These results suggest that sPD-1 and sPD-L2 contribute to disease development in SSc via the regulation of cognate interactions with T cells and B cells.
The insufficiency of Friend leukaemia virus integration 1 (Fli1), a member of the Ets family transcription factors, is implicated in the pathogenesis of vasculopathy associated with systemic sclerosis (SSc). Fli1 deficiency accelerates early steps of angiogenesis, including detachment of pre-existing pericytes and extracellular matrix degradation by endothelial proteinases, but the impact of Fli1 deficiency on the other steps of angiogenesis has not been investigated. Therefore, we evaluated the effect of Fli1 deficiency on migration, proliferation, cell survival and tube formation of human dermal microvascular endothelial cells (HDMECs). HDMECs transfected with FLI1 siRNA exhibited a greater migratory property in scratch assay and transwell migration assay and a higher proliferation rate in BrdU assay than HDMECs transfected with non-silencing scrambled RNA. In flow cytometry-based apoptosis assay, FLI1 siRNA-transduced HDMECs revealed the decreased number of annexin and propidium iodide-double-positive apoptotic cells compared with control cells, reflecting the promotion of cell survival. On the other hand, tubulogenic activity on Matrigel was remarkably suppressed in Fli1-deficient HDMECs relative to control cells. These results indicate that Fli1 deficiency promotes migration, proliferation and cell survival, while abating tube formation of endothelial cells, suggesting that Fli1 deficiency is potentially attributable to the development of both proliferative obliterative vasculopathy (occlusion of arterioles and small arteries) and destructive vasculopathy (loss of small vessels) characteristic of SSc vasculopathy.
Dermal fibroblasts promote skin-localized transdifferentiation of regulatory T cells to T helper (Th) type 2-like cells in systemic sclerosis (SSc). However, the entire effect of SSc dermal fibroblasts on immune cells still remains unknown. Because galectin-9 induces Th2 cytokine-predominant immune imbalance by negatively regulating Th1/Th17 cells in inflammatory diseases, we investigated the contribution of galectin-9 to Th immune balance in SSc lesional skin. We used human clinical samples and Fli1 mice because Fli1 deficiency induces SSc-like phenotypes in various cell types. Galectin-9 was overexpressed in SSc dermal fibroblasts in vivo and in vitro. Serum galectin-9 levels were significantly elevated in SSc patients and positively correlated with skin score. Galectin-9 was up-regulated by autocrine endothelin stimulation and Fli1 deficiency, and Fli1 occupied the LGALS9 promoter in dermal fibroblasts. Co-culture of splenic CD4 T cells with Fli1 dermal fibroblasts significantly increased IL-4-producing cell proportion, and this effect was cancelled in parallel with the increased interferon-γ production when Fli1 dermal fibroblasts were transfected with Lgals9 small interfering RNA. Furthermore, Lgals9 small interfering RNA suppressed dermal collagen deposition by increasing interferon-γ production of skin-infiltrating CD4 T cells in bleomycin-treated mice. These results suggest that SSc dermal fibroblasts suppress interferon-γ expression of skin-infiltrating CD4 T cells through galectin-9 overproduction, promoting skin fibrosis development.
BackgroundFriend 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.MethodsCytokine 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.ResultsTh2- 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.ConclusionsFli1 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.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1521-3) contains supplementary material, which is available to authorized users.
In order to suppress the power consumption in low-voltage processors, a threshold voltage hopping (TH-hopping) scheme is proposed where the threshold voltage is dynamically controlled through software depending on a workload. TH-hopping is shown to reduce the power to 18% of the fixed low-threshold voltage circuits in 0.5-V supply voltage regime for multimedia applications. A positive back-gate bias scheme with TH-hopping is presented for the high-performance and low-voltage processors. In order to verify the effectiveness of TH-hopping, a small-scale RISC processor with TH-hopping capability and the positive back-gate bias scheme is fabricated in a 0.6m CMOS technology. MPEG4 encoding is simulated based on the measured data. The result shows that 86% power saving can be achieved by using TH-hopping compared with the fixed positive back-gate bias scheme.
In order to investigate the topological effects of chain molecules, united-atom molecular dynamics simulations of a 500-mer polyethylene linked by 50 hexyl groups (a grafted polymer having 52 ends) are carried out and analyzed in terms of Voronoi space division. We find that the volume of a Voronoi polyhedron for a chain end is larger than that for an internal or junction atom, and that it is the most sensitive to temperature, both of which suggest higher mobility of chain ends. Moreover, chain ends dominantly localize at the surface of the globule: The striking evidence is that while the ratio of surface atoms is only 24% of all atoms, the ratio of ends at the surface is 91% out of all ends. The shape of Voronoi polyhedra for internal atoms is prolate even in the bulk, and near the surface it becomes more prolate. We propose the concept of bonding faces, which play a significant role in the Voronoi space division of covalently bonding polymers. Two bonding faces occupy 38% of the total surface area of a Voronoi polyhedron and determine the prolate shape.
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.
Interleukin (IL)-34 is a hematopoietic cytokine promoting proliferation and differentiation of macrophages. Because abnormal activation of macrophages is involved in the development of systemic sclerosis (SSc), we investigated serum IL-34 levels in patients with SSc. Serum IL-34 levels were significantly increased in diffuse cutaneous SSc compared with limited cutaneous SSc and healthy controls, while there were no significant differences between limited cutaneous SSc and healthy controls. In addition, SSc patients with increased serum IL-34 levels more often had interstitial lung disease (ILD) than those with normal levels. Moreover, in SSc patients, serum IL-34 levels negatively correlated with the percentage of predicted vital capacity, while they positively correlated with ground-glass opacity score and fibrotic score on chest computed tomography. Collectively, increased serum IL-34 levels were associated with greater frequency and severity of ILD in SSc patients. Serum IL-34 levels may be a useful serological marker for SSc-associated ILD.
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