Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy.
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.
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Ocular Biology and Therapeutics, University College London (UCL) Institute of Ophthalmology, London, United Kingdom.
Sarah D
SD
Ahadome
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.
Rose
R
Mathew
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.
Nancy J
NJ
Reyes
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.
Priyatham S
PS
Mettu
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Scott W
SW
Cousins
Department of Ocular Biology and Therapeutics, University College London (UCL) Institute of Ophthalmology, London, United Kingdom.
Virginia L
VL
Calder
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Daniel R
DR
Saban