STING-STAT3-mediated endothelial-mesenchymal transition promotes pulmonary fibrosis in SAVI patients 9089

Abstract Description Stimulator of interferon genes (STING)-Associated Vasculopathy with Onset in Infancy (SAVI) leads to early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary fibrosis. The cellular and molecular mechanisms of high prevalence of early-onset pulmonary fibrosis in SAVI patients remains unknown, and effective treatment options are limited. Here, we show that an endothelial-to-mesenchymal transition (EndMT) signature is identified in lung biopsies from SAVI patients, characterized by a loss of endothelial markers and a gain of mesenchymal markers on immunohistology and transcriptional analysis. Induced pluripotent stem cell-derived endothelial cells (iECs) from SAVI patients spontaneously undergo EndMT, which is abrogated in isogenic and healthy controls. STING activates STAT3, leading to the initiation of a Slug-dependent mesenchymal program and profound downregulation of a SOX18 endothelial maintenance program at transcriptional and epigenetic levels. The STING inhibitor IFM35883, but not anti-fibrotic drugs Pirfenidone or Nintedanib, was fully effective in preventing EndMT in SAVI iECs. Collectively, this work highlights a novel role for the cGAS-STING/STAT3/SOX18 pathway in SAVI lung fibrosis through epigenetic remodeling, resulting in the loss of the alveolar endothelial cell phenotype and activation of a mesenchymal program as part of EndMT-mediated lung fibrosis in SAVI, and proposes STING as a therapeutic target for inflammatory lung fibrosis. Topic Categories Immune Mechanisms of Human Disease (HUM)