Systemic Sclerosis Dermal Fibroblasts Suppress Th1 Cytokine Production via Galectin-9 Overproduction due to Fli1 Deficiency

Saigusa, Ryosuke; Asano, Yoshihide; Nakamura, Kouki; Hirabayashi, Megumi; Miura, Shunsuke; Yamashita, Takashi; Taniguchi, Takashi; Ichimura, Yohei; Takahashi, Takehiro; Yoshizaki, Ayumi; Miyagaki, Tomomitsu; Sugaya, Makoto; Sato, Shinichi

doi:10.1016/j.jid.2017.04.035

Cited by 32 publications

(22 citation statements)

References 36 publications

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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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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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“…So far, a total of 15 mammalian galectins have been identified, [ ] and we and others have previously reported that some of galectins are potentially involved in the development of SSc. [ ] Galectin‐7 is a prototype galectin that appears in all types of stratified epithelia, but not in simple and transitional epithelia, serving as a marker of both keratinized and non‐keratinized stratified epithelia. [ ] The gene encoding galectin‐7 was first described for its responsiveness to retinoic acid and for its downregulated expression in actively proliferating keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

A potential contribution of decreased galectin‐7 expression in stratified epithelia to the development of cutaneous and oesophageal manifestations in systemic sclerosis

Saigusa

Yamashita

Miura

et al. 2019

Experimental Dermatology

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Backgrounds Stratified epithelia have caught much attention as potential contributors to the development of dermal and oesophageal fibrosis in systemic sclerosis (SSc). Galectin‐7 is a marker of all types of stratified epithelia, which is involved in the maintenance of epidermal homeostasis. So far, the role of galectin‐7 has not been studied in SSc. Objectives To investigate the potential contribution of galectin‐7 to the development of clinical manifestations in SSc. Methods Galectin‐7 expression was examined in skin samples and cultured keratinocytes by immunostaining and/or quantitative reverse transcription PCR. Serum galectin‐7 levels were determined by enzyme‐linked immunosorbent assay in 63 SSc and 20 healthy subjects. Results Galectin‐7 expression was markedly decreased in the epidermis of SSc lesional skin compared with that of healthy control skin. Serum galectin‐7 levels were significantly lower in SSc patients than in healthy controls and inversely correlated with skin score. In addition, SSc patients with diffuse pigmentation and those with oesophageal dysfunction had significantly decreased serum galectin‐7 levels as compared to those without each symptom. Importantly, endothelin‐1 stimulation suppressed galectin‐7 expression in normal human keratinocytes, and bosentan, a dual endothelin receptor antagonist, reversed circulating galectin‐7 levels and epidermal galectin‐7 expression in SSc patients. Conclusions Galectin‐7 downregulation in stratified epithelia, which is mediated at least partially by autocrine endothelin stimulation, may contribute to the development of cutaneous manifestations and oesophageal dysfunction in SSc patients.

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“…In SSc patients, galectin‐9 is overexpressed in SSc dermal fibroblasts, and serum galectin‐9 levels are significantly elevated and positively correlated with skin score in SSc patients. Importantly, galectin‐9‐producing dermal fibroblasts increase the proportion of the IL‐4‐producing CD4 + T cell population in co‐culture assay, and galectin‐9 loss suppresses dermal collagen deposition by increasing IFN‐γ production of skin‐infiltrating CD4 + T cells in bleomycin‐treated mice . Therefore, it is speculated that SSc dermal fibroblasts suppress IFN‐γ expression of skin‐infiltrating CD4 + T cells through galectin‐9 overproduction, promoting skin fibrosis development in the Th2/Th17 predominant microenvironment.…”

Section: Activation Of Fibroblastsmentioning

confidence: 99%

Systemic sclerosis

Asano

2017

The Journal of Dermatology

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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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Systemic Sclerosis Dermal Fibroblasts Suppress Th1 Cytokine Production via Galectin-9 Overproduction due to Fli1 Deficiency

Cited by 32 publications

References 36 publications

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

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

A potential contribution of decreased galectin‐7 expression in stratified epithelia to the development of cutaneous and oesophageal manifestations in systemic sclerosis

Systemic sclerosis

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