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Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy.

ABSTRACT: Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b+ DCs in the ocular mucosa showed increased activity of aldehyde dehydrogenase (ALDH), the enzyme required for retinoic acid synthesis. In vitro, CD11b+ DC-derived ALDH was associated with 9-cis-retinoic acid ligation to retinoid x receptor (RXR), which induced conjunctival fibroblast activation. In vivo, stimulating RXR led to rapid onset of ocular mucosal fibrosis, whereas inhibiting ALDH activity in DCs or selectively depleting DCs markedly reduced fibrosis. Collectively, these data reveal a profibrotic ALDH-dependent pathway by DCs and uncover a role for DC retinoid metabolism.

SUBMITTER: Ahadome SD

PROVIDER: S-EPMC5004741 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy.

Ahadome Sarah D SD Mathew Rose R Reyes Nancy J NJ Mettu Priyatham S PS Cousins Scott W SW Calder Virginia L VL Saban Daniel R DR

JCI insight 20160801 12

Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b<sup>+</sup> DCs in the ocular mucosa showed increased activity of aldehyde deh ...[more]

PMID: 27595139

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Project description:BACKGROUND:In the classical pathway of retinoic acid (RA) mediated gene transcription, RA binds to a nuclear hormone receptor dimer composed of retinoic acid receptor (RAR) and retinoid X receptor (RXR), to induce the expression of its downstream target genes. In addition to nuclear receptors, there are other intracellular RA binding proteins such as cellular retinoic acid binding proteins (CRABP1 and CRABP2) and cytochrome P450 (CYP) enzymes, whose contributions to the RA signaling pathway have not been fully understood. The objective of this study was to compare the significance of various RA binding receptors, i.e. CRABP1, CRABP2, CYP and RAR in the RA signaling pathway. In this regard, we developed a mathematical model of the RA pathway, which is one of the few models, if not the only one, that includes all main intracellular RA binding receptors. We then performed a global sensitivity analysis (GSA) to investigate the contribution of the RA receptors to RA-induced mRNA production, when the cells were treated with a wide range of RA levels, from physiological to pharmacological concentrations. RESULTS:Our results show that CRABP2 and RAR are the most and the least important proteins, respectively, in controlling the model performance at physiological concentrations of RA (1-10 nM). However, at higher concentrations of RA, CYP and RAR are the most sensitive parameters of the system. Furthermore, we found that depending on the concentrations of all RA binding proteins, the rate of metabolism of RA can either change or remain constant following RA therapy. The cellular levels of CRABP1 are more important than that of CRABP2 in controlling RA metabolite formation at pharmacological conditions (RA?=?0.1-1 ?M). Finally, our results indicate a significant negative correlation between total mRNA production and total RA metabolite formation at pharmacological levels of RA. CONCLUSIONS:Our simulations indicate that the significance of the RA binding proteins in the RA pathway of gene expression strongly depends on intracellular concentration of RA. This study not only can explain why various cell types respond to RA therapy differently, but also can potentially help develop pharmacological methods to increase the efficacy of the drug.

Dataset Information

Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy.

Publications

Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy.

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