Cargando…
The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration
BACKGROUND & AIMS: Liver ischemia-reperfusion (IR) injury represents a major risk factor in both partial hepatectomy and liver transplantation. Nerve injury–induced protein 1 (Ninj1) is widely recognized as an adhesion molecule in leukocyte trafficking under inflammatory conditions, but its role...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036740/ https://www.ncbi.nlm.nih.gov/pubmed/36731792 http://dx.doi.org/10.1016/j.jcmgh.2023.01.008 |
_version_ | 1784911722708992000 |
---|---|
author | Hu, Yuanchang Zhan, Feng Wang, Yong Wang, Dong Lu, Hao Wu, Chen Xia, Yongxiang Meng, Lijuan Zhang, Feng Wang, Xun Zhou, Shun |
author_facet | Hu, Yuanchang Zhan, Feng Wang, Yong Wang, Dong Lu, Hao Wu, Chen Xia, Yongxiang Meng, Lijuan Zhang, Feng Wang, Xun Zhou, Shun |
author_sort | Hu, Yuanchang |
collection | PubMed |
description | BACKGROUND & AIMS: Liver ischemia-reperfusion (IR) injury represents a major risk factor in both partial hepatectomy and liver transplantation. Nerve injury–induced protein 1 (Ninj1) is widely recognized as an adhesion molecule in leukocyte trafficking under inflammatory conditions, but its role in regulating sterile inflammation during liver IR injury remains unclear. METHODS: Myeloid Ninj1-deficient mice were generated by bone marrow chimeric models using Ninj1 knockout mice and wild-type mice. In vivo, a liver partial warm ischemia model was applied. Liver injury and hepatic inflammation were investigated. In vitro, primary Kupffer cells (KCs) isolated from Ninj1 knockout and wild-type mice were used to explore the function and mechanism of Ninj1 in modulating KC inflammation upon lipopolysaccharide stimulation. RESULTS: Ninj1 deficiency in KCs protected mice against liver IR injury during the later phase of reperfusion, especially in neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis. This prompted ischemia-primed KCs to decrease proinflammatory cytokine production. In vitro and in vivo, using small-interfering RNA against dual-specificity phosphatase 1 (DUSP1), we found that Ninj1 deficiency diminished the inflammatory response in KCs and neutrophil infiltration through DUSP1-dependent deactivation of the c-Jun-N-terminal kinase and p38 pathways. Sivelestat, a neutrophil elastase inhibitor, functioned similarly to Ninj1 deficiency, resulting in both mitigated hepatic IR injury in mice and a more rapid recovery of liver function in patients undergoing liver resection. CONCLUSIONS: The Ninj1/Dusp1 axis contributes to liver IR injury by regulating the proinflammatory response of KCs, and influences neutrophil infiltration, partly by subsequent regulation of C-X-C motif chemokine ligand 1 (CXCL1) production after IR. |
format | Online Article Text |
id | pubmed-10036740 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-100367402023-03-25 The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration Hu, Yuanchang Zhan, Feng Wang, Yong Wang, Dong Lu, Hao Wu, Chen Xia, Yongxiang Meng, Lijuan Zhang, Feng Wang, Xun Zhou, Shun Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Liver ischemia-reperfusion (IR) injury represents a major risk factor in both partial hepatectomy and liver transplantation. Nerve injury–induced protein 1 (Ninj1) is widely recognized as an adhesion molecule in leukocyte trafficking under inflammatory conditions, but its role in regulating sterile inflammation during liver IR injury remains unclear. METHODS: Myeloid Ninj1-deficient mice were generated by bone marrow chimeric models using Ninj1 knockout mice and wild-type mice. In vivo, a liver partial warm ischemia model was applied. Liver injury and hepatic inflammation were investigated. In vitro, primary Kupffer cells (KCs) isolated from Ninj1 knockout and wild-type mice were used to explore the function and mechanism of Ninj1 in modulating KC inflammation upon lipopolysaccharide stimulation. RESULTS: Ninj1 deficiency in KCs protected mice against liver IR injury during the later phase of reperfusion, especially in neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis. This prompted ischemia-primed KCs to decrease proinflammatory cytokine production. In vitro and in vivo, using small-interfering RNA against dual-specificity phosphatase 1 (DUSP1), we found that Ninj1 deficiency diminished the inflammatory response in KCs and neutrophil infiltration through DUSP1-dependent deactivation of the c-Jun-N-terminal kinase and p38 pathways. Sivelestat, a neutrophil elastase inhibitor, functioned similarly to Ninj1 deficiency, resulting in both mitigated hepatic IR injury in mice and a more rapid recovery of liver function in patients undergoing liver resection. CONCLUSIONS: The Ninj1/Dusp1 axis contributes to liver IR injury by regulating the proinflammatory response of KCs, and influences neutrophil infiltration, partly by subsequent regulation of C-X-C motif chemokine ligand 1 (CXCL1) production after IR. Elsevier 2023-01-31 /pmc/articles/PMC10036740/ /pubmed/36731792 http://dx.doi.org/10.1016/j.jcmgh.2023.01.008 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Hu, Yuanchang Zhan, Feng Wang, Yong Wang, Dong Lu, Hao Wu, Chen Xia, Yongxiang Meng, Lijuan Zhang, Feng Wang, Xun Zhou, Shun The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration |
title | The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration |
title_full | The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration |
title_fullStr | The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration |
title_full_unstemmed | The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration |
title_short | The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration |
title_sort | ninj1/dusp1 axis contributes to liver ischemia reperfusion injury by regulating macrophage activation and neutrophil infiltration |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036740/ https://www.ncbi.nlm.nih.gov/pubmed/36731792 http://dx.doi.org/10.1016/j.jcmgh.2023.01.008 |
work_keys_str_mv | AT huyuanchang theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT zhanfeng theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wangyong theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wangdong theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT luhao theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wuchen theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT xiayongxiang theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT menglijuan theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT zhangfeng theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wangxun theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT zhoushun theninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT huyuanchang ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT zhanfeng ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wangyong ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wangdong ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT luhao ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wuchen ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT xiayongxiang ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT menglijuan ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT zhangfeng ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT wangxun ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration AT zhoushun ninj1dusp1axiscontributestoliverischemiareperfusioninjurybyregulatingmacrophageactivationandneutrophilinfiltration |