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Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury.

ABSTRACT: Pyroptosis, a proinflammatory form of programmed cell death, plays important roles in the pathogenesis of many diseases. Inflammasome activation, which has been shown in hepatic ischemia-reperfusion injury (IRI), is demonstrated to be closely associated with pyroptosis, indicating that pyroptosis may occur and perform functions in hepatic IRI. However, there is no direct evidence showing the function of pyroptosis in hepatic IRI. In this study, by detecting the pyroptosis markers, we showed that pyroptosis may be induced during hepatic IRI. Furthermore, by adopting caspase-1 inhibitors, we showed that inhibition of pyroptosis could significantly ameliorate liver injury and suppress inflammatory response during hepatic IRI. Interestingly, caspase-1 inhibitors have no protective effects on in vitro hepatocytes under hypoxic reoxygenation condition. To investigate pyroptosis induced in which specific cell types may affect hepatic IRI, we generated hepatocyte-specific Gsdmd-knockout (Hep-Gsdmd-/-) and myeloid-specific Gsdmd-knockout (LysmCre+Gsdmdf/f) mice. Functional experiments showed that compared to control mice (Gsdmdf/f), there were alleviated liver injury and inflammation in LysmCre+Gsdmdf/f mice, but not in AlbCre+Gsdmdf/f mice. In parallel in vitro studies, cytokine expression and production decreased in bone-marrow-derived macrophages and Kupffer cells from LysmCre+Gsdmdf/f mice compared to their controls. Our findings demonstrated that pyroptosis in innate immune cells aggravates hepatic IRI and implied that hepatic IRI could be protected by blocking pyroptosis, which may become a potential therapeutic target in the clinic.

SUBMITTER: Li J

PROVIDER: S-EPMC7165177 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury.

Li Jichang J Zhao Jie J Xu Min M Li Meng M Wang Bingrui B Qu Xiaoye X Yu Chang C Hang Hualian H Xia Qiang Q Wu Hailong H Sun Xuehua X Gu Jinyang J Kong Xiaoni X

Cell death & disease 20200417 4

Pyroptosis, a proinflammatory form of programmed cell death, plays important roles in the pathogenesis of many diseases. Inflammasome activation, which has been shown in hepatic ischemia-reperfusion injury (IRI), is demonstrated to be closely associated with pyroptosis, indicating that pyroptosis may occur and perform functions in hepatic IRI. However, there is no direct evidence showing the function of pyroptosis in hepatic IRI. In this study, by detecting the pyroptosis markers, we showed that ...[more]

PMID: 32303674

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Project description:BackgroundHepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous.MethodsInsig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2.ResultsHepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate).ConclusionsInsig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

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Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury.

Publications

Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury.

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