Regulation of skin fibrosis by RALDH1-producing dermal dendritic cells via retinoic acid-mediated regulatory T cell induction: A role in scleroderma

Background: Skin fibrosis of systemic sclerosis (SSc) is believed to be driven by complex processes including immune abnormalities, but the underlying immune response remains enigmatic. In particular, the role of dermal dendritic cells (DCs) is totally unknown. Objective: We investigated the impact of CD103 loss on bleomycin-induced skin fibrosis because CD103 is a critical molecule determining DC phenotypes. Methods: Bleomycin-induced skin fibrosis was generated with Cd103^−/− mice. The alterations of tissue fibrosis and related inflammation were investigated by histologic examination, hydroxyproline assay, quantitative reverse transcription PCR and flow cytometry. SSc skin samples were evaluated by immunofluorescence. Results: CD103 loss decreased bleomycin-induced dermal thickness and collagen contents, along with TGF-β1 and CTGF suppression. Treg proportion was increased, while Th1/Th2/Th17 cell proportions were decreased in the skin of bleomycin-treated Cd103^−/− mice. Bleomycin injection enhanced CD11b^-CD103^- DC proportion in wild-type mice, which was further augmented in Cd103^−/− mice. Importantly, RALDH1/ALDH1A1 enzyme oxidizing retinaldehyde to retinoic acid, an inducer of Tregs, was preferentially expressed by CD11b^-CD103^- DCs and its expression levels were elevated in bleomycin-injected skin lesions, to a greater extent in Cd103^−/− mice than in wild-type mice. Importantly, the number of RALDH1-positive DCs was decreased in the lesional skin of SSc patients and tended to inversely correlate with skin fibrosis severity. Conclusion: This study identified a critical role of dermal DCs as a regulator of Treg development through RALDH1 in bleomycin-treated mice and possibly in human SSc. This finding sheds new light on dermal DCs as a new therapeutic target of SSc.