The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc

Liang, Ruiying; Šumová, Barbora; Cordazzo, Cinzia; Mallano, Tatjana; Zhang, Yun; Wohlfahrt, Thomas; Dees, Clara; Ramming, Andreas; Krasowska, Dorota; Michalska-Jakubus, Małgorzata; Distler, Oliver; Schett, Georg; Šenolt, Ladislav; Distler, Jörg H W

doi:10.1136/annrheumdis-2016-209698

Cited by 37 publications

(36 citation statements)

References 46 publications

(30 reference statements)

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“…Similar to the results of previous studies, [24][25][26][27][28] we demonstrated that the Hh pathway was activated during pulmonary fibrosis through the study of SSc-ILD patients. TGF-b1 signaling has been confirmed to play a crucial and indispensable role in the pathogenesis of lung fibrosis 29,30 and pirfenidone has consistently been demonstrated to possess the ability to modulate this canonical pathway property by suppressing TGF-b1.…”

Section: Discussionsupporting

confidence: 91%

Anti‐fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis‐associated interstitial lung disease

et al. 2018

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Section: Discussionsupporting

confidence: 91%

Anti‐fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis‐associated interstitial lung disease

et al. 2018

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“…We and others provided evidence for a cross-talk of hedgehog and TGFβ signalling and demonstrated that TGFβ promotes hedgehog signalling by inducing the ligand SHH and in particular the transcription factor GLI2 4 5 7 14–20. We now extend those findings and provide evidence that TGFβ may particularly promote long-range hedgehog signals.…”

Section: Discussionsupporting

confidence: 73%

“…Aberrant hedgehog signalling has been characterised as a central mechanism underlying the persistent fibroblast activation in SSc4–7 and other fibrotic diseases 8. Hedgehog signalling is activated by two different mechanisms in SSc.…”

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confidence: 99%

“…Sonic hedgehog (SHH), the predominant ligand in the skin, is overexpressed, which promotes stabilisation of the downstream transcription factor GLI2 5. In addition, GLI2 is a direct transcriptional target of transforming growth factor-β (TGFβ) 7. Activation of hedgehog signalling promotes fibroblast-to-myofibroblast transition and fibrosis, whereas targeted inhibition of hedgehog signalling ameliorates fibrosis in various preclinical models 5–7…”

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confidence: 99%

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Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc

et al. 2019

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ObjectivesSystemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc.MethodsExpression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models.ResultsThe expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-β (TGFβ)/SMAD-dependent manner. Knockdown of HHAT reduced TGFβ-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis.ConclusionHHAT is regulated in SSc in a TGFβ-dependent manner and in turn stimulates TGFβ-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.

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“…Extensive research has been done to elucidate the role of regulators of the Th differentiation (transcription factors, cytokines, and other immune derived cell molecules), but little is known about the contribution of non-immune factors, such as HH pathway-associated genes like GLI2 . A recent report demonstrates that hedgehog pathways and TGF-β signaling both converge to GLI2 [ 72 ]. The crosstalk of these signaling pathways and their role in respiratory allergic diseases requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

GLI2 promoter hypermethylation in saliva of children with a respiratory allergy

et al. 2018

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BackgroundThe prevalence of respiratory allergy in children is increasing. Epigenetic DNA methylation changes are plausible underlying molecular mechanisms.ResultsSaliva samples collected in substudies of two longitudinal birth cohorts in Belgium (FLEHS1 & FLEHS2) were used to discover and confirm DNA methylation signatures that can differentiate individuals with respiratory allergy from healthy subjects. Genome-wide analysis with Illumina Methylation 450K BeadChips revealed 23 differentially methylated gene regions (DMRs) in saliva from 11y old allergic children (N=26) vs. controls (N=20) in FLEHS1. A subset of 7 DMRs was selected for confirmation by iPLEX MassArray analysis. First, iPLEX analysis was performed in the same 46 FLEHS1 samples for analytical confirmation of the findings obtained during the discovery phase. iPLEX results correlated significantly with the 450K array data (P <0.0001) and confirmed 4 out of the 7 DMRs. Aiming for additional biological confirmation, the 7 DMRs were analyzed using iPLEX in a substudy of an independent birth cohort (FLEHS2; N=19 cases vs. 20 controls, aged 5 years). One DMR in the GLI2 promoter region showed a consistent statistically significant hypermethylation in individuals with respiratory allergy across the two birth cohorts and technologies. In addition to its involvement in TGF-β signaling and T-helper differentiation, GLI2 has a regulating role in lung development.ConclusionGLI2 is considered an interesting candidate DNA methylation marker for respiratory allergy.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0484-1) contains supplementary material, which is available to authorized users.

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The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc

Cited by 37 publications

References 46 publications

Anti‐fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis‐associated interstitial lung disease

Anti‐fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis‐associated interstitial lung disease

Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc

GLI2 promoter hypermethylation in saliva of children with a respiratory allergy

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