Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma

Takahashi, Takehiro; Asano, Yoshihide; Sugawara, Koji; Yamashita, Takashi; Nakamura, Kouki; Saigusa, Ryosuke; Ichimura, Yohei; Toyama, Tetsuo; Taniguchi, Takashi; Akamata, Kaname; Noda, Shinichi; Yoshizaki, Ayumi; Tsuruta, Daisuke; Trojanowska, Maria; Sato, Shinichi

doi:10.1084/jem.20160247

Cited by 77 publications

(74 citation statements)

References 86 publications

(135 reference statements)

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“…Pathological activation of epithelial keratinocytes may also play a role in fibrogenesis. Takahashi et al demonstrated that knockout of the transcription factor FLI1 in keratinocytes results in autoimmunity and fibrosis 32. Our immunohistochemical data suggest that PARP-1 expression is also decreased in keratinocytes of patients with SSc, and this mechanism may also be relevant for the pathogenesis of SSc.…”

Section: Discussionsupporting

confidence: 61%

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

et al. 2018

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Section: Discussionsupporting

confidence: 61%

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

et al. 2018

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“…On the other hand, it is generally accepted that dcSSc is characterized by Th2/Th17-skewed immune polarization, especially in its active phase, 41,42 and that IL-4, IL-13 and IL-17A, which are representative cytokines produced by Th2 and Th17 cells, are involved in the development of SSc-associated tissue fibrosis. [43][44][45] Given that various types of cells, such as dermal fibroblasts, endothelial cells, keratinocytes and macrophages, coordinately generate the microenvironment preferentially promoting Th2/Th17-skewed immune polarization in fibrotic organs of SSc, 35,[46][47][48][49] it is plausible that serum CXCL14 levels are decreased in SSc patients, especially in dcSSc patients.…”

Section: Discussionmentioning

confidence: 99%

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

Fukui

Miyagawa

Hirabayashi

et al. 2019

The Journal of Dermatology

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CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T‐helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14‐mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17‐skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2‐skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc.

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“…123 The deficiency of transcription factor Fli1, which is epigenetically suppressed in SSc lesional skin, 124 recapitulates SSc-like phenotypes in various cell types, including keratinocytes. 41,53,123,125 Of note, epithelial cell-specific Fli1 knockout mice (Fli1 flox/flox ;K14-Cre mice), which possess epithelial cells with SSc-like properties, spontaneously develop dermal and esophageal fibrosis due to the activation of epithelial cells in the skin and esophagus. Furthermore, this murine model spontaneously develops interstitial lung disease mediated at least by autoreactive T cells to lung antigens due to the impairment of negative selection and Treg development in the thymus.…”

Section: Potential Role Of Epithelial Cells In the Pathogenesis Of Sscmentioning

confidence: 99%

Systemic sclerosis

Asano

2017

The Journal of Dermatology

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100

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Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by vasculopathy and tissue fibrosis of the skin and various internal organs. A series of genetic and epidemiological studies have demonstrated that SSc onset is determined by the accumulation of predisposing factors related to environmental influences, while genetic factors affect the susceptibility to and the severity of this disease. This notion has been confirmed by recent advance in animal models. The initial trigger of SSc is believed to be autoimmune attacks to endothelial cells, which occur in individuals with the genetic susceptibility to autoimmune diseases and/or the cumulative exposure to certain SSc-related environmental influences. Then, endothelial cells are aberrantly activated or damaged, leading to the development of vascular structural changes, such as destructive vasculopathy and proliferative obliterative vasculopathy, and tissue fibrosis. In parallel, inflammatory cells activate SSc fibroblasts and modify the metabolism of extracellular matrix by soluble factors and autoantibodies. Prior to or during these processes, SSc fibroblasts acquire the ability to selectively respond to profibrotic growth factors and cytokines, persistently producing excessive amount of extracellular matrix. SSc fibroblasts also modify immune responses, at least those of CD4 T cells, in the microenvironment through the secretion of immune regulatory molecules. Thus, various types of individually activated cells interact with each other and coordinately drive an SSc-specific disease cascade, leading to the development of unique clinical symptoms. This article provides an overview of the current understanding of the pathogenesis of SSc with the recent advance in the research field of this disease.

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Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma

Cited by 77 publications

References 86 publications

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

Systemic sclerosis

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