Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury

Abstract Hepatic ischemia–reperfusion injury (HIRI) elicits an immune-inflammatory response that may result in hepatocyte necrosis and apoptosis, ultimately culminating in postoperative hepatic dysfunction and hepatic failure. The precise mechanisms governing the pathophysiology of HIRI remain incom...

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Main Authors: Siyou Tan, Xiang Lu, Wenyan Chen, Bingbing Pan, Gaoyin Kong, Lai Wei
Format: Article
Language:English
Published: Nature Portfolio 2024-03-01
Series:Scientific Reports
Subjects:
Online Access:https://doi.org/10.1038/s41598-024-57139-2
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author Siyou Tan
Xiang Lu
Wenyan Chen
Bingbing Pan
Gaoyin Kong
Lai Wei
author_facet Siyou Tan
Xiang Lu
Wenyan Chen
Bingbing Pan
Gaoyin Kong
Lai Wei
author_sort Siyou Tan
collection DOAJ
description Abstract Hepatic ischemia–reperfusion injury (HIRI) elicits an immune-inflammatory response that may result in hepatocyte necrosis and apoptosis, ultimately culminating in postoperative hepatic dysfunction and hepatic failure. The precise mechanisms governing the pathophysiology of HIRI remain incompletely understood, necessitating further investigation into key molecules and pathways implicated in disease progression to guide drug discovery and potential therapeutic interventions. Gene microarray data was downloaded from the GEO expression profile database. Integrated bioinformatic analyses were performed to identify HIRI signature genes, which were subsequently validated for expression levels and diagnostic efficacy. Finally, the gene expression was verified in an experimental HIRI model and the effect of anti-IL17A antibody intervention in three time points (including pre-ischemic, post-ischemic, and at 1 h of reperfusion) on HIRI and the expression of these genes was investigated. Bioinformatic analyses of the screened characterized genes revealed that inflammation, immune response, and cell death modulation were significantly associated with HIRI pathophysiology. CCL2, BTG2, GADD45A, FOS, CXCL10, TNFRSF12A, and IL-17 pathway were identified as key components involved in the HIRI. Serum and liver IL-17A expression were significantly upregulated during the initial phase of HIRI. Pretreatment with anti-IL-17A antibody effectively alleviated the damage of liver tissue, suppressed inflammatory factors, and serum transaminase levels, and downregulated the mRNA expression of CCL2, GADD45A, FOS, CXCL10, and TNFRSF12A. Injection of anti-IL17A antibody after ischemia and at 1 h of reperfusion failed to demonstrate anti-inflammatory and attenuating HIRI benefits relative to earlier intervention. Our study reveals that the IL-17 pathway and related genes may be involved in the proinflammatory mechanism of HIRI, which may provide a new perspective and theoretical basis for the prevention and treatment of HIRI.
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spelling doaj.art-88f5e7d84dec46bdaf6a0eb60a0691232024-03-24T12:18:17ZengNature PortfolioScientific Reports2045-23222024-03-0114111510.1038/s41598-024-57139-2Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injurySiyou Tan0Xiang Lu1Wenyan Chen2Bingbing Pan3Gaoyin Kong4Lai Wei5Department of Anesthesiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Anesthesiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Anesthesiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Anesthesiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Anesthesiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Department of Anesthesiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Abstract Hepatic ischemia–reperfusion injury (HIRI) elicits an immune-inflammatory response that may result in hepatocyte necrosis and apoptosis, ultimately culminating in postoperative hepatic dysfunction and hepatic failure. The precise mechanisms governing the pathophysiology of HIRI remain incompletely understood, necessitating further investigation into key molecules and pathways implicated in disease progression to guide drug discovery and potential therapeutic interventions. Gene microarray data was downloaded from the GEO expression profile database. Integrated bioinformatic analyses were performed to identify HIRI signature genes, which were subsequently validated for expression levels and diagnostic efficacy. Finally, the gene expression was verified in an experimental HIRI model and the effect of anti-IL17A antibody intervention in three time points (including pre-ischemic, post-ischemic, and at 1 h of reperfusion) on HIRI and the expression of these genes was investigated. Bioinformatic analyses of the screened characterized genes revealed that inflammation, immune response, and cell death modulation were significantly associated with HIRI pathophysiology. CCL2, BTG2, GADD45A, FOS, CXCL10, TNFRSF12A, and IL-17 pathway were identified as key components involved in the HIRI. Serum and liver IL-17A expression were significantly upregulated during the initial phase of HIRI. Pretreatment with anti-IL-17A antibody effectively alleviated the damage of liver tissue, suppressed inflammatory factors, and serum transaminase levels, and downregulated the mRNA expression of CCL2, GADD45A, FOS, CXCL10, and TNFRSF12A. Injection of anti-IL17A antibody after ischemia and at 1 h of reperfusion failed to demonstrate anti-inflammatory and attenuating HIRI benefits relative to earlier intervention. Our study reveals that the IL-17 pathway and related genes may be involved in the proinflammatory mechanism of HIRI, which may provide a new perspective and theoretical basis for the prevention and treatment of HIRI.https://doi.org/10.1038/s41598-024-57139-2Hepatic ischemia–reperfusion injuryInflammationIL-17BioinformaticsCytokinesChemokines
spellingShingle Siyou Tan
Xiang Lu
Wenyan Chen
Bingbing Pan
Gaoyin Kong
Lai Wei
Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury
Scientific Reports
Hepatic ischemia–reperfusion injury
Inflammation
IL-17
Bioinformatics
Cytokines
Chemokines
title Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury
title_full Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury
title_fullStr Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury
title_full_unstemmed Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury
title_short Analysis and experimental validation of IL-17 pathway and key genes as central roles associated with inflammation in hepatic ischemia–reperfusion injury
title_sort analysis and experimental validation of il 17 pathway and key genes as central roles associated with inflammation in hepatic ischemia reperfusion injury
topic Hepatic ischemia–reperfusion injury
Inflammation
IL-17
Bioinformatics
Cytokines
Chemokines
url https://doi.org/10.1038/s41598-024-57139-2
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