Modulation of Stimulator of Interferon Genes (STING) Signaling Differentially Affects Outcomes of AKI
- AKI: Mechanisms - III
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Tonnus, Wulf, Technische Universitat Dresden, Dresden, Sachsen, Germany
- Linkermann, Andreas, Technische Universitat Dresden, Dresden, Sachsen, Germany
Group or Team Name
- Linkermann Lab.
Activation of cGAS/STING signaling leads to both type I interferon production and NFkB-dependent transcription in a Tbk1-dependent manner. During acute kidney injury (AKI), we recently described a population of innate immune cells expressing gasdermin D to be recruited to the surroundings of acute tubular necroses. Interestingly, these GSDMD+ cells seemed to signal back on the ongoing cell death, a concept termed necroinflammation. As recent work demonstrated a crucial role for free DNA and RNA fragments in the pathogenesis of AKI, we hypothesized that these might contribute to innate immune activation via the cGAS/STING pathway.
We tested STING-deficient mice in two established models of AKI, which reflect toxic tubular injury (cisplatin-induced AKI, CP-AKI) and redox stress (ischemia/reperfusion injury, IRI). Furthermore, pharmacological activation of STING by diABZI or inhibition by C-176 was investigated. Next to blood values, organ injury was determined by histological workup. Mechanistic insights were derived from immunohistochemistry and Western Blot analyzes in addition to cell culture experiments.
STING-deficient mice were less susceptible to IRI as exemplified by less strongly elevated values of serum creatinine and urea as well as lower tissue injury scores, whereas STING activation by diABZI did not ameliorate AKI. In contrast, STING-deficiency did not influence CP-AKI, but co-treatment with diABZI led to massively accelerated lethality. We found this to be dependent on regulated cell death, which was neither apoptosis, necroptosis, nor ferroptosis. Interestingly, GSDMD-deficient mice (the effector protein of pyroptosis, already identified as a protective factor against cisplatin-induced AKI) could not be further sensitized by STING-activation. Western Blot analyzes from primary tissue confirmed a correlation between pSTING and both GSDMD expression and proteolytic activation.
We found STING to be critically involved in different models of AKI. Unexpectedly, the results of STING activation seem to be context-dependent, as STING-deficiency was protective in IRI, whereas concomitant STING activation accelerated lethality in CP-AKI. Further workup is ongoing to identify underlying mechanisms.