title: RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells.
abstract: All-trans retinoic acid (ATRA) has a key role in dendritic cells (DCs) and affects T cell subtype specification 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 efficient signaling. These permissive cell types include CD103(+) DCs, granulocyte-macrophage colony-stimulating factor, and interleukin-4-treated bone marrow-derived 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 γ (PPARγ) 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 PPARγ and therefore form a linear pathway. This now functionally validated PPARγ-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Gyöngyösi
authors.forename: Istvan
authors.initials: I
authors.lastname: Szatmari
authors.forename: Attila
authors.initials: A
authors.lastname: Pap
authors.forename: Balazs
authors.initials: B
authors.lastname: Dezso
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Pos
authors.forename: Lajos
authors.initials: L
authors.lastname: Széles
authors.forename: Tamas
authors.initials: T
authors.lastname: Varga
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
mesh_terms: D000429:Alcohol Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007422:Intestines / Q000166:cytology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology; D055611:Natural Killer T-Cells / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D021381:Protein Transport; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050697:Retinal Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D011503:Transglutaminases / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D047495:PPAR gamma; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: all-trans retinoic acid; cellular retinoic acid binding protein 2; iNKT cells; lipid antigen presentation; lipid transport; peroxisome proliferator-activated receptor γ; retinoic acid receptor signaling; retinoid metabolism