Retinoid receptor‐activating ligands are produced within the mouse thymus during postnatal development

Abstract

Vitamin A deficiency is known to be accompanied with immune deficiency and susceptibility to a wide range of infectious diseases. Experimental evidence suggests that the active metabolites of vitamin A that mediate its effects on the immune system are the retinoic acids (RA), which are ligands for the nuclear RA receptor (RAR) family. RA were previously shown both to promote proliferation and to regulate apoptosis of thymocytes. In this study we detected the age-dependent mRNA expression of retinaldehyde dehydrogenases (RALDH1 and 2), cellular RA binding protein-II and CYP26A, proteins responsible for the synthesis, nuclear transport and degradation of RA in the postnatally developing thymus. RALDH1 was located in thymic epithelial cells. However, the amount of all-trans RA in thymic homogenates was close to the detection limit, suggesting that in this tissue all-trans RA is not the main RAR-regulating product of retinol metabolism. At the same time, by measuring the induction of a RARresponsive transgene in two independent transgenic mouse strains, we demonstrated the production of an RAR-activating ligand, which was age and RALDH dependent. Our data provide evidence for the existence of endogenous retinoid synthesis in the thymus and suggest that retinoids similar to glucocorticoids might indeed be involved in the regulation of thymic proliferation and selection processes by being present in the thymus in functionally effective amounts.

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

“…In line with our previous publication (39), neither the cis-isomers 13-cis, 9-cis RA, nor ATRA were detectable or were around the detection limit of our LC MS/MS technique (∼10 29 M), indicating that they were present in much lower concentrations than that responsible for potential RAR activation. In addition, there was no indication that their levels were altered by administration of dexamethasone.…”

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

“…Our observation that a subset of mesenchymal cells maintains the ability to generate RA after birth suggests that RA signals may help to regulate TEC homeostasis in the adult. Consistent with this possibility, endogenous RA signaling in the postnatal thymus has been demonstrated using RA-reporter mice (36,67). Based on the presence of Aldh1a1 expression in TECs and the detection of dexamethasone-induced Aldh1a1 and Aldh1a2 in thymic macrophages (36,67), these studies proposed that TECs and macrophages contribute to the generation of RA in the steady-state and glucocorticoid-stimulated thymus, respectively.…”

“…Consistent with this possibility, endogenous RA signaling in the postnatal thymus has been demonstrated using RA-reporter mice (36,67). Based on the presence of Aldh1a1 expression in TECs and the detection of dexamethasone-induced Aldh1a1 and Aldh1a2 in thymic macrophages (36,67), these studies proposed that TECs and macrophages contribute to the generation of RA in the steady-state and glucocorticoid-stimulated thymus, respectively. By flow cytometry, we identified two major mesenchymal cell populations in the adult thymus based on expression of Ly51 and gp38: Ly51 int gp38 + and Ly51 hi gp38 2 cells.…”

“…The potential ability of RA to interfere with later stages of thymus development has been suggested based on hypoplastic and ectopic thymus phenotypes generated in embryos treated with teratogenic doses of exogenous retinoids (35). Notably, there is also evidence of continual RAR signaling in the postnatal thymus (36), and the broad spectrum of immune abnormalities observed in vitamin A-deficient animals includes a marked atrophy of the thymus (37), indicating that RA signaling events may play additional roles in thymus ontogeny.…”

Τα Επίπεδα Της Ρετινόλης Και Των Μεταβολιτών Της Σε Ασθενείς Με Χρόνιες Παθήσεις Του Ήπατος

“…Πέρα από την προαναφερθείσα δράση της στα CD4+ Τ κύτταρα, η βιταμίνη Α επιδρά στην οντογένεση, τη λειτουργία και τη διαφοροποίηση των ώριμων Τ κυττάρων, καθώς φαίνεται πως μπορεί να συντεθεί ενδογενώς στο θύμο αδένα και να αποτρέψει την αρνητική επιλογή, ενώ υπάρχουν ενδείξεις πως στη διαδικασία συμμετέχουν και οι RAR/RXR πυρηνικοί υποδοχείς (38,39 …”