Fli1 deficiency suppresses RALDH1 activity of dermal dendritic cells and related induction of regulatory T cells: a possible role in scleroderma

• Published in: Arthritis research & therapy Vol. 23; no. 1; p. 137
• Main Authors: Miura, Shunsuke, Watanabe, Yusuke, Saigusa, Ryosuke, Yamashita, Takashi, Nakamura, Kouki, Hirabayashi, Megumi, Miyagawa, Takuya, Yoshizaki, Ayumi, Trojanowska, Maria, Sato, Shinichi, Asano, Yoshihide
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08.05.2021; BioMed Central; BMC
• Subjects: Acids; Aldehyde Dehydrogenase 1 Family - metabolism; Aldehyde dehydrogenase 1 family member A1; Animals; Antibodies; Antigens; Arthritis; Biotechnology; Dehydrogenases; Dendritic Cells; Dermal dendritic cells; Development and progression; Disease Models, Animal; Enzymes; Fibroblasts; Fibrosis; Fli1; Health aspects; Humans; Langerhans Cells; Lymphatic system; Lymphocytes; Medical research; Mice; Oxidoreductases; Pathogenesis; Physiological aspects; Proto-Oncogene Protein c-fli-1 - genetics; Regulatory T cells; Retinal Dehydrogenase - metabolism; Scleroderma; Scleroderma (Disease); Scleroderma, Systemic - genetics; Scleroderma, Systemic - pathology; Skin - pathology; Statistical analysis; Suppressor cells; Systemic scleroderma; Systemic sclerosis; T-Lymphocytes, Regulatory; Transcription factors; Japan; United States > US; Dermal dendritic cells; Aldehyde dehydrogenase 1 family member A1; Regulatory T cells; Systemic sclerosis; Fli1
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-021-02520-z

Aldehyde dehydrogenase 1 family member A1 (RALDH1)-producing dermal dendritic cells (DCs), a conventional DC subset regulating skin fibrosis, are decreased in the involved skin of patients with systemic sclerosis (SSc). In this study, we investigated the contribution of Fli1 deficiency, a potential predisposing factor of SSc, to the phenotypical alteration of RALDH1-producing dermal DCs by using SSc model mice and SSc skin samples. Bleomycin (BLM)-induced skin fibrosis was generated with Fli1 and wild-type mice. The proportions of DC and CD4 T cell subsets were determined by flow cytometry in the dermis of BLM-treated mice. Fli1 expression in dermal DCs was evaluated by immunofluorescence with skin samples of SSc and healthy control subjects. RALDH activity of dermal DCs was significantly decreased in BLM-treated Fli1 mice compared with BLM-treated wild-type mice, whereas the proportion of CD103 CD11b dermal DCs, a major DC subset producing RALDH1 in response to BLM injection, was comparable between groups. Relevant to this finding, the proportion of regulatory T cells (Tregs) in the dermis was decreased in BLM-treated Fli1 mice relative to BLM-treated wild-type mice, while the proportions of Th1, Th2 and Th17 cells were unaltered. In the involved skin of SSc patients, Fli1 was downregulated in CD11c cells, including dermal DCs. Fli1 deficiency inhibits RALDH1 activity of CD103 CD11b dermal DCs and related induction of Tregs in BLM-treated mice. Considering Fli1 reduction in SSc dermal DCs, Fli1deficiency may impair the dermal DC-Treg system, contributing to the development of skin fibrosis in SSc.