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

作者全名："Peng, Dadi; Huang, Zuotian; Yang, Hang; Luo, Yunhai; Wu, Zhongjun"

作者地址："[Peng, Dadi; Yang, Hang; Luo, Yunhai; Wu, Zhongjun] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Huang, Zuotian] Chongqing Univ, Canc Hosp, Dept Hepatobiliary Pancreat Tumor Ctr, Chongqing, Peoples R China"

通信作者："Wu, ZJ (通讯作者)，Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing, Peoples R China."

来源：IMMUNITY INFLAMMATION AND DISEASE

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001164326800001

JCR分区：Q3

影响因子：3.1

年份：2024

卷号：12

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：cell activation; inflammatory pathways; ischemia/reperfusion injury; macrophage polarization; monocytes/macrophages; protein kinases/phosphatases

摘要："BackgroundIschemia/reperfusion injury (IRI) is generally unavoidable following liver transplantation. Here, we investigated the role of protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) in hepatic IRI.MethodsHepatic 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-alpha 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.ResultsFollowing 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.ConclusionPPM1G suppresses hepatic IRI and macrophage M1 phenotype by repressing STING-mediated inflammatory pathways. PPM1G was downregulated in hepatic IRI, thus promoting STING phosphorylation. PPM1G restricts macrophage M1 polarization. image"

基金机构：National Natural Science Foundation of China

基金资助正文：No Statement Availabler No Statement Available