Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury

Kaltenmeier, Christof; Wang, Ronghua; Popp, Brandon; Geller, David A.; Tohme, Samer; Yazdani, Hamza O.

doi:10.3390/cells11142222

Cited by 48 publications

(22 citation statements)

References 55 publications

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“…Therefore, we analyzed the function of the significantly differentially expressed target genes to gain a preliminary understanding of the potential function of the differentially expressed lncRNAs. In the Biological Process ontology category of GO enrichment analysis, DEGs were mostly enriched in cellular divalent inorganic cation homeostasis, response to molecule of bacterial origin, response to lipopolysaccharide, regulation of body fluid levels, and hormone metabolic process, which is consistent with the previously known pathophysiological mechanisms of post‐transplantation HIRI 40,41 . Apart from this, KEGG enrichment analysis revealed that DEGs were mostly enriched in the PI3K‐Akt signaling pathway, focal adhesion, Hippo signaling pathway, TNFα signaling pathway, etc 42 .…”

Section: Discussionsupporting

confidence: 78%

“…Hua et al 39 the previously known pathophysiological mechanisms of posttransplantation HIRI. 40,41 Apart from this, KEGG enrichment analysis revealed that DEGs were mostly enriched in the PI3K-Akt signaling pathway, focal adhesion, Hippo signaling pathway, TNFα signaling pathway, etc. 42 Some of these pathways have been recognized as canonical pathways associated with HIRI.…”

Section: Discussionmentioning

confidence: 99%

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Functional analysis of hepatic long non‐coding ribonucleic acids during liver transplantation in humans

Tang

Zhang

Liu

et al. 2023

The Journal of Gene Medicine

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Background The potential function of long non‐coding RNAs (lncRNAs) in human hepatic ischemia–reperfusion injury (HIRI) remains to be clarified. Methods Clinical samples of transplanted liver tissues from 26 patients undergoing liver transplantation (LT) and normal liver tissues from seven patients undergoing hepatic hemangiomactomy (Con) were collected. Typical samples were subjected to whole transcriptome sequencing (RNA‐seq). Differentially expressed genes between groups were identified by DEGseq and were analyzed by enrichment analysis including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis. Transcription of five lncRNAs including NONHSAG039942, NONHSAG071405, NONHSAG027516, LXLOC_058190, and LXLOC_024376 that presented significant difference in RNA‐sequencing were validated by a quantitative real‐time PCR (qRT‐PCR), for which the subcellular localization and the binding ability to known human RNA‐binding proteins (RBPs) were respectively predicted by LncLocator and catRAPID genomics v2.1. Results We identified 2917 lncRNAs and 2811 mRNAs that were differentially expressed (p < 0.05 and log2 fold change > 1 or < −1) between groups (LT vs. Con). NONHSAG039942, NONHSAG071405, LXLOC_058190, and LXLOC_024376 were validated by qRT‐PCR to be significantly increased in the LT group, and were all predicted to be localized in cytoplasm or cytosol. NONHSAG039942, NONHSAG071405, and LXLOC_058190 held an RBP interaction propensity score of 98.07%, 76.95%, and 152.99%, respectively, with heterogeneous‐nuclear ribonucleoprotein U (HNRNPU). Pathways significantly activated in transplant livers that involved HNRNPU as a core enrichment gene included hypoxia, ACE2 expression, apoptosis, spliceosome formation, etc. Conclusions NONHSAG039942, NONHSAG071405, and LXLOC_058190 were significantly increased in transplant livers after reperfusion and their role in HIRI may be associated with HNRNPU, a core protein that participates in hypoxia and chromatin accessibility.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Functional analysis of hepatic long non‐coding ribonucleic acids during liver transplantation in humans

Tang

Zhang

Liu

et al. 2023

The Journal of Gene Medicine

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“…Cytoplasmic HMGB1 is further increased in the damaged hepatocytes in the centrilobular area on day 1. Released HMGB1 stimulates monocytes/macrophages through the cell-surface receptors such as TLRs (in particular, TLR2, TLR4, and TLR9) and RAGE 54 , 81 , 82 , 83 , 84 , 89 . An increased expression of TLR-4 is confirmed in the TAA-induced liver lesion 54 .…”

Section: Macrophage-related Events In the Early Stage Of Chemical-ind...mentioning

confidence: 99%

Macrophage pathology in hepatotoxicity

2023

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The liver is the most important organ that metabolizes and detoxifies chemicals taken into the body. Therefore, there is always a risk of liver damage owing to the toxic effects of chemicals. The mechanisms of hepatotoxicity have been studied extensively and deeply based on toxic effects of chemicals themselves. However, it is important to note that liver damage is variously modified by the patho-biological reactions evoked mainly via macrophages. Macrophages appearing in hepatotoxicity are evaluated by the M1/M2 polarization; M1 macrophages promote tissue injury/inflammation, whereas M2 macrophages show anti-inflammatory action including reparative fibrosis. The "portal vein-liver barrier" regulated by Kupffer cells and dendritic cells in and around the Glisson's sheath may be related to the initiation of hepatotoxicity. In addition, Kupffer cells exhibit the two-sides of functions (that is, M1 or M2 macrophage-like functions), depending on microenvironmental conditions which may be raised in part by gut microbiota-derived lipopolysaccharide. Furthermore, damage-associated molecular patterns (DAMPs) (in particular, HMGB1) and autophagy (which degrades DAMPs) also play roles in the polarity of M1/M2 macrophages. The mutual relation of "DAMPs (HMGB-1)autophagy-M1/M2 macrophage polarization" as the patho-biological reaction should be taken into consideration in hepatotoxicity evaluation.

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“…In ammatory responses play key roles in the initiation and progression of hepatic I/R injury [19]. Since KLF6 has been shown to be involved in in ammatory responses [20], we next investigated whether KLF6 affected the in ammatory response after hepatic I/R injury in mice.…”

Section: Klf6 De Ciency Exacerbates Hepatic I/r Injurymentioning

confidence: 99%

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy

Zhang

Yu³

et al. 2022

Preprint

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Hepatic ischemia-reperfusion (I/R) injury, a common clinical complication of liver transplantation, gravely affects patient prognosis. Krüppel-like factors (KLFs) are a family of C2/H2 zinc finger DNA-binding proteins. KLF6, a member of the KLF family proteins, plays crucial roles in proliferation, metabolism, inflammation and injury responses; however, its role in HIR largely remains unclear. Herein, we found that KLF6 expression was significantly up-regulated in mice and hepatocytes after I/R injury. Subsequently, mice were subjected to I/R after tail vein injection of shKLF6- and KLF6-overexpressing adenovirus. KLF6 deficiency markedly aggravated liver damage and cell apoptosis along with the activation of hepatic inflammatory responses, whereas hepatic overexpression of KLF6 in mice showed opposite effects. Furthermore, we knocked out or overexpressed KLF6 in AML12 cells, and then exposed to hypoxia-reoxygenation challenge. KLF6 knockout significantly reduced cell viability, and increased hepatocyte inflammation, apoptosis, and ROS, whereas overexpression of KLF6 showed the opposite effects. Mechanistically, KLF6 inhibited the overactivation of autophagy at the initial stage, and the regulatory effect of KLF6 on I/R injury was autophagy-dependent. CHIP-qPCR and luciferase reporter gene assays confirmed that KLF6 was bound to the promoter region of Beclin1 and inhibited its transcription. Moreover, KLF6 activated the mTOR/ULK1 pathway. Finally, we retrospectively analyzed the clinical data of liver transplantation patients and observed significant associations between KLF6 expression and liver function after liver transplantation. In summary, KLF6 inhibited the overactivation of autophagy by transcriptional regulation of Beclin1 and activation of the mTOR/ULK1 pathway, thereby playing a protective role against hepatic I/R injury. KLF6 is expected to serve as a biomarker to predict the severity of I/R injury after liver transplantation.

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Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury

Cited by 48 publications

References 55 publications

Functional analysis of hepatic long non‐coding ribonucleic acids during liver transplantation in humans

Functional analysis of hepatic long non‐coding ribonucleic acids during liver transplantation in humans

Macrophage pathology in hepatotoxicity

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy

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