 10.3390/nu9010068.

Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity

Paulo Czarnewski  1 , Srustidhar Das  2 , Sara M Parigi  3 , Eduardo J Villablanca  4
Affiliations
Review

Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity

Paulo Czarnewski et al. Nutrients. .

Abstract

Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA) has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs) and innate lymphoid cells (ILCs). Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs.

Keywords: dendritic cells; innate immunity; innate lymphoid cells; retinoic acid; vitamin A.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Role of all-trans retinoic acid (atRA) in regulating differentiation of dendritic cells (DC) precursors. Bone marrow (BM) resident pre-DCs have the potential to differentiate into pre-mucosal DC (pre-μDC), characterized by the expression of gut homing receptors. Expansion of pre-μDC is atRA-dependent. Pre-μDC gives rise to intestinal CD103+DCs, which is enhanced by the presence of atRA. Pre-DCs can migrate to the spleen, where they may sense atRA skewing the differentiation toward CD11b+CD8− DCs instead of CD11b−CD8α+ DCs.
Figure 2
Figure 2
Role of atRA in modulating intestinal DC differentiation, maturation and function. CD103+ DCs reside beneath the epithelial layer, in close contact with CX3CR1+ macrophages, which are responsible for taking up luminal antigens and transferring them to CD103+ DCs (step-1). Several molecules are described to induce atRA-producing CCR7+ DCs, such as toll-like receptor (TLR) ligands and atRA itself, making DCs equipped to migrate to the mesenteric lymph nodes (MLN) (step-2). Within the MLN, CD103+ DCs are responsible for antigen presentation and differentiation of regulatory T cells in the presence of atRA and TGF-β (step-3). Moreover, DC-derived atRA is crucial to induce the expression of gut homing receptors in T cells (step-3). Finally, regulatory T cells reach the intestinal mucosa and gain the capacity to produce IL-10, becoming IL-10 producing TREG, which play a key role in the establishment of oral tolerance in the intestinal lamina propria (step-4); TREG induced in this manner are able to migrate to peripheral tissues and promote tolerance (step-5). Steps 1 to 5 denote the main processes involved in the establishment of oral immunological tolerance.
Figure 3
Figure 3
Role of DC-derived atRA in induction of gut-homing TREG and innate lymphoid cells (ILCs). Mature DCs arrive in the MLN and are capable to produce atRA, as well as other stromal cells. atRA is important for generating TREG by attenuating CD44hi cells that inhibit TREG differentiation. In addition, atRA in the MLN is crucial for induction of gut-homing receptors in T cells and in ILC1 and ILC3.
Figure 4
Figure 4
Role of atRA modulating ILC migration and function. ILC2 progenitors in the bone marrow (BM) express gut-homing receptors and migrate to the intestine independently of atRA. On the other hand, ILC1 and ILC3 progenitors deploy from the BM to the MLN. DC-derived atRA induce the expression of gut-homing molecules on ILC1 and ILC3 there, conferring the ability to migrate to the intestinal mucosa. Once in the gut tissue, ILC1 can potentially differentiate into ILC3 in the presence of IL-23. This plasticity may be enhanced by IL-1β and atRA. IL-23 induces IL-22 production by ILC3, which can be enhanced by atRA.
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