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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Shunsuke Miura, Yusuke Watanabe, Ryosuke Saigusa, Takashi Yamashita, Kouki Nakamura, Megumi Hirabayashi, Takuya Miyagawa, Ayumi Yoshizaki, Maria Trojanowska, Shinichi Sato, Yoshihide Asano
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 23 Issue 1 Pg. 137 (05 08 2021) ISSN: 1478-6362 [Electronic] England
• PMID: 33964960 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fli1 protein, mouse
• Proto-Oncogene Protein c-fli-1
• Aldehyde Dehydrogenase 1 Family
• ALDH1A1 protein, mouse
• Retinal Dehydrogenase

Topics

• Aldehyde Dehydrogenase 1 Family (metabolism)
• Animals
• Dendritic Cells
• Disease Models, Animal
• Fibrosis
• Humans
• Langerhans Cells
• Mice
• Proto-Oncogene Protein c-fli-1 (genetics)
• Retinal Dehydrogenase (metabolism)
• Scleroderma, Systemic (genetics, pathology)
• Skin (pathology)
• T-Lymphocytes, Regulatory