Suppressive Regulation by MFG‐E8 of Latent Transforming Growth Factor β–Induced Fibrosis via Binding to αv Integrin: Significance in the Pathogenesis of Fibrosis in Systemic Sclerosis

Fujiwara, Chisako; Uehara, Akihito; Sekiguchi, Akiko; Uchiyama, Akihiko; Yamazaki, Sunao; Ogino, Sachiko; Yokoyama, Yoko; Torii, Ryoko; Hosoi, Mari; Suto, Chiaki; Tsunekawa, Katsuhiko; Murakami, Masami; Ishikawa, Osamu; Motegi, Sei‐ichiro

doi:10.1002/art.40701

Cited by 16 publications

(24 citation statements)

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“…Integrin‐dependent efferocytosis is indirect and mediated by MFG‐E8, a protein secreted by MΦ and dendritic cell, which acts as a link between “eat me” signals on apoptotic cells and integrins on phagocytic cells . A recent report by Fujiwara et al described of MFG‐E8 in the serum of SSc patients and more severe fibrotic manifestations in mouse models of SSc knockout for MFG‐E8 . Interestingly, MFG‐E8 knockout mice also presented autoimmune features including an increased production of autoantibodies such as ANA .…”

Section: Resultsmentioning

confidence: 99%

“…18 A recent report by Fujiwara et al described of MFG-E8 in the serum of SSc patients and more severe fibrotic manifestations in mouse models of SSc knockout for MFG-E8. 19 Interestingly, MFG-E8 knockout mice also presented autoimmune features including an increased production of autoantibodies such as ANA. 19,20 Therefore, these results in mouse models suggest that integrinmediated efferocytosis by phagocytic cells might play a key role in the prevention of autoimmunity.…”

Section: Comparison Of Efferocytosis Capacities Of Monocytederived Mamentioning

confidence: 99%

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Efferocytosis capacities of blood monocyte‐derived macrophages in systemic sclerosis

et al. 2018

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A defect in the apoptotic cell clearance (efferocytosis) by phagocytic cells may participate in autoimmunity and chronic inflammation. The mechanisms leading to the emergence of autoimmunity in systemic sclerosis (SSc) are still to be determined. In this study, the efferocytosis capacities of blood monocyte‐derived macrophages (MDM) from patients with SSc were evaluated. Blood monocytes obtained from patients with SSc and healthy donors (HD) were differentiated in vitro into macrophages. The capacities of MDM to engulf CFSE+ apoptotic Jurkat human T lymphocytes were compared between SSc MDM and HD using flow cytometry. The expression of classical engulfing receptors in SSc MDM and HD MDM was also evaluated and their involvement in the modulation of efferocytosis was confirmed using a siRNA approach. The mean phagocytic index (PI) reflecting efferocytosis capacities of SSc MDM (PI = 19.3 ± 3.0; n = 21) was significantly decreased in comparison with the PI of HD MDM (PI = 35.9 ± 3.0; n = 31; P < 0.001). In comparison with HD, SSc MDM exhibited a downregulated expression of scavenger receptor (SR)‐B1, SR‐A1 and integrin β5 (ITGβ5). In HD MDM, the extinction of these receptors was followed by a reduction of efferocytosis only for the repression of ITGβ5, suggesting a possible selective role of this integrin in the impaired efferocytosis observed in SSc. As efferocytosis may be at the crossroads of inflammation, autoimmunity and fibrosis, in showing impaired efferocytosis capacities of blood MDM in SSc, our study offers new pathogenesis considerations for the involvement of macrophages in the autoimmune processes driving this disorder.

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Section: Resultsmentioning

confidence: 99%

Section: Comparison Of Efferocytosis Capacities Of Monocytederived Mamentioning

confidence: 99%

Efferocytosis capacities of blood monocyte‐derived macrophages in systemic sclerosis

et al. 2018

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“…Dermal fibrosis was induced in 8-week-old C57BL/6 or OKD48 (Keap1-dependent oxidative stress detector, NO-48) mice with injections of bleomycin. Injections of 300 ml of bleomycin (Nippon Kayaku) at a concentration of 1 mg/ml were given 5 times per week for 2 weeks as previously described [16,17]. To examine the effect of kaempferol, mice received intraperitoneally kaempferol (40 mg/ kg/day) dissolved in 100 ml of DMSO or DMSO alone 5 times per week for 2 weeks.…”

Section: Bleomycin-induced Skin Fibrosis Modelmentioning

confidence: 99%

“…Total soluble collagen in the skin was quantified using a Sircol collagen assay (Biocolor, County Antrim, UK) according to the manufacturer's protocol and the previously described protocols [17,18].…”

Section: Quantitative Assessment Of Collagen Contentmentioning

confidence: 99%

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Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress

Sekiguchi

Motegi

Fujiwara

et al. 2019

Journal of Dermatological Science

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iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Rispoli,

Scandiuzzi Piovesan,

Decorti

et al. 2023

WIREs Mechanisms of Disease

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Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC‐derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs‐derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC‐derived 2D models, iPSC‐derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC‐derived organoids present advantages in terms of versatility, patient‐specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs.This article is categorized under: Cancer > Stem Cells and Development

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Suppressive Regulation by MFG‐E8 of Latent Transforming Growth Factor β–Induced Fibrosis via Binding to αv Integrin: Significance in the Pathogenesis of Fibrosis in Systemic Sclerosis

Cited by 16 publications

References 50 publications

Efferocytosis capacities of blood monocyte‐derived macrophages in systemic sclerosis

Efferocytosis capacities of blood monocyte‐derived macrophages in systemic sclerosis

Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

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