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 August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e87012. https://doi.org/10.1172/jci.insight.87012.
View: Text | PDF
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

×

Figure 3

Development of ocular mucosal fibrosis during allergic eye disease (AED) is associated with augmented cDC2-derived ALDH activity.

Options: View larger image (or click on image) Download as PowerPoint
Development of ocular mucosal fibrosis during allergic eye disease (AED)...
Mice were immunized with OVA/adjuvant and challenged topically once daily with an OVA instillation to induce AED. (A and B) Ocular mucosal fibrosis develops in AED (black arrows). Data from whole eyes sectioned and stained with Masson’s trichrome are representative of n = 3 per group (inset shows fibrosis/opaque white lesion in AED, not seen in naive mice). (C–F) Ocular (Oc) mucosal type-2 classical DC (cDC2) confer increased aldehyde dehydrogenase (ALDH) activity in AED. (C) Whole mount immunofluorescence of the ocular mucosa is representative of n = 5 per group. (D and E) Ocular mucosa and draining lymph node (LN) in AED were collected for flow cytometry analysis. Representative flow cytometry plots are shown from tissues collected at 6 hr after challenge on day 3. (F) Quantitation was performed on tissues collected at 20 min (20) and 6 hr (6) after OVA challenge on days (d) 0 through 3 to measure ALDH activity by flow cytometry. (G) Ocular mucosal cDC2 increase in number during AED. Flow cytometry was carried out for enumeration of cDCs. Data shown for the ocular mucosal cDCs are representative of duplicate data points from 2 separate experiments. Cell suspensions were pooled samples from n = 10 naive mice or n = 6 mice for each experiment (error bars represent ±SEM; *P < 0.05, **P < 0.005; 1-way ANOVA with Bonferroni correction). Each experiment was carried out at least twice.