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The CCL20–integrin α5β1 interaction enhances TGF-β/Smad signaling to promote fibroblast activation and facilitate pulmonary fibrosis

ABSTRACT: Limited therapeutic options are available for pulmonary fibrosis (PF) because its molecular pathogenesis remains unclear. Here, we found that chemokine (C-C motif) ligand 20 (CCL20) expression was increased in murine PF models and PF patients. Type 2 alveolar epithelial cells (AEC2s) were identified as the major producers of CCL20, and increased CCL20 expression resulted from decreased expression of the transcription factor JUN. AEC2-specific deletion of CCL20 protected mice from bleomycin (BLM)-induced PF. Mechanistic studies revealed that CCL20 interacted with integrin α5β1, but not the classical receptor CCR6, on fibroblasts and subsequently enhanced transforming growth factor-β (TGF-β)/Smad signaling, which promoted the differentiation of lung fibroblasts into myofibroblasts. Antibody blockade of CCL20 or disruption of the CCL20–integrin α5β1 interaction attenuated established PF. Overall, our study highlights the CCL20–integrin α5β1–TGF-β signaling cascade as a potential therapeutic target for PF.

ORGANISM(S): Homo Sapiens

SUBMITTER: Shanshan Liu

PROVIDER: PXD064810 | iProX | Tue Jun 10 00:00:00 BST 2025

REPOSITORIES: iProX

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The CCL20-integrin α5β1 interaction enhances TGF-β/Smad signaling to promote fibroblast activation and facilitate pulmonary fibrosis

Project description:Pulmonary fibrosis (PF) has limited therapeutic options because its molecular pathogenesis remains unclear. Chemokine (C-C motif) ligand 20 (CCL20) plays crucial roles in the pathogenesis of various immune diseases. However, its role in PF is unknown. Here, we showed that CCL20 expression was significantly increased in the lung tissues of PF mouse models and PF patients compared with healthy controls. Type 2 alveolar epithelial cells (AEC2s) were identified as the major producers of CCL20, and increased CCL20 expression resulted from decreased expression of the transcription factor JUN. AEC2-specific deletion of CCL20 protected mice from bleomycin (BLM)-induced PF. Mechanistic studies revealed that CCL20 interacted with integrin α5β1, but not the classical receptor CCR6, on fibroblasts and subsequently enhanced transforming growth factor-β (TGF-β)/Smad signaling, which promoted the differentiation of lung fibroblasts into myofibroblasts. Antibody blockade of CCL20 or disruption of the CCL20-integrin α5β1 interaction reduced established PF. Overall, our study highlights the CCL20-integrin α5β1-TGF-β signaling cascade as a potential therapeutic target for PF.

2025-02-24 | PXD061156 |

The role of aV Integrin in regulating macrophage phenotype and function during cardiac remodeling after myocardial infarction

Project description:Macrophages infiltrate the infarcted heart and play a critical role in repair, remodeling and fibrosis. Macrophages sense changes in the extracellular matrix (ECM) environment through Integrins, thus activating signaling pathways that regulate their function. Our data show that av integrin is highly expressed in isolated bone marrow macrophages and is markedly upregulated in response to TGF-β, a growth factor known to be activated in the infarcted heart. Accordingly, we hypothesize that aV integrin induction in infarct macrophages may regulate macrophage phenotype, function and response to key macrophage-activating signals following MI.

2022-12-31 | GSE190868 | GEO

Whole-genome microarray analysis of human skin fibroblasts

Project description:Connective tissue growthfactor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor-beta (TGF-beta) and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We have previously shown that keratinocytes in vitro downregulate TGF-beta induced expression of CTGF in fibroblasts by an interleukin-1 alfa (IL-1alfa) dependent mechanism. With this study we want to get a better overall perspective who fibroblasts respond on TGF-beta and in a TGF-Beta stinulated system, what effect addition of IL-1 alfa have. This to understand the expression of CTGF in human fibroblasts which in turn have implications for the pathogenesis of fibrotic conditions involving the skin. Microarray was performed on human skin fibroblast RNA from one patient, Fibroblasts were seeded in vitro as a control (Control, C), TGF-beta were added to fibroblasts and incubated for 16 h (addition of TGF-beta, T) and both IL-1alfa and TGF-beta were added to fibroblasts for 16 h (addition of IL-1alfa and TGF-beta, IT). Each condition (C,T and IT) were done in three replicates.

2016-04-14 | E-GEOD-69447 | biostudies-arrayexpress

SOX11 promotes skin fibrosis by inducing fibrotic factors

Project description:In this study, we demonstrated that baseline SOX11 expression was significantly higher in dermal fibroblasts (DFs) isolated from patients with SSc than that in controls, and increased in response to TGF-b. We then showed that SOX11 is involved in the expression of periostin and some periostin-dependent fibrotic factors identified in lung fibroblasts previously. Moreover, we identified some fibrotic factors induced by SOX11 in DNA microarrays combining TGF-b induction and SOX11 knockdown. Finally, we showed that genetic deletion of SOX11 in Postn positive fibroblast cells protects from bleomycin (BLM)-induced skin fibrosis. Altogether, our data indicate that SOX11 and periostin forms a vicious circle and that TGF-b activates this circle specifically in SSc dermal fibroblasts.

2023-01-29 | GSE206473 | GEO

Transcriptomic analysis of the role of the integrin a6b4 in detached cells

Project description:Analysis of gene expression profiles of matrix-detached cells with and without expression of ITGB4, in clustering and non-clustering conditions. The experiment tested the hypothesis that the integrin beta 4 (ITGB4) mediates a significant amount of pro-survival signaling in matrix-detached conditions. Expression of ITGB4 in cancer is correlated with poor patient survival and is impliated in increased metastatic spread. Survival in matrix-deprived conditions is essential to metastasis and targeting signaling downstream of the integrin beta 4 may help curtail metasasis.

2019-04-16 | GSE115059 | GEO

Distinct phenotypes induced by acute hypoxia and TGF-β1 in human adult cardiac fibroblasts

Project description:Myocardial infarctions cause hypoxic injury to downstream tissue and a consequent fibrotic remodeling process to replace injured tissue with a scar. Scar formation occurs through phases of wound healing in which stimuli such as transforming growth factor-beta (TGF-β) drive cardiac fibroblasts to activate into a myofibroblast phenotype and deposit matrix molecules that form a scar. While this is necessary to repair injured tissue, excessive fibrosis commonly occurs which is correlated with heart failure. Therefore, defining cardiac fibroblast phenotypes under hypoxic stimuli and TGF-β is essential for understanding and treating pathological fibrosis. We robustly characterized fibroblast phenotype through immunofluorescence, quantitative RT-PCR, and proteomic analysis, after either TGF-β treatment or hypoxia durations that mimic acute hypoxic injury post-infarction. We find that hypoxic fibroblasts respond to low oxygen with increased hypoxia inducible factor 1 (HIF-1) but not HIF-2 activity by 4h. This is accompanied by increased gene and protein levels of VEGFA and LOX, respectively, which are both targets of HIF-1. Both TGF-β1 and hypoxia inhibit proliferation by 24h. While TGF-β1 treatment upregulated various fibrotic pathways, hypoxia causes a global reduction in protein synthesis, including collagen biosynthesis. This study discerns overlapping from distinctive outcomes of TGF-β1 and hypoxia treatment, which is important for elucidating their roles in fibrotic remodeling post-MI.

2024-07-03 | PXD051197 | Pride

Analysis of human myeloma cell lines expressing beta 3 integrin

Project description:The aim of these experiments was designed to compare gene expression in human myeloma cell lines expressing beta 3 integrin vs counterpart cell lines that do not express beta 3 integrin. Keywords: Gene expression,cell lines, siRNA

2009-04-29 | GSE15867 | GEO

Integrin beta 3 regulates cellular senescence by activating the TGFβ pathway

Project description:Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanism(s) regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3) is epigenetically regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts, by activating the TGFβ pathway in a cell autonomous and non-cell autonomous manner. β3 levels are dynamically increased during oncogeneinduced senescence (OIS) through CBX7 epigenetic regulation. DNA-damage and therapy-induced senescence (TIS) also induce β3 expression. In fact, downregulation of β3 levels override OIS and TIS, independently of its ligand-binding activity. Moreover, cilengitide, a αvβ3 antagonist, has the ability to block the SASP without affecting proliferation. Finally, we show an increase in β3 levels during aging in mice and humans. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

2017-03-09 | PXD005717 | Pride

Fibroblast-specific Proteo-transcriptomes of Human Sinoatrial Node in Non-failing and Failing Hearts

Project description:Sinoatrial node (SAN), and right atrial (RA) fibroblasts were isolated from explanted non-failing (nHF) and HF human hearts, cultured, passaged once, and treated +/- transforming growth factor beta 1(TGF beta-1). Fibroblast pellets were subjected to comprehensive high-throughput proteomic analyses.

2021-01-12 | MSV000086692 | MassIVE

Cre-mediated deletion of b1 integrin in pancreatic b-cells

Project description:In this study, we investigated the function of beta integrins in developing islet beta-cells by targeting the deletion of exon 3 of the B1 integrin gene using a Cre-lox approach. Our results demonstrate that this class of integrin receptors is critically important for proper beta cell expansion during development

2013-07-31 | E-MEXP-3736 | biostudies-arrayexpress

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