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

• Published in: Cell communication and signaling 2023-04, Vol.21 (1), p.80-80, Article 80
• Main Authors: Wang, Zengbin, Sun, Pei, Pan, Banglun, Qiu, Jiacheng, Zhang, Xiaoxia, Shen, Shuling, Ke, Xiaoling, Tang, Nanhong
• Format: Article
• Language: English
• Subjects: Acetaminophen; Acetaminophen - adverse effects; Acetaminophen-induced liver injury; Acetylation; Analgesics; Animals; Antibodies; Autophagy; Beclin-1; C-Terminus; Cells; Cloning; CRISPR; Dimerization; Hepatotoxicity; IL-33/ST2; Immunity; Immunity, Innate - genetics; Immunofluorescence; Immunoprecipitation; Interferon; Interferon regulatory factor 3; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Laboratory animals; Liver; Mass spectrometry; Mass spectroscopy; Mice; Mice, Inbred C57BL; Nuclear transport; Nucleotidyltransferases - metabolism; Penicillin; Phosphorylation; Plasmids; Proteins; Scientific imaging; Signal Transduction; STING; Tumorigenicity
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-023-01114-3

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. 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. 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. 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.