Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy
Sarah D. Ahadome, … , Virginia L. Calder, Daniel R. Saban
Sarah D. Ahadome, … , Virginia L. Calder, Daniel R. Saban
Published September 23, 2016; First published August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e87012. https://doi.org/10.1172/jci.insight.87012.
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Categories: Research Article Immunology Ophthalmology

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.

Authors

Sarah D. Ahadome, Rose Mathew, Nancy J. Reyes, Priyatham S. Mettu, Scott W. Cousins, Virginia L. Calder, Daniel R. Saban

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Figure 1

Uniquely high aldehyde dehydrogenase (ALDH) activity in steady-state type-2 classical DCs (cDC2) is conserved in multiple tissues.

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Uniquely high aldehyde dehydrogenase (ALDH) activity in steady-state typ...
(A–C) Gating strategies for analyzing steady-state cDC1 and cDC2 in ocular (Oc) mucosa, draining submandibular/cervical lymph node (LN), and lung from normal C57BL/6 mice (PMN, neutrophils; Eo, eosinophils; Mo/MF, classical monocytes and macrophages). (D and E) Comparison of ALDH activity in cDC1s and cDC2s. Cell suspensions were stained with ALDEFLUOR to assess ALDH activity. Negative controls are shown for the respective cDC2 populations, which were ALDEFLUOR-stained samples treated with the ALDH inhibitor diethylaminobenzaldehyde (DEAB). Data are representative of duplicate data points from 2 separate experiments on pooled conjunctiva from n = 10 mice. Lung data is representative of triplicate data points from 3 separate samples from n = 20 mice (error bars represent ±SEM, ***P < 0.0005, ****P < 0.00005, 1-way ANOVA with Bonferroni correction). Each experiment was carried out at least twice.