Stimulator of Interferon Genes: A New Player in Peritoneal Damage

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Background: Peritoneal dialysis (PD) is a current replacement therapy for ESRD patients. However, long-term exposure to PD fluids (PDF) may lead to a peritoneal membrane (PM) damage and solute transport failure through mechanisms that include activation of the inflammatory/immune response, mesothelial to mesenchymal transition (MMT), and fibrosis. Stimulator of Interferon Genes (STING) is a cytosolic DNA sensor involved in the innate immune response that induces the transcription of type I interferons, cytokines, chemokines, and interferon-stimulated genes (ISGs). This work aimed to study the role of STING in peritoneal damage development. Methods: STING+ cells were first studied in peritoneal biopsies from PD patients and mice exposed to PDF. Then, we performed 2 models of peritoneal damage in WT and STING-KO mice: a fibrosis model induced by daily ip. injections of 0.1% chlorhexidine gluconate (CHX) for 4 weeks and a 5-day model of post-surgical adhesions (ischaemic buttons). Animals were euthanized and peritoneal tissue and lavage fluids were collected. Peritoneal mRNA and protein levels of STING pathway, MMT, fibrosis, and inflammatory markers were measured by qPCR, western blot, or immunohistochemistry. Cell populations present in the peritoneal cavity were assayed by flow cytometry. Results: STING+ cells were found in the peritoneum of both PD patients and mice exposed to PDF. In CHX-treated WT mice, peritoneal levels of STING and their downstream effectors (TBK1, IRF3, and ISGs) were increased and STING+ cells were found in PM thickness and cell infiltration areas. In STING-KO mice, the absence of STING improved CHX-induced peritoneal damage including decreased PM thickness and fibrosis, inflammatory cell tissue infiltration, and cell recruitment into the peritoneal cavity. At the molecular level, the absence of STING prevented NFκB pathway activation and reduced the peritoneal expression of MMT/fibrosis markers, cytokines, chemokines, and ISGs. Additionally, STING-KO showed less peritoneal adhesion formation and decreased expression of inflammatory markers and ISGs. Conclusions: The absence of STING prevented peritoneal damage suggesting that it may become a new potential therapeutic target in PD-associated peritoneal damage. Funding: Government Support - Non-U.S.

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