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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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 4

Local inhibition of cDC2-derived aldehyde dehydrogenase (ALDH) protects mice from ocular mucosal fibrosis during allergic inflammation.

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Local inhibition of cDC2-derived aldehyde dehydrogenase (ALDH) protects ...
Mice induced with allergic eye disease (AED) were treated with topical diethylaminobenzaldehyde (DEAB) in one eye and vehicle control in the fellow/contralateral eye. (A and B) Equivalent levels of allergic inflammation in AED is achieved in the setting of unilateral DEAB instillation (black arrows). Clinical image and scores are derived from n = 12 mice. (B) Unilateral DEAB instillation in AED leads to reduced ALDH activity in type-2 classical DC (cDC2), as compared with those from the vehicle-treated contralateral eye. Flow cytometry data are derived from triplicate data points of pooled conjunctiva from n = 12 mice. (C) Unilateral DEAB instillation during AED leads to reduced collagen deposition in the ocular mucosa of the treated eye (black arrows). Images represent n = 6 mice. (D and E) Unilateral DEAB instillation restores normal levels of proliferation, contractility, collagen production, and α smooth muscle actin (α) of AED conjunctival fibroblasts from the treated eye. Fibroblast data are represented by triplicate data points from 3 separate fibroblast cultures from 3 different mice (error bars represent ±SEM; *P < 0.05, ****P < 0.00005; 1-way ANOVA with Bonferroni correction). Each experiment was carried out at least twice.