RDH10, RALDH2 and CRABP2 are required components of PPARg-directed all-trans-retinoic acid synthesis and signaling in human dendritic cells

Gyöngyösi, Adrienn and Szatmári, István and Papp, Attila and Dezső, Balázs and Pós, Zoltán and Széles, Lajos and Varga, Tamás and Nagy, László (2013) RDH10, RALDH2 and CRABP2 are required components of PPARg-directed all-trans-retinoic acid synthesis and signaling in human dendritic cells. JOURNAL OF LIPID RESEARCH, 54 (9). pp. 2458-2474. ISSN 0022-2275

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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.

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