Trends in Immunology
Volume 38, Issue 3, March 2017, Pages 168-180
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Review
Retinoic Acid and Immune Homeostasis: A Balancing Act

https://doi.org/10.1016/j.it.2016.12.006Get rights and content

Trends

RA is instrumental to the function of tolerogenic dendritic cells during immune homeostasis.

RA has a role in balancing Th17 and Treg responses, and is also essential for proper T helper cell responses.

The outcome of RA signaling is determined by the microenvironment in which the signal is received.

RA deficiency can result in the development of a broad spectrum of autoimmune diseases.

RA has therapeutic potential for autoimmune diseases.

In the immune system, the vitamin A metabolite retinoic acid (RA) is known for its role in inducing gut-homing molecules in T and B cells, inducing regulatory T cells (Tregs), and promoting tolerance. However, it was suggested that RA can have a broad spectrum of effector functions depending on the local microenvironment. Under specific conditions, RA can also promote an inflammatory environment. We discuss the dual role of RA in immune responses and how this might be regulated. Furthermore, we focus on the role of RA in autoimmune diseases and whether RA might be used as a therapeutic agent.

Section snippets

Importance of Vitamin A in Health

The active metabolite of vitamin A, retinoic acid (RA, see Glossary), has a role in a broad spectrum of biological functions such as cell growth and differentiation, both during development and in adults. Therefore, vitamin A deficiency can severely affect health. Because vitamin A deficiency is common in the developing world, supplementation of vitamin A to pregnant women and small children is a well-established program of the World Health Organization (WHO) and is thought to reduce child

RA as a Central Molecule in Orchestrating Immune Responses

The function of the immune system is dependent on RA at multiple levels because it is instrumental in the initial phase of secondary lymphoid organ formation (reviewed in 3, 4) and is crucial for proper immune regulation in homeostasis and during inflammatory responses in adult life. To maintain sufficient levels of vitamin A, the body relies on the uptake of retinol from the intestinal lumen by intestinal epithelial cells. These cells are known not only to be able to metabolize retinol into RA

Intestinal DCs Are Important in Mediating both Inflammatory and Tolerogenic Responses

Both macrophages and DCs are present in the intestinal lamina propria. DC precursors require gut-homing molecules to be able to migrate to the intestines, and the expression of these molecules is regulated by RA [5]. Furthermore, lack of RA changes the composition of DC subsets, suggesting that RA is essential for the generation and transcriptional programming of DCs in the intestines [6]. In addition, the stromal compartment of gut-draining lymph nodes is also imprinted by RA, allowing these

Induction of ALDH1a Expression in DCs and Macrophages

Because DCs and macrophages are the major source of RA for T and B cells, it is important to determine which factors govern RA metabolism in these cells and how this is regulated. Interestingly, RA itself appears to be an important inducer of aldehyde dehydrogenase 1a (ALDH1a) in DCs as expression of this enzyme was strongly reduced in vitamin A deficient mice [24]. Furthermore, retinoid levels in the gut correlate with the degree to which gut-homing molecules can be induced 6, 16. However,

Dual Role of RA in Modulating T Cell Responses

As mentioned, DCs and macrophages can induce gut-homing molecules on T cells, B cells, and ILCs via their production of RA, but RA has also a supplementary role in inducing effector functions in T cells. Although RA is mostly known for its tolerogenic function, it can also have proinflammatory capacities. Whether RA evokes tolerogenic or inflammatory effects depends on the microenvironment and the synergizing cytokines to which the cells are exposed to (summarized in Figure 3).

RA as a Therapeutic Molecule in Autoimmune Diseases

Because of the determining role of RA in shaping the immune system, it was suggested that RA concentrations are tightly balanced via the expression levels of the ALDH1a enzymes, on the one hand, and the catabolizing enzymes CYP26 on the other. Therefore, an imbalance in either ALDH1a or CYP26 enzymes is expected to result in pathologies such as immune-related diseases and cancer.

In addition to proper Th1 and Th2 responses, a balance between Tregs and Th17 cells is thought to be crucial for

RA in Inflammatory Bowel Diseases

The inflammatory bowel diseases Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by severely inflamed intestines, especially the colon. Although the pathogenesis of IBD is still largely unclear, it is thought that the cause of inflammation is an abnormal immune response towards commensal flora. Many polymorphisms have been associated with IBD and, in particular, reduced ALDH1a1 and increased CYP26A1 levels have been associated with UC 58, 59. In the adoptive transfer colitis

RA in Systemic Autoimmunity

The role of RA has not only been of interest in autoimmunity at mucosal sites but has received increasing attention in systemic autoimmune diseases as they are also associated with an imbalance between Tregs and Th17 cells [69]. Therefore, RA was suggested to have therapeutic impact in these diseases. Indeed, a synthetic RAR agonist could inhibit Th17 differentiation in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and treatment with RA or retinal resulted in more Foxp3

Concluding Remarks and Future Perspectives

Overall, RA is an important molecule in orchestrating local immune responses and has been shown to have a dual role. The effector functions of RA are determined by many different factors such as local RA concentrations, TLR signaling, the presence of additional cytokines, and the cellular and molecular composition of the microenvironment. Intracellularly, RA can not only induce the transcription of multiple genes via binding to nuclear receptors but can also influence translation or evoke

Acknowledgements

The authors would like to thank Dr J.J. Koning for critical reading of the manuscript. M.E. was supported by the Institute of Chemical Immunology which has come about with the support of the Gravitation Program of The Netherlands Organization for Scientific Research.

Glossary

Adoptive transfer colitis mouse model
a model of colitis that relies on the transfer of CD4+CD45RBhigh T cells to a T cell-deficient host (e.g., Rag−/−) resulting in T cell activation and intestinal inflammation.
Alcohol dehydrogenase (ADH)
enzymes that metabolize retinol into retinal.
Aldehyde dehydrogenase 1a (ALDH1a)
enzyme that converts retinal into RA. There are several isoforms, of which ALDH1a1, ALDH1a2, and ALDH1a3 are the best-studied in immune cells.
Cellular retinoic acid-binding protein 1

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