TY - JOUR
T1 - Fli1-haploinsufficient dermal fibroblasts promote skin-localized transdifferentiation of Th2-like regulatory T cells
AU - Saigusa, Ryosuke
AU - Asano, Yoshihide
AU - Taniguchi, Takashi
AU - Hirabayashi, Megumi
AU - Nakamura, Kouki
AU - Miura, Shunsuke
AU - Yamashita, Takashi
AU - Takahashi, Takehiro
AU - Ichimura, Yohei
AU - Toyama, Tetsuo
AU - Yoshizaki, Ayumi
AU - Trojanowska, Maria
AU - Sato, Shinichi
N1 - Funding Information:
Funding for this work was provided as a project grant for research on intractable diseases from the Ministry of Health, Labour, and Welfare of Japan (16H05366).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/2/7
Y1 - 2018/2/7
N2 - Background: Friend leukemia virus integration 1 (Fli1) deficiency, a predisposing factor of systemic sclerosis (SSc), induces SSc-like phenotypes in various cell types. A recent study demonstrated the transdifferentiation of T helper type 2 cell (Th2)-like regulatory T cells (Tregs) in SSc lesional skin through interleukin (IL)-33 produced by fibroblasts. Therefore, we investigated the role of Fli1 deficiency in dermal fibroblast-mediated transdifferentiation of Tregs. Methods: Cytokine expression was assessed in Tregs by flow cytometry and in skin samples and cultivated cells by immunostaining, immunoblotting, and/or qRT-PCR. Fli1 binding to the target gene promoters was examined by chromatin immunoprecipitation. Murine dermal fibroblasts and Tregs were cocultured with or without blocking antibodies against target cytokines. Results: Th2- and Th17-like cell proportions in skin-homing Tregs were increased in bleomycin-treated Fli1 +/- mice compared with bleomycin-treated wild-type mice, whereas Th1-, Th2-, and Th17-like cell proportions in splenic Tregs were comparable. Fli1 +/- fibroblasts overproduced IL-33 and IL-6, in particular IL-33, and Fli1 occupied the IL33 and IL6 promoters in dermal fibroblasts. Importantly, the IL-4-producing cell proportion was significantly higher in wild-type Tregs cocultured with Fli1 +/- fibroblasts than in those cocultured with wild-type fibroblasts, which were canceled by neutralizing anti-IL-33 antibody. Under the same coculture condition, an increased tendency of IL-17A-producing cell proportion, which was possibly mediated by IL-6, was evident. Conclusions: Fli1 haploinsufficiency increases the proportions of Th2- and Th17-like Tregs in bleomycin-induced profibrotic skin conditions, in which IL-33-producing dermal fibroblasts contribute to Th2-like Treg transdifferentiation, suggesting a critical role of Fli1 deficiency in the interaction of dermal fibroblasts with immune cells in pathological skin fibrosis.
AB - Background: Friend leukemia virus integration 1 (Fli1) deficiency, a predisposing factor of systemic sclerosis (SSc), induces SSc-like phenotypes in various cell types. A recent study demonstrated the transdifferentiation of T helper type 2 cell (Th2)-like regulatory T cells (Tregs) in SSc lesional skin through interleukin (IL)-33 produced by fibroblasts. Therefore, we investigated the role of Fli1 deficiency in dermal fibroblast-mediated transdifferentiation of Tregs. Methods: Cytokine expression was assessed in Tregs by flow cytometry and in skin samples and cultivated cells by immunostaining, immunoblotting, and/or qRT-PCR. Fli1 binding to the target gene promoters was examined by chromatin immunoprecipitation. Murine dermal fibroblasts and Tregs were cocultured with or without blocking antibodies against target cytokines. Results: Th2- and Th17-like cell proportions in skin-homing Tregs were increased in bleomycin-treated Fli1 +/- mice compared with bleomycin-treated wild-type mice, whereas Th1-, Th2-, and Th17-like cell proportions in splenic Tregs were comparable. Fli1 +/- fibroblasts overproduced IL-33 and IL-6, in particular IL-33, and Fli1 occupied the IL33 and IL6 promoters in dermal fibroblasts. Importantly, the IL-4-producing cell proportion was significantly higher in wild-type Tregs cocultured with Fli1 +/- fibroblasts than in those cocultured with wild-type fibroblasts, which were canceled by neutralizing anti-IL-33 antibody. Under the same coculture condition, an increased tendency of IL-17A-producing cell proportion, which was possibly mediated by IL-6, was evident. Conclusions: Fli1 haploinsufficiency increases the proportions of Th2- and Th17-like Tregs in bleomycin-induced profibrotic skin conditions, in which IL-33-producing dermal fibroblasts contribute to Th2-like Treg transdifferentiation, suggesting a critical role of Fli1 deficiency in the interaction of dermal fibroblasts with immune cells in pathological skin fibrosis.
KW - Fibroblasts
KW - Fli1
KW - IL-33
KW - Regulatory T cells
KW - Systemic sclerosis
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U2 - 10.1186/s13075-018-1521-3
DO - 10.1186/s13075-018-1521-3
M3 - Article
C2 - 29415756
AN - SCOPUS:85041835793
SN - 1478-6354
VL - 20
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
IS - 1
M1 - 23
ER -