IL-33/ST2 antagonizes STING signal transduction via autophagy in response to acetaminophen-mediated toxicological immunity

by Selleckchem | Jun 09 2023

Background: Interleukin-33 (IL-33), defined as "alarming", exert diverse functions through signaling via the suppression of tumorigenicity 2 (ST2). However, the physiological roles of IL-33/ST2 signaling during acetaminophen (APAP)-induced liver injury are still poorly understood by modern medicine (AILI). This research aims to explore the relationship between IL-33/ST2 and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction.

Methods: C57BL/6N mice (WT) and IL-33-deficient mice (KO) were intraperitoneally injected with APAP (250 mg/kg). Recombinant IL-33 (500 ng/mouse) and the cGAS/STING inhibitor RU.521 (200 g/kg) were combined to treat AILI. For mechanistic research in vitro, CRISPR-mediated KD technology, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized.

Results: We discovered that IL-33 deficient mice had increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis revealed that IL-33/ST2 enhanced the interaction between Beclin-1 and STING, disrupting STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription in HepaRG and Huh7 cells. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. Surprisingly, the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo.

Conclusions: These results shed insight on the potential of inhibiting cGAS/STING as a therapy for AILI and emphasize the crucial role of IL-33/ST2 signaling in the regulation of APAP-induced STING signaling. Video Abstract.

Comments：

This study investigated the relationship between interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) signaling and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction in acetaminophen (APAP)-induced liver injury (AILI). The authors used C57BL/6N mice and IL-33-deficient mice to demonstrate that IL-33 deficiency increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis in HepaRG and Huh7 cells revealed that IL-33/ST2 disrupted STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription by enhancing the interaction between Beclin-1 and STING. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. However, the authors surprisingly found that the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo. The results suggest that inhibiting cGAS/STING may be a potential therapy for AILI and highlight the important role of IL-33/ST2 signaling in regulating APAP-induced STING signaling.