Inhibition of activator protein 1 signaling abrogates transforming growth factor β–mediated activation of fibroblasts and prevents experimental fibrosis

Avouac, Jérôme; Palumbo, Katrin; Tomčík, Michal; Zerr, Pawel; Dees, Clara; Horn, Angelika; Maurer, Britta; Akhmetshina, Alfiya; Beyer, Christian; Sadowski, Anika; Schneider, Holm; Shiozawa, Shunichi; Distler, Oliver; Schett, Georg; Allanore, Yannick; Distler, Jörg H W

doi:10.1002/art.33501

Cited by 82 publications

(82 citation statements)

References 30 publications

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“…Interestingly, AP-1 is implicated both in inflammatory response and fibrosis. AP-1 is up-regulated in a TGF-β-dependent manner in SSc, and pharmacological inhibition of AP-1 prevents the pathological activation of dermal fibroblasts and the development of experimental dermal fibrosis (11). The reduced expression of c-jun and c-fos observed on T cells and fibroblasts from ox40l −/− mice upon bleomycin challenge suggests that OX40L may regulate inflammation and fibroblast activation through AP-1 signaling in inflammation-driven skin fibrosis.…”

Section: Discussionmentioning

confidence: 98%

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OX40L blockade protects against inflammation-driven fibrosis

Elhaï

Avouac

Hoffmann-Vold

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

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Section: Discussionmentioning

confidence: 98%

“…The four groups consisted of 30 mice in total. Validated parameters (11,33) were used for evaluation. Mice were killed by cervical dislocation after 3 wk of treatment, and the injected skin was processed further for analysis.…”

Section: Methodsmentioning

confidence: 99%

OX40L blockade protects against inflammation-driven fibrosis

Elhaï

Avouac

Hoffmann-Vold

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In this setting, JNK activity alone may be insufficient for fibrosis; cooperation with other signaling intermediates may be necessary. The actions of JNK-MAPK and other MAPKs including ERK form AP-1 complexes of Jun, Fos, and related proteins (19), and transcription by AP-1 is required for TGF-␤-mediated fibrosis in other systems (2). However, TGF-␤-dependent transcription typically involves interdependent activity of AP-1 and Smads (11,25,42,50), suggesting that AP-1 formed downstream of JNK needs to interact with Smads to cause fibrosis.…”

Section: Discussionmentioning

confidence: 99%

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

Lan

Geng

Polichnowski

et al. 2012

American Journal of Physiology-Renal Physiology

102

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We investigated the signaling basis for tubule pathology during fibrosis after renal injury. Numerous signaling pathways are activated physiologically to direct tubule regeneration after acute kidney injury (AKI) but several persist pathologically after repair. Among these, transforming growth factor (TGF)-β is particularly important because it controls epithelial differentiation and profibrotic cytokine production. We found that increased TGF-β signaling after AKI is accompanied by PTEN loss from proximal tubules (PT). With time, subpopulations of regenerating PT with persistent loss of PTEN (phosphate and tension homolog) failed to differentiate, became growth arrested, expressed vimentin, displayed profibrotic JNK activation, and produced PDGF-B. These tubules were surrounded by fibrosis. In contrast, PTEN recovery was associated with epithelial differentiation, normal tubule repair, and less fibrosis. This beneficial outcome was promoted by TGF-β antagonism. Tubule-specific induction of TGF-β led to PTEN loss, JNK activation, and fibrosis even without prior AKI. In PT culture, high TGF-β depleted PTEN, inhibited differentiation, and activated JNK. Conversely, TGF-β antagonism increased PTEN, promoted differentiation, and decreased JNK activity. Cre-Lox PTEN deletion suppressed differentiation, induced growth arrest, and activated JNK. The low-PTEN state with JNK signaling and fibrosis was ameliorated by contralateral nephrectomy done 2 wk after unilateral ischemia, suggesting reversibility of the low-PTEN dysfunctional tubule phenotype. Vimentin-expressing tubules with low-PTEN and JNK activation were associated with fibrosis also after tubule-selective AKI, and with human chronic kidney diseases of diverse etiology. By preventing tubule differentiation, the low-PTEN state may provide a platform for signals initiated physiologically to persist pathologically and cause fibrosis after injury.

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“…Among the transcription factors, the AP-1 family and FOXOs are the 2 types of being identified as typical regulators of skeletal muscle development. An AP-1 factor might play an important role in the maintenance of muscle mass, and the decrease in its transcriptional activity might contribute to the loss of muscle mass in atrophic conditions (Lecker et al, 2004;Sacheck et al, 2007;Markou et al, 2008;Avouac et al, 2012). FOXOs belong to the FOX (Forkhead box) family of transcription factors.…”

Section: Characteristics Of the Duck Mustn1 Genementioning

confidence: 99%

Characterization of MUSTN1 gene and its relationship with skeletal muscle development at postnatal stages in Pekin ducks

Xu¹,

Gu²,

Sun³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Musculoskeletal embryonic nuclear protein 1 (MUSTN1) gene is involved in myogenic fusion and differentiation in rats. We previously showed the differential expression of MUSTN1 in week (W) 2 and W6 breast muscles of Pekin ducks. In this study, we further investigated its molecular characteristics and expression profiles in different tissues at W7 and in breast and leg muscles at W1, W3, W5, W7, and W9. The relationship between muscle development and MUSTN1 and skeletal muscle development muscle fiber areas was also investigated. A 358-bp cDNA sequence was obtained. The coding sequence of duck MUSTN1 cDNA encoded a 78-amino acid sequence, which showed high similarity with those of other species (96% similarity with zebra finch and 94% with chicken). In addition, a 6435-bp genomic DNA sequence of MUSTN1 was obtained. In total, 231 transcription factor-binding sites were found in the promoter region, and many of these transcription factors were involved in the regulation of muscle development. MUSTN1 expression in breast muscle increased from W1 to W5 and then decreased at W9. In leg muscle, the expression increased from W1 to W3 and then decreased. The relative growth rates of breast and leg muscle fibers reached their peaks at W3-W5 and W1-W3, respectively. Since the greatest relative growth rates appeared at the highest expression levels of the MUSTN1 gene, it was thought to play roles in duck muscle development. Our findings would be helpful in understanding the molecular characteristics and functions of the MUSTN1 gene in breast muscle development of ducks.

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Inhibition of activator protein 1 signaling abrogates transforming growth factor β–mediated activation of fibroblasts and prevents experimental fibrosis

Cited by 82 publications

References 30 publications

OX40L blockade protects against inflammation-driven fibrosis

OX40L blockade protects against inflammation-driven fibrosis

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

Characterization of MUSTN1 gene and its relationship with skeletal muscle development at postnatal stages in Pekin ducks

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