Background/Purpose:  Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by autoimmunity/inflammation, vasculopathy, and tissue fibrosis. Fli1 is a member of Ets family transcription factor, the deficiency of which is a potential predisposing factor of SSc. Although the detailed mechanism explaining Fli1 downregulation still remains unknown, an epigenetic mechanism is reported at least in dermal fibroblasts, and Fli1 deficiency contributes to the induction of an SSc-like phenotype in those cells. A recent study has demonstrated that activated dermal fibroblasts regulate skin-localized transdifferentiation of regulatory T cells (Tregs) into T helper (Th) 2-like cells through the production of IL-33 in SSc, suggesting that activated dermal fibroblasts induce and/or amplify aberrant immune response characteristic of SSc. Based on these backgrounds, we conducted experiments with Fli1^+/-mice to elucidate the potential role of Fli1 deficiency in dermal fibroblast-dependent modification of Tregs.

Methods:  The cytokine expression profile of skin-homing Tregs was assessed by Flow cytometry. Cytokine expression was examined in the skin and cultivated cells by immunostaining and/or quantitative reverse transcription PCR. Fli1 binding to the target gene promoters was assessed by chromatin immunoprecipitation. Co-culture of Fli1^+/- fibroblasts and wild type Tregs was performed with or without blocking antibodies against target cytokines.

Results:  The proportions of Th2- and Th17-like Tregs were increased in the lesional skin of BLM-treated Fli1^+/- mice. Fli1^+/- fibroblasts abundantly expressed IL-33 and IL-6, in particular IL-33, and Fli1 occupied the promoters of the IL33 and IL6 genes in human dermal fibroblasts. More importantly, the proportions of IL-4- and IL-17A-producing cells were higher in wild type Tregs co-cultured with Fli1^+/- fibroblasts than in those co-cultured with wild type fibroblasts. To investigate the impact of IL-33 and IL-6 overexpression in Fli1^+/- fibroblasts on Tregs, we next co-cultured them in the presence of neutralizing antibodies against these cytokines, which revealed that the increased proportions of IL-4- and IL-17A-producing Tregs co-cultured with Fli1^+/- fibroblasts were decreased by neutralizing IL-33 and IL-6, respectively.

Conclusion:  IL-33 and IL-6 overexpression in dermal fibroblasts due to Fli1 deficiency may contribute to the induction of Th2- and Th17-like Tregs in the skin, respectively, leading to the development of skin fibrosis in SSc. These data indicate a pivotal contribution of Fli1-deficienct dermal fibroblasts to the aberrant immune response in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fli1-haploinsufficient-dermal-fibroblasts-promote-skin-localized-transdifferentiation-of-th2-and-th17-like-regulatory-t-cells/