Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing

Margadant, Coert; Sonnenberg, Arnoud

doi:10.1038/embor.2009.276

Cited by 550 publications

(485 citation statements)

References 80 publications

(92 reference statements)

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“…For instance, TGF-b contributes to the pathogenesis of systemic sclerosis and scleroderma as well as pulmonary fibrosis (21). Thus, TGF-b-exposed pDC-induced Th17 may contribute to fibrosis-associated diseases (21). In contrast, TGF-b-exposed pDC-induced Th17 may also participate to tissue repair through IL-22 secretion (38) to antagonize fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, disrupted TGF-b regulation leads to fibrosis, an aberrant response to organ injury. For instance, TGF-b contributes to the pathogenesis of systemic sclerosis and scleroderma as well as pulmonary fibrosis (21). Thus, TGF-b-exposed pDC-induced Th17 may contribute to fibrosis-associated diseases (21).…”

Section: Discussionmentioning

confidence: 99%

“…As such, TGF-b plays a dual role, and for instance, it is implicated in both the resolution of inflammation and in the process of chronic inflammation (20). Indeed, TGF-b participates to fibrosis by stimulating extracellular matrix production and deposition as well as fibroblast proliferation and their differentiation into myofibroblasts (21). To date, limited data are available concerning TGF-b and pDC (22,23).…”

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confidence: 99%

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TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

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TGF-β is required for both Foxp3+ regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-β on pDC, and to our knowledge, no study has assessed the capacity of TGF-β–exposed pDC to polarize naive CD4+ T cells. In this paper, we show that TGF-β–treated pDC favor Th17 but not Treg commitment. This process involves a TGF-β/Smad signal, because TGF-β treatment induced Smad2 phosphorylation in pDC and blockade of TGF-β signaling with the SD208 TGF-βRI kinase inhibitor abrogated Th17 commitment induced by TGF-β–treated pDC. Moreover, TGF-β mRNA synthesis and active TGF-β release were induced in TGF-β–treated pDC and anti–TGF-β Ab blocked Th17 commitment. Unexpectedly, TGF-β treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-β–exposed pDC, because elimination of IL-6–mediated signal with either IL-6– or IL-6Rα–specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-β–treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-β–treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-β–rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

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“…This suggests that endogenous CCN1 is, either directly or indirectly, activating the TbR1/ALK5 receptor; alternatively, it may cooperatively augment signaling via this pathway by its binding to integrin receptors. Integrins are known to regulate TGF-b1 signaling through trans-activation of TGF-b1 receptors and downstream signaling (43)(44)(45). CCN1 binds to integrin a avb3 and avb5, which are known to enhance TGF-b signaling by physical association with TGF-bRII (46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Kurundkar

Rangarajan

et al. 2016

FASEB j.

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Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 signaling that promotes lung

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“…Both reactions are potently induced by integrins (2,9). The invasive phenotype in carcinomas is linked to TGFβ-induced epithelial-mesenchymal transition, and the activation of the latent TGFβ complex occurs mainly via binding to integrin αvβ6 in carcinomas (10). The high TGFβ activity will in addition have other effects promoting tumor growth, including the formation of a collagen-rich stiff extracellular matrix (ECM) by resident fibroblast-like cells.…”

Section: Introductionmentioning

confidence: 99%

Common and Diverging Integrin Signals Downstream of Adhesion and Mechanical Stimuli and Their Interplay with Reactive Oxygen Species

Zeller

Johansson

2014

Biophys. Rev. Lett.

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The integrin family of adhesion receptors regulates basic functions of cells, and the signals they induce are altered in tumor cells. In this review we discuss how different integrin-dependent signals are generated during cell adhesion and by physical forces acting on cells. We also describe how reactive oxygen species are integral parts of integrin signaling and highlight a few important questions in the field. Answers to those may improve our understanding of integrins and their role in the development of cancer.

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Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing

Cited by 550 publications

References 80 publications

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Common and Diverging Integrin Signals Downstream of Adhesion and Mechanical Stimuli and Their Interplay with Reactive Oxygen Species

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