PPM1G Regulates Hepatic Ischemia/reperfusion Injury Through STING-mediated Inflammatory Pathways in Macrophages

Overview

Journal Immun Inflamm Dis

Specialties Allergy & Immunology
Infectious Diseases

Date 2024 Feb 19

PMID 38372470

Authors

Dadi Peng

Zuotian Huang

Hang Yang

Yunhai Luo

Zhongjun Wu

Affiliations

Soon will be listed here.

Abstract

Background: Ischemia/reperfusion injury (IRI) is generally unavoidable following liver transplantation. Here, we investigated the role of protein phosphatase, Mg /Mn dependent 1G (PPM1G) in hepatic IRI.

Methods: Hepatic IRI was mimicked by employing a hypoxia/reperfusion (H/R) model in RAW 264.7 cells and a 70% warm ischemia model in C57BL/6 mice, respectively. In vitro, expression changes of tumor necrosis factor-α and interleukin were detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The protein expressions of PPM1G and the stimulator of interferon genes (STING) pathway components were analyzed by western blot. Interaction between PPM1G and STING was verified by coimmunoprecipitation (CO-IP). Immunofluorescence was applied for detection of p-IRF3. Flow cytometry, qRT-PCR and western blot were utilized to analyze markers of macrophage polarization. In vivo, histological analyses of mice liver were carried out by TUNEL and H&E staining. Changes in serum aminotransferases were also detected.

Results: Following H/R intervention, a steady decline in PPM1G along with an increase in inflammatory cytokines in vitro was observed. Addition of plasmid with PPM1G sequence limited the release of inflammatory cytokines and downregulated phosphorylation of STING. CO-IP validated the interaction between PPM1G and STING. Furthermore, inhibition of PPM1G with lentivirus enhanced phosphorylation of STING and its downstream components; meanwhile, p65, p38, and Jnk were also surged to phosphorylation. Expression of INOS and CD86 was surged, while CD206, Arg-1, and IL-10 were inhibited. In vivo, PPM1G inhibition further promoted liver damage, hepatocyte apoptosis, and transaminases release. Selective inhibition of STING with C-176 partially reversed the activation of STING pathway and inflammatory cytokines in vitro. M1 markers were also suppressed by C-176. In vivo, C-176 rescued liver damage and transaminase release caused by PPM1G inhibition.

Conclusion: PPM1G suppresses hepatic IRI and macrophage M1 phenotype by repressing STING-mediated inflammatory pathways.

Citing Articles

Exploring the effects of hypoxia and reoxygenation time on hepatocyte apoptosis and inflammation.

Xu X, Zhou T, Tulahong A, Ruze R, Shao Y PLoS One. 2024; 19(11):e0310535.

PMID: 39570857 PMC: 11581257. DOI: 10.1371/journal.pone.0310535.

PPM1G and its diagnostic, prognostic and therapeutic potential in HCC (Review).

Zhang X, Wang H, Yuan Y, Zhang J, Yang J, Zhang L Int J Oncol. 2024; 65(5).

PMID: 39329206 PMC: 11436262. DOI: 10.3892/ijo.2024.5697.

PPM1G regulates hepatic ischemia/reperfusion injury through STING-mediated inflammatory pathways in macrophages.

Peng D, Huang Z, Yang H, Luo Y, Wu Z Immun Inflamm Dis. 2024; 12(2):e1189.

PMID: 38372470 PMC: 10875902. DOI: 10.1002/iid3.1189.

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