Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis

Avouac, Jérôme; Fürnrohr, Barbara G.; Tomčík, Michal; Palumbo, Katrin; Zerr, Pawel; Horn, Angelika; Dees, Clara; Akhmetshina, Alfiya; Beyer, Christian; Distler, Oliver; Schett, Georg; Allanore, Yannick; Distler, Jörg H W

doi:10.1002/art.30171

Cited by 76 publications

(66 citation statements)

References 49 publications

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“…The collagen content in lesional skin samples was explored by hydroxyproline assay, as previously described (33,35). For direct visualization of collagen fibers, trichrome staining was performed using the Masson's Trichrome Staining Kit (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Myofibroblasts were identified by staining for α-SMA as previously described (33). T cells, B cells, NK cells, macrophages, and c-fos + and c-jun + cells were identified by staining for CD3, CD22, CD57, CD68, c-fos, and c-jun, respectively (all antibodies were from Abcam) (33,35). The expression of OX40L in lesional skin from patients with SSc and in skin from controls was detected by staining with polyclonal rabbit anti-human OX40L antibody or isotype control (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

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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“…Interestingly, the key role of STAT4 in inXammation has been conWrmed by the analysis of diVerent SSc mouse models in STAT4 knock-out mice (Avouac et al 2011). These authors reported that stat4 ¡/¡ mice showed protection against the inXammatory processes triggered in the bleomycin SSc-model, but collagen deposition was not decreased in tight-skin mice models lacking STAT4.…”

Section: Stat4mentioning

confidence: 99%

Unraveling the genetic component of systemic sclerosis

2012

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Systemic sclerosis (SSc) is a severe connective tissue disorder characterized by extensive fibrosis, vascular damage, and autoimmune events. During the last years, the number of genetic markers convincingly associated with SSc has exponentially increased. In this report, we aim to offer an updated review of the classical and novel genetic associations with SSc, analyzing the firmest and replicated signals within HLA and non-HLA genes, identified by both candidate gene and genome-wide association (GWA) studies. We will also provide an insight into the future perspectives and approaches that might shed more light into the complex genetic background underlying SSc. In spite of the remarkable advance in the field of SSc genetics during the last decade, the use of the new genetic technologies such as next generation sequencing (NGS), as well as the deep phenotyping of the study cohorts, to fully characterize the genetic component of this disease is imperative.

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“…A different approach, using two various mouse models of experimental dermal fi brosis, examined the contribution of the signal transducer and activator of transcription 4 (STAT4), associated with autoimmunity, in the development of the fi brotic phenotype in SSc. STAT4-defi cient mice turned out protected against bleomycin-mediated fi brotic reaction, thereby suggesting that the infl ammation engendered by bleomycin may promote fibrosis through a Th1-like response characterized by STAT4 expression [15]. Nevertheless, it should be noted that the fi brosis induced by bleomycin treatment might occur even in the absence of functioning T cells.…”

Section: Animal Models Of Sscmentioning

confidence: 99%