The role of X-linked inhibitor of apoptosis protein (XIAP) in Systemic Sclerosis and other fibrosing disorders

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Fibrosing disorders include multiple diseases that are characterized by the extensive accumulation of extracellular matrix (ECM) in different organs. The excessive accumulation of ECM disrupts the tissue architecture and leads to organ dysfunction. The growing incidence of fibrosing disorders, their high morbidity and mortality and the lack of effective antifibrotic therapies result in a very high medical need for targeted antifibrotic therapies. Systemic Sclerosis (SSc) is a prototypical systemic fibrotic disease. SSc is characterized by the highest case-related mortality among the rheumatic diseases. The 10-year survival is as low as 60% in the diffuse cutaneous forms. Myofibroblasts are key cells in fibrotic tissue remodeling. In normal wound healing, myofibroblasts occur transiently in the granulation tissue and disappear during the resolution phase. In contrast, myofibroblasts persist in fibrosis and maintain continuous repair responses. The mechanisms leading to the persistence of myofibroblasts are incompletely understood. Although individual, central profibrotic pathways such as TGFß and WNT/ß-catenin signaling have been identified, the consequences of the concomitant upregulation of these pathways and their crosstalk are incompletely characterized. We provide in our preliminary data first evidence that XIAP might be a pivotal regulator of fibroblast activation in fibrotic disorders such as SSc. We demonstrate that XIAP is upregulated in fibroblasts of involved skin of SSc patients, in particular in patients with progressive disease, and in experimental models of SSc. TGFß induces the expression of XIAP. Inactivation of XIAP inhibits fibroblast-to-myofibroblast transition and collagen release in vitro and ameliorates bleomycin-induced skin fibrosis in vivo. The antifibrotic effects of XIAP inactivation may result from its inhibitory effects on WNT/ß-catenin signaling, which is sufficient and required for tissue fibrosis. In summary, our preliminary data provide evidence that XIAP is a central regulator of fibroblast activation in SSc, as it sustains a profibrotic feed-forward loop between two core fibrotic pathways, the TGFß pathway and WNT/ß-catenin signaling. Targeting XIAP offers a way to ameliorate this feed-forward loop and to target fibroblast activation in fibrotic diseases. With the current application we aim to further analyze: the molecular mechanisms that mediate the induction of XIAP by TGFß, the effects of XIAP inhibition on the activated fibroblast phenotype, the molecular mechanisms by which XIAP regulates WNT/ß-catenin signaling, the role of XIAP in fibrotic disease in additional preclinical fibrosis models of SSc and the role of XIAP in the pathogenesis of other fibrotic diseases in addition to SSc.