Scleroderma, fibroblasts, signaling, and excessive extracellular matrix

Ihn, Hironobu

doi:10.1007/s11926-005-0069-9

Cited by 41 publications

(29 citation statements)

References 84 publications

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“…Fibrosis is a hallmark of many connective tissue diseases, including scleroderma and systemic sclerosis (reviewed by Ihn 2005;Krieg et al 2007;Olson and Soriano 2009). One of the factors expressed by keratinocytes that promotes fibroblast activation in systemic sclerosis is IL1-a (Aden et al 2010).…”

Section: Fibrosismentioning

confidence: 99%

“…TGF-b is a key mediator of fibrosis and acts by stimulating fibroblast proliferation and ECM synthesis (Ihn 2005;Trojanowska 2002). TGF-b also inhibits ECM degradation by downregulating MMP-1, which mediates collagen degradation, and up-regulating tissue inhibitors of matrix metalloproteinases (TIMPs) (Ihn 2005).…”

Section: Fibrosismentioning

confidence: 99%

“…TGF-b also inhibits ECM degradation by downregulating MMP-1, which mediates collagen degradation, and up-regulating tissue inhibitors of matrix metalloproteinases (TIMPs) (Ihn 2005). Activation of the TGF-b pathway in postnatal fibroblasts is sufficient to induce skin fibrosis in mice, including epidermal thinning, loss of hair follicles and dermal fibrosis (Sonnylal et al 2007).…”

Section: Fibrosismentioning

confidence: 99%

“…Increased PDGFRa signaling is sufficient to drive excessive fibroblast proliferation and ECM deposition, and acts either independently or downstream from TGF-b (Olson and Soriano 2009). CTGF, which also modulates fibroblast growth and ECM synthesis, is induced by TGF-b (Ihn 2005).…”

Section: Fibrosismentioning

confidence: 99%

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Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Watt

Fujiwara²

2011

Cold Spring Harbor Perspectives in Biology

320

269

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Mammalian skin comprises a multi-layered epithelium, the epidermis, and an underlying connective tissue, the dermis. The epidermal extracellular matrix is a basement membrane, whereas the dermal ECM comprises fibrillar collagens and associated proteins. There is considerable heterogeneity in ECM composition within both epidermis and dermis. The functional significance of this extends beyond cell adhesion to a range of cell autonomous and nonautonomous processes, including control of epidermal stem cell fate. In skin, cell-ECM interactions influence normal homeostasis, aging, wound healing, and disease. Disturbed integrin and ECM signaling contributes to both tumor formation and fibrosis. Strategies for manipulating cell-ECM interactions to repair skin defects and intervene in a variety of skin diseases hold promise for the future.

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Section: Fibrosismentioning

confidence: 99%

Section: Fibrosismentioning

confidence: 99%

Section: Fibrosismentioning

confidence: 99%

Section: Fibrosismentioning

confidence: 99%

See 2 more Smart Citations

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Watt

Fujiwara²

2011

Cold Spring Harbor Perspectives in Biology

320

269

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“…As the disease progresses, the vascular inflammation becomes more fibrotic in nature with the accumulation of extracellular matrix composed of different collagen types, proteoglycans, and elastic fibers such as fibrillin (3,4) The mechanisms that promote immune dysfunction and fibrosis are poorly understood. In recent years, experimental models focusing on the fibrotic remodeling component of SSc have highlighted a role for the TGF-b pathway (5)(6)(7)(8). Direct targeting of this critical pathway has proved a complex undertaking due to anti-inflammatory and wound healing activities of TGF-b (9), but recent demonstration of clinical improvement in SSc patients treated with fresolimumab supports a fibrogenic role for TGF-b in human disease (10).…”

mentioning

confidence: 99%

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Delaney¹,

Morehouse²,

Brohawn³

et al. 2016

The Journal of Immunology

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Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-α levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma.

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Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin‐4 from T cells

Distler

Jüngel

Caretto

et al. 2005

Arthritis & Rheumatism

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Objective. Monocyte chemoattractant protein 1 (MCP-1; CCL2) has been implicated in the pathogenesis of fibrotic diseases and is up-regulated in patients with systemic sclerosis (SSc). The aim of the present study was to examine the mechanisms by which MCP-1 mediates its profibrotic effects in the setting of SSc.Methods. The expression of receptors for MCP-1 on dermal fibroblasts was analyzed by real-time polymerase chain reaction and fluorescence-activated cell sorting. The ability of extracellular matrix proteins to bind and release MCP-1 was quantified by enzymelinked immunosorbent assay. Th0 cells were isolated using a magnetic-activated cell sorting system and were stimulated twice in the presence of MCP-1. The synthesis of collagen was measured using the Sircol collagen assay kit.Results. The glycosaminoglycan chondroitin sulfate, but not fibronectin or collagens, bound and released MCP-1 in a time-dependent manner. MCP-1 that was released from chondroitin sulfate induced the differentiation of interleukin-4 (IL-4)-producing T cells in a dose-dependent manner. In turn, dermal fibroblasts from patients with SSc expressed IL-4 receptor, and stimulation with IL-4 significantly increased the production of collagen in dermal fibroblasts. In contrast, CCR2a and CCR2b, as well as D6 and US28 (other potential receptors of MCP-1), were not detectable in SSc and normal fibroblasts, and their expression was not induced by platelet-derived growth factor, IL-1␤, or IL-4. In addition, MCP-1 had no direct effects on collagen production by fibroblasts.Conclusion. MCP-1 has no direct effects on dermal fibroblasts but contributes to fibrosis in patients with SSc by inducing the differentiation of IL-4-producing T cells. Because MCP-1 has both proinflammatory and profibrotic effects, pharmacologic targeting of MCP-1 could be a promising therapeutic approach in SSc.Systemic sclerosis (SSc) is a chronic fibrotic disorder of unknown etiology that affects the skin and a variety of internal organs. In the early stages of disease, inflammatory infiltrates are a histopathologic hallmark of SSc. The inflammatory infiltrates are T cell dominated and localized predominantly in perivascular regions. Later stages of the disease are characterized by an excessive accumulation of extracellular matrix components. The extracellular matrix components are produced by activated fibroblasts and include glycosaminoglycans (GAGs) such as chondroitin sulfate, fibronectin, type I collagen, type III collagen, type VI collagen, and type VII collagen (1,2).The mechanisms leading to the activation of

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Scleroderma, fibroblasts, signaling, and excessive extracellular matrix

Cited by 41 publications

References 84 publications

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin‐4 from T cells

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