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Systemic sclerosis (SSc) is a complex heterogeneous autoimmune disease with unknown etiology. It has three major pathologic hallmarks: vasculopathy, immune activation and extensive fibrosis that is an excessive accumulation of extracellular matrix proteins released from activated fibroblasts and destroys the physiological tissue architecture and function of the involved organs. Particularly, diffuse cutaneous SSc (dcSSc) has a highly increased risk of morbidity and mortality. Unfortunately, no targeted treatment is approved for fibrosis in SSc and there is a great medical need for new anti-fibrotic therapies for SSc. In this thesis, we evaluated the anti-fibrotic effects of targeting ATF3 and EN1 transcription factors. Both molecules have a distinct contribution to the disease’s pathogenesis and each one could serve as a potential target for the treatment of fibrosis in SSc. In the first part of this thesis, we evaluated the role of ATF3 in skin fibrosis as the most commonly affected tissue. Furthermore, we showed that ATF3 is a crucial regulator of TGF-β signaling in SSc. ATF3-deficient fibroblasts are less responsive to TGF-β with impaired production of extracellular matrix components such as collagens and activation of Smad-dependent transcription, reduced activity in reporter assays and decreased levels of TGF-β target genes. On the contrary, overexpression of ATF3 amplified the effect of TGF-β on fibroblast activation. Given that TGF-β stimulates the expression of ATF3 in a Smad3-dependent manner, ATF3 may represent an endogenous enhancer of canonical TGF-β signaling and its overexpression may thus contribute to the aberrant activation of TGF-β signaling in SSc. Furthermore, ATF3 deletion ameliorated fibrosis in several complementary mouse models of SSc. In the second part of this thesis, we investigated the role of EN1 in the pathogenesis of SSc. We demonstrated that EN1 regulates TGF-β signaling which is the core pathway in fibrotic diseases. Inactivation of EN1 signaling reduced the TGF-β mediated activation of fibroblasts and production of collagens and target genes. Moreover, fibroblast-specific knockout of EN1 ameliorated fibrosis in several mouse models. The results of both parts of the thesis might have clinical implications. Targeted inactivation of ATF3 and EN1 may thus offer potential to interfere with persistent TGF-β signaling and aberrant fibroblast activation in fibrotic diseases.

Systemic sclerosis (SSc) is a complex heterogeneous autoimmune disease with unknown etiology. It has three major pathologic hallmarks: vasculopathy, immune activation and extensive fibrosis that is an excessive accumulation of extracellular matrix proteins released from activated fibroblasts and destroys the physiological tissue architecture and function of the involved organs. Particularly, diffuse cutaneous SSc (dcSSc) has a highly increased risk of morbidity and mortality. Unfortunately, no targeted treatment is approved for fibrosis in SSc and there is a great medical need for new anti-fibrotic therapies for SSc. In this thesis, we evaluated the anti-fibrotic effects of targeting ATF3 and EN1 transcription factors. Both molecules have a distinct contribution to the disease’s pathogenesis and each one could serve as a potential target for the treatment of fibrosis in SSc. In the first part of this thesis, we evaluated the role of ATF3 in skin fibrosis as the most commonly affected tissue. Furthermore, we showed that ATF3 is a crucial regulator of TGF-β signaling in SSc. ATF3-deficient fibroblasts are less responsive to TGF-β with impaired production of extracellular matrix components such as collagens and activation of Smad-dependent transcription, reduced activity in reporter assays and decreased levels of TGF-β target genes. On the contrary, overexpression of ATF3 amplified the effect of TGF-β on fibroblast activation. Given that TGF-β stimulates the expression of ATF3 in a Smad3-dependent manner, ATF3 may represent an endogenous enhancer of canonical TGF-β signaling and its overexpression may thus contribute to the aberrant activation of TGF-β signaling in SSc. Furthermore, ATF3 deletion ameliorated fibrosis in several complementary mouse models of SSc. In the second part of this thesis, we investigated the role of EN1 in the pathogenesis of SSc. We demonstrated that EN1 regulates TGF-β signaling which is the core pathway in fibrotic diseases. Inactivation of EN1 signaling reduced the TGF-β mediated activation of fibroblasts and production of collagens and target genes. Moreover, fibroblast-specific knockout of EN1 ameliorated fibrosis in several mouse models.