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Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy
Sarah D Ahadome1,2, Rose Mathew1, Nancy J Reyes1
1Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.
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.
Insights
Dendritic cells (DCs) directly induce ocular fibrosis through a novel pathway involving aldehyde dehydrogenase (ALDH) and retinoid metabolism. This discovery offers new targets for treating blinding fibrotic eye diseases.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Fibrosis is a common pathway to organ failure, including in the conjunctiva, leading to blindness.
- Dendritic cells (DCs) are known to indirectly promote fibrosis through immune cell activation.
- A direct fibrogenic role for DCs has not been previously established.
Purpose of the Study:
- To investigate the direct role of dendritic cells (DCs) in inducing ocular mucosal fibrosis.
- To elucidate the molecular mechanisms by which DCs contribute to conjunctival fibrosis.
- To identify potential therapeutic targets for fibrotic eye diseases.
Main Methods:
- Utilized a mouse model of allergic eye disease (AED).
- Assessed aldehyde dehydrogenase (ALDH) activity in conjunctival CD11b+ DCs.
- Investigated the effects of 9-cis-retinoic acid, retinoid x receptor (RXR) activation, and ALDH inhibition in vitro and in vivo.
Main Results:
- CD11b+ DCs in AED mice exhibited increased ALDH activity, crucial for retinoic acid synthesis.
- DC-derived retinoic acid activated conjunctival fibroblasts via RXR ligation.
- RXR stimulation accelerated ocular fibrosis, while ALDH inhibition or DC depletion reduced it.
Conclusions:
- DCs possess a direct, profibrotic capacity mediated by an ALDH-dependent pathway.
- DC retinoid metabolism plays a critical role in inducing ocular mucosal fibrosis.
- Targeting DC ALDH activity or retinoid metabolism may offer novel therapeutic strategies for fibrotic eye conditions.
