Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Arthritis Center, Boston University School of Medicine, Boston, MA, USA.
Arthritis Res Ther. 2021 May 8;23(1):137. 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 CD103CD11b 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 CD103CD11b 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.
醛脱氢酶 1 家族成员 A1（RALDH1）产生的真皮树突状细胞（DCs）是调节皮肤纤维化的常规 DC 亚群，在系统性硬皮病（SSc）患者受累皮肤中减少。在这项研究中，我们通过 SSc 模型小鼠和 SSc 皮肤样本研究了 Fli1 缺陷（SSc 的潜在易感因素）对 RALDH1 产生的真皮 DC 表型改变的贡献。
用 Fli1 和野生型小鼠诱导博来霉素（BLM）诱导的皮肤纤维化。通过流式细胞术在 BLM 处理的小鼠真皮中确定 DC 和 CD4 T 细胞亚群的比例。用 SSc 和健康对照受试者的皮肤样本通过免疫荧光评估真皮 DC 中的 Fli1 表达。
与 BLM 处理的野生型小鼠相比，BLM 处理的 Fli1 小鼠真皮 DC 的 RALDH 活性显着降低，而对 BLM 注射产生 RALDH1 的主要 DC 亚群 CD103CD11b 真皮 DC 的比例在两组之间相当。与此发现相关的是，BLM 处理的 Fli1 小鼠中真皮中的调节性 T 细胞（Tregs）比例相对于 BLM 处理的野生型小鼠降低，而 Th1、Th2 和 Th17 细胞的比例不变。在 SSc 患者的受累皮肤中，Fli1 在包括真皮 DC 在内的 CD11c 细胞中下调。
Fli1 缺乏抑制 BLM 处理小鼠中 CD103CD11b 真皮 DC 的 RALDH1 活性和相关的 Treg 诱导。考虑到 SSc 真皮 DC 中的 Fli1 减少，Fli1 缺陷可能会破坏真皮 DC-Treg 系统，导致 SSc 皮肤纤维化的发展。
