Loss-of-STING function by nitro-fatty acids reduces endometriotic lesion formation in a syngeneic model of endometriosis

Abstract

Endometriosis is a painful, chronic inflammatory disease that impacts fertility and the overall well-being in 10% of reproductive age women. Current therapies include hormonal treatment to induce a hypoestrogenic state, causing serious complications from side effects. STING (Stimulator of Interferon Genes) plays an essential role in innate immunity but also exacerbates inflammation in chronic inflammatory diseases. Recently, STING was found aberrantly upregulated in endometriosis patients. Nitro-fatty acids (NO2-FAs) are bioactive lipids that exert anti-inflammatory and protective roles in preclinical models of inflammation and fibrosis, in part via inhibition of STING. We hypothesized that NO2-FAs protect against STING-dependent endometriosis lesion formation and tested its therapeutic potential using a syngeneic transplant model of endometriosis. Mice expressing green fluorescent protein (EGFP) were treated with Pregnant Mare Serum Gonadotrophin (PMSG) to induce decidualization. Decidualized uterine fragments were transplanted into wild-type (WT) female recipients randomized to receive NO2-FA or vehicle. Endometriosis was allowed to develop for 28 days. In vivo imaging of EGFP donor-derived endometrial lesions demonstrates that NO2-FA administration significantly reduces peritoneal endometriotic lesion formation in female recipients. Furthermore, loss-of-STING function, using STING KO female mice as recipients, demonstrates that STING plays a systemic functional role on endometriosis development. Finally, our studies demonstrate that NO2-FAs inhibit cyclic GMP-AMP Synthase (cGAS)-induced type I interferon signaling in bone-marrow derived macrophages (BMDM) and in the peritoneum of WT female mice but not STING KO mice. In summary, we show that STING is a novel, essential factor contributing to the pathogenesis of endometriosis and that NO2-FA administration may serve as a novel non-hormonal therapy against endometriosis by targeting STING. This study is funded by the American Physiological Society William Townshend Predoctoral Fellowship (MP), NIMHD U54-MD007602 (WT), R01-HL162294 (MGB) and R01-HL123333 (LV). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.