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

Authors :
Miura, Shunsuke
Watanabe, Yusuke
Saigusa, Ryosuke
Yamashita, Takashi
Nakamura, Kouki
Hirabayashi, Megumi
Miyagawa, Takuya
Yoshizaki, Ayumi
Trojanowska, Maria
Sato, Shinichi
Asano, Yoshihide
Source :
Arthritis Research & Therapy (formerly Arthritis Research); December 2021, Vol. 23 Issue: 1
Publication Year :
2021

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<superscript>+/−</superscript>and wild-type mice. The proportions of DC and CD4<superscript>+</superscript>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<superscript>+/−</superscript>mice compared with BLM-treated wild-type mice, whereas the proportion of CD103<superscript>−</superscript>CD11b<superscript>−</superscript>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<superscript>+/−</superscript>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<superscript>+</superscript>cells, including dermal DCs. Conclusions: Fli1 deficiency inhibits RALDH1 activity of CD103<superscript>−</superscript>CD11b<superscript>−</superscript>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.

Details

Language :
English
ISSN :
14786354 and 14786362
Volume :
23
Issue :
1
Database :
Supplemental Index
Journal :
Arthritis Research & Therapy (formerly Arthritis Research)
Publication Type :
Periodical
Accession number :
ejs56164941
Full Text :
https://doi.org/10.1186/s13075-021-02520-z