RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells

Abstract

This article is available online at http://www.jlr.org cellular retinoic acid binding protein 2 • all-trans retinoic acid • peroxisome proliferator-activated receptor ␥ There is an increasing appreciation that metabolic processes contribute to immune cell specifi cation. One of the prime examples of such regulation is the generation and function of all-trans retinoic acid (ATRA) in several cell types of the immune system, primarily in the gut. However, it remains elusive which cell types have the capacity to produce retinoic acid, which genes are required for ATRA biosynthesis and signaling, and which factors contribute to their induction in dendritic cells (DCs).Abstract All-trans retinoic acid (ATRA) has a key role in dendritic cells (DCs) and affects T cell subtype specifi cation and gut homing. However, the identity of the permissive cell types and the required steps of conversion of vitamin A to biologically active ATRA bringing about retinoic acid receptor-regulated signaling remains elusive. Here we present that only a subset of murine and human DCs express the necessary enzymes, including RDH10, RALDH2, and transporter cellular retinoic acid binding protein (CRABP)2, to produce ATRA and effi cient signaling. These permissive cell types include CD103 + DCs, granulocyte-macrophage colonystimulating factor, and interleukin-4-treated bone marrowderived murine DCs and human monocyte-derived DCs (mo-DCs). Importantly, in addition to RDH10 and RALDH2, CRABP2 also appears to be regulated by the fatty acid-sensing nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR ␥ ) and colocalize in human gut-associated lymphoid tissue DCs. In our model of human mo-DCs, all three proteins (RDH10, RALDH2, and CRABP2) appeared to be required for ATRA production induced by activation of PPAR ␥ and therefore form a linear pathway. This now functionally validated PPAR ␥ -regulated ATRA producing and signaling axis equips the cells with the capacity to convert precursors to active retinoids in response to receptor-activating fatty acids and is potentially amenable to intervention in diseases involving or affecting mucosal immunity.

Seeing through the dark: New insights into the immune regulatory functions of vitamin A

“…Outside of the gut, examination of peripheral DC subsets have identified DCs expressing aldh1a2 residing in the lung and skin, pointing to a role for RA in steady‐state immune responses at barrier sites . Although the majority of peripheral DCs express negligible or low levels of RALDH, the identification of cytokines and pathogen‐associated molecular patterns that can induce RALDH expression indicates that RA synthesis and signaling may be a widespread occurrence during the course of a peripheral immune response.…”

Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells

“…Thus, DC RA production is thought to contribute to intestinal tolerance to commensal bacteria and dietary antigens. RA is generated from retinol (ROL, Vitamin A) through a two-step reaction, the first step involving oxidation of ROL to retinal by a retinol dehydrogenase, most importantly RDH10, and the second step involving further oxidation of retinal to all- trans RA by tissue-specific isoforms of retinaldehyde dehydrogenase, RALDH1, RALDH2 and RALDH3 ( 9 ). The ability of intestinal DCs to generate RA depends on tissue-specific crosstalk between epithelial cells and DCs.…”

Retinol dehydrogenases: Membrane-bound enzymes for the visual function

“…However, the wide RDH10 tissue distribution (Cammas et al 2007;Picozzi et al 2003;Shou et al 2005) and its activity leading to an increase of retinynaldehyde and retinoic acid concentration (Belyaeva et al 2008) suggest a role for this enzyme also in embryonic development and differentiation (Ashique et al 2012;Rhinn et al 2011;Sandell et al 2007). This role was further confirmed by recent studies linking RDH10 to DHRS3 (Adams et al 2014) or to PPAR␥ activity (Gyongyosi et al 2013). It is thus well established that RDH10 has a dual function in the retinoid metabolism.…”