Biology subjects

Ozen, S.

Publications and source records attributed to Ozen, S..

3 recordsLinked to original sources

bioRxiv2026

STING-STAT3-SOX18 Axis Drives EndMT and Epigenetic Reprogramming in SAVI Lung Fibrosis

A high prevalence of early-onset interstitial lung disease, including pulmonary fibrosis, in pediatric patients with Stimulator of interferon genes (STING)-Associated Vasculopathy with onset in infancy (SAVI) suggests a critical role for the cGAS-STING pathway in the pathogenesis of pulmonary fibrosis. We identified an endothelial-to-mesenchymal transition (EndMT) signature in lesional lung biopsies from SAVI patients, marked by a loss of endothelial and acquisition of mesenchymal markers. Consistently, induced pluripotent stem cell-derived endothelial cells (iECs) from SAVI patients harboring gain-of-function STING1 mutations spontaneously undergo EndMT, a process rescued in isogenic-correction. In endothelial cells, STING activation induces IRF3-independent STAT3 phosphorylation, initiating a SLUG-dependent mesenchymal transcriptional program while repressing SOX18 and an epigenetically-regulated endothelial maintenance network. Our studies define a non-canonical cGAS-STING-STAT3 signaling axis that couples a mesenchymal transcriptional program with epigenetic silencing of an endothelial maintenance program, promoting TGF{beta}-independent STING-mediated EndMT and endothelial dysfunction, and suggesting STING as a therapeutic target for inflammatory pulmonary fibrosis.

cell biology↗

bioRxiv2023

5,6-dimethylxanthenone-4-acetic acid (DMXAA), a Partial STING Agonist, Competes for Human STING Activation

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA can not fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative--3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xhanthen-9one (HHMX)--that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.

immunology↗

bioRxiv2022

Galantamine Attenuates Autoinflammation in a Mouse Model of Familial Mediterranean Fever

Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine. Here, we tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Long-term treatment with galantamine attenuated the associated splenomegaly, amyloidosis, and anemia that are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch. These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.

immunology↗