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Park SJ, Garcia Diaz J, Comlekoglu T, Hahn YS. Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling. Front Immunol 2025; 16:1528382. [PMID: 40260261 PMCID: PMC12009845 DOI: 10.3389/fimmu.2025.1528382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/11/2025] [Indexed: 04/23/2025] Open
Abstract
Liver macrophages play a role in the development of liver fibrosis progression via the regulation of inflammatory signaling. However, the precise mechanisms of macrophages contributing to liver fibrosis progression remain unclear. Using a preclinical model of CCl4-treated mice, we determined the composition of immune cells and the alteration of inflammatory gene expression. Our findings revealed a significant increase in liver macrophages, particularly those derived from infiltrating blood monocytes, in fibrotic mice. Moreover, the expression levels of type I IFN signature genes such as IFNα, IFNβ, ISG15, USP18, Ifi44, Ifit1, Ifit2, IRF3, and IRF7 were elevated in fibrotic mice. To determine the role of type I IFN signaling in liver fibrosis, we administered an IFNAR-1 antibody to block this pathway for 3 days prior to harvesting the liver. Notably, IFNAR-1 blockade reduced macrophage numbers compared to control mice and alleviated liver fibrosis in mice with increased hepatocyte proliferation and apoptosis. The ratio of P-STAT3/P-STAT1 in monocyte-derived macrophages was increased in the IFNAR-1 blockade group compared to fibrotic mice, and this was related to the appearance of M2 macrophage differentiation. Additionally, single-cell RNA-seq analysis indicated that IFNAR blockade affected inflammatory pathways involved in hepatocyte regeneration and fibrosis prevention. Taken together, IFNAR-1 blockade alleviates liver fibrosis progression by modulating macrophage inflammatory responses. These results provide insights for developing anti-fibrotic therapies against type I IFN signaling.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
| | - Josefina Garcia Diaz
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States
| | - Tina Comlekoglu
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States
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Zhuang Y, Ortega-Ribera M, Nagesh PT, Joshi R, Huang H, Wang Y, Zivny A, Mehta J, Parikh SM, Szabo G. Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1. Hepatology 2024; 79:752-767. [PMID: 37725754 PMCID: PMC10948324 DOI: 10.1097/hep.0000000000000611] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 08/31/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIMS Cell death and inflammation play critical roles in chronic tissue damage caused by cholestatic liver injury leading to fibrosis and cirrhosis. Liver cirrhosis is often associated with kidney damage, which is a severe complication with poor prognosis. Interferon regulatory factor 3 (IRF3) is known to regulate apoptosis and inflammation, but its role in cholestasis remains obscure. In this study. APPROACH AND RESULTS We discovered increased IRF3 phosphorylation in the liver of patients with primary biliary cholangitis and primary sclerosing cholangitis. In the bile duct ligation model of obstructive cholestasis in mice, we found that tissue damage was associated with increased phosphorylated IRF3 (p-IRF3) in the liver and kidney. IRF3 knockout ( Irf3-/- ) mice showed significantly attenuated liver and kidney damage and fibrosis compared to wide-type mice after bile duct ligation. Cell-death pathways, including apoptosis, necroptosis, and pyroptosis, inflammasome activation, and inflammatory responses were significantly attenuated in Irf3-/- mice. Mechanistically, we show that bile acids induced p-IRF3 in vitro in hepatocytes. In vivo , activated IRF3 positively correlated with increased expression of its target gene, Z-DNA-Binding Protein-1 (ZBP1), in the liver and kidney. Importantly, we also found increased ZBP1 in the liver of patients with primary biliary cholangitis and primary sclerosing cholangitis. We discovered that ZBP1 interacted with receptor interacting protein 1 (RIP1), RIP3, and NLRP3, thereby revealing its potential role in the regulation of cell-death and inflammation pathways. In conclusion. CONCLUSIONS Our data indicate that bile acid-induced p-IRF3 and the IRF3-ZBP1 axis play a central role in the pathogenesis of cholestatic liver and kidney injury.
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Affiliation(s)
- Yuan Zhuang
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Martí Ortega-Ribera
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Prashanth Thevkar Nagesh
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Radhika Joshi
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Huihui Huang
- Division of Nephrology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Yanbo Wang
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Adam Zivny
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Jeeval Mehta
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Samir M. Parikh
- Division of Nephrology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern, Dallas, TX, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
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Salzmann RJ, Krötz C, Mocan T, Mocan LP, Grapa C, Rottmann S, Reichelt R, Keller CM, Langhans B, Schünemann F, Pohl A, Böhler T, Bersiner K, Krawczyk M, Milkiewicz P, Sparchez Z, Lammert F, Gehlert S, Gonzalez-Carmona MA, Willms A, Strassburg CP, Kornek MT, Dold L, Lukacs-Kornek V. Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis. Hepatol Commun 2024; 8:e0380. [PMID: 38358371 PMCID: PMC10871749 DOI: 10.1097/hc9.0000000000000380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/17/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression. METHODS Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study. RESULTS Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, β and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC. CONCLUSIONS The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.
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Affiliation(s)
- Rebekka J.S. Salzmann
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Christina Krötz
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Tudor Mocan
- UBBMed Department, Babes-Bolyai University, Cluj-Napoca, Romania
- Department of Gastroenterology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lavinia P. Mocan
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristiana Grapa
- Department of Physiology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Sophia Rottmann
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Ramona Reichelt
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Cindy M. Keller
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Bettina Langhans
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Frederik Schünemann
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Alexander Pohl
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Thomas Böhler
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Käthe Bersiner
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Zeno Sparchez
- 3rd Medical Department, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | - Sebastian Gehlert
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Maria A. Gonzalez-Carmona
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Arnulf Willms
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
- Department of General and Visceral Surgery, German Armed Forces Hospital, Hamburg, Germany
| | - Christian P. Strassburg
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Miroslaw T. Kornek
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
| | - Leona Dold
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Veronika Lukacs-Kornek
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
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Zhang W, Liu K, Ren GM, Wang Y, Wang T, Liu X, Li DX, Xiao Y, Chen X, Li YT, Zhan YQ, Xiang SS, Chen H, Gao HY, Zhao K, Yu M, Ge CH, Li CY, Ge ZQ, Yang XM, Yin RH. BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury. Cell Death Dis 2023; 14:743. [PMID: 37968261 PMCID: PMC10651896 DOI: 10.1038/s41419-023-06268-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 11/17/2023]
Abstract
BRISC (BRCC3 isopeptidase complex) is a deubiquitinating enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1β, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.
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Affiliation(s)
- Wen Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China
| | - Kai Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Guang-Ming Ren
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yu Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Ting Wang
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, 100124, China
| | - Xian Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Dong-Xu Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
| | - Yang Xiao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xu Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ya-Ting Li
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, 100124, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Shen-Si Xiang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Hui-Ying Gao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ke Zhao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chang-Hui Ge
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Zhi-Qiang Ge
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
| | - Xiao-Ming Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Rong-Hua Yin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
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5
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Wu J, Kim A, Wu X, Ray S, Allende DS, Welch N, Bellar A, Dasarathy J, Dasarathy S, Nagy LE. 5S rRNA pseudogene transcripts are associated with interferon production and inflammatory responses in alcohol-associated hepatitis. Hepatology 2023; 77:1983-1997. [PMID: 36645226 PMCID: PMC10192046 DOI: 10.1097/hep.0000000000000024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/15/2022] [Indexed: 01/17/2023]
Abstract
BACKGROUND AND AIMS Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH. APPROACH AND RESULTS Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver diseases, were positively correlated with certain RNA5SP transcripts. Real-time quantitative PCR demonstrated that RNA5SP transcripts were upregulated in peripheral blood mononuclear cells (PBMCs) from patients with sAH. In sAH livers, increased 5S rRNA and reduced nuclear MAF1 (MAF1 homolog, negative regulator of RNA polymerase III) protein suggested a higher activity of RNA polymerase III (Pol III); inhibition of Pol III reduced RNA5SP expression in monocytic THP-1 cells. Expression of several RNA5SP transcript-interacting proteins was downregulated in sAH, potentially unmasking transcripts to immunosensors. Indeed, siRNA knockdown of interacting proteins potentiated the immunostimulatory activity of RNA5SP transcripts. Molecular interaction and cell viability assays demonstrated that RNA5SP transcripts adopted Z-conformation and contributed to ZBP1-mediated caspase-independent cell death. CONCLUSIONS Increased expression and binding availability of RNA5SP transcripts was associated with hepatic IFN production and inflammation in sAH. These data identify RNA5SP transcripts as a potential target to mitigate inflammation and hepatocellular injury in AH.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Adam Kim
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Xiaoqin Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Semanti Ray
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Nicole Welch
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Annette Bellar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jaividhya Dasarathy
- Department of Family Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
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6
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Pang L, Yeung OWH, Ng KTP, Liu H, Zhu J, Liu J, Yang X, Ding T, Qiu W, Wang Y, Chiu TLS, Chen Z, Lo CM, Man K. Postoperative Plasmacytoid Dendritic Cells Secrete IFNα to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence. Cancer Res 2022; 82:4206-4218. [PMID: 36112065 DOI: 10.1158/0008-5472.can-22-1199] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/01/2022] [Accepted: 09/12/2022] [Indexed: 12/14/2022]
Abstract
Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNα serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNα, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNα was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNα-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNα upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFNα, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNα-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNα/CX3CL1/CX3CR1 axis could inhibit surgical stress-induced HCC recurrence by attenuating postoperative immunosuppression. SIGNIFICANCE IFNα secreted by plasmacytoid dendritic cells drives postoperative immunosuppression and early recurrence of hepatocellular carcinoma, providing new biomarkers and therapeutic targets to improve patient outcomes after surgical resection.
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Affiliation(s)
- Li Pang
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oscar W H Yeung
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kevin T P Ng
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hui Liu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jiye Zhu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Xinxiang Yang
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tao Ding
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wenqi Qiu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuewen Wang
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - T L Shirley Chiu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiwei Chen
- Department of Microbiology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Chung-Mau Lo
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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7
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Nishimoto S, Sata M, Fukuda D. Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases. Front Cardiovasc Med 2022; 9:881181. [PMID: 36176986 PMCID: PMC9513035 DOI: 10.3389/fcvm.2022.881181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/15/2022] [Indexed: 11/14/2022] Open
Abstract
In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases.
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Affiliation(s)
- Sachiko Nishimoto
- Faculty of Clinical Nutrition and Dietetics, Konan Women’s University, Kobe, Japan
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Daiju Fukuda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Cardiovascular Medicine, Osaka Metropolitan University, Osaka, Japan
- *Correspondence: Daiju Fukuda, ,
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8
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de Brito CB, Ascenção FR, Arifa RDN, Lima RL, Menezes Garcia Z, Fagundes M, Resende BG, Bezerra RO, Queiroz-Junior CM, Dos Santos ACPM, Oliveira MAP, Teixeira MM, Fagundes CT, Souza DG. FcᵧRIIb protects from reperfusion injury by controlling antibody and type I IFN-mediated tissue injury and death. Immunol Suppl 2022; 167:428-442. [PMID: 35831251 DOI: 10.1111/imm.13547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 07/05/2022] [Indexed: 11/30/2022]
Abstract
Intestinal ischemia and reperfusion (I/R) is accompanied by an exacerbated inflammatory response characterized by deposition of IgG, release of inflammatory mediators, and intense neutrophil influx in the small intestine, resulting in severe tissue injury and death. We hypothesized that FcᵧRIIb activation by deposited IgG could inhibit tissue damage during I/R. Our results showed that I/R induction led to the deposition of IgG in intestinal tissue during the reperfusion phase. Death upon I/R occurred earlier and was more frequent in FcᵧRIIb-/- than WT mice. The higher lethality rate was associated with greater tissue injury and bacterial translocation to other organs. FcᵧRIIb-/- mice presented changes in the amount and repertoire of circulating IgG, leading to increased IgG deposition in intestinal tissue upon reperfusion in these mice. Depletion of intestinal microbiota prevented antibody deposition and tissue damage in FcᵧRIIb-/- mice submitted to I/R. We also observed increased production of ROS on neutrophils harvested from the intestines of FcᵧRIIb-/- mice submitted to I/R. In contrast, FcᵧRIII-/- mice presented reduced tissue damage and neutrophil influx after reperfusion injury, a phenotype reversed by FcᵧRIIb blockade. In addition, we observed reduced IFN-β expression in the intestines of FcᵧRIII-/- mice after I/R, a phenotype that was also reverted by blocking FcᵧRIIb. IFNAR-/- mice submitted to I/R presented reduced lethality and TNF release. Altogether our results demonstrate that antibody deposition triggers FcᵧRIIb to control IFN-β and IFNAR activation and subsequent TNF release, tailoring tissue damage, and death induced by reperfusion injury.
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Affiliation(s)
- Camila Bernardo de Brito
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Fernando Roque Ascenção
- Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Raquel Duque Nascimento Arifa
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Renata Lacerda Lima
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Zélia Menezes Garcia
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Micheli Fagundes
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.,Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Brenda Gonçalves Resende
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rafael Oliveira Bezerra
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Celso Martins Queiroz-Junior
- Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Anna Clara Paiva Menezes Dos Santos
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Milton A P Oliveira
- Department of Microbiology, Immunology, Parasitology and Pathology, Tropical Pathology and Public Health Institute, Federal University of Goiás, Goiania, Goiás, Brazil
| | - Mauro Martins Teixeira
- Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Caio Tavares Fagundes
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.,Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Daniele G Souza
- Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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9
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Kageyama S, Kadono K, Hirao H, Nakamura K, Ito T, Gjertson DW, Sosa RA, Reed EF, Kaldas FM, Busuttil RW, Kupiec-Weglinski JW, Zhai Y. Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury. Transplantation 2021; 105:1989-1997. [PMID: 33065722 PMCID: PMC8046839 DOI: 10.1097/tp.0000000000003488] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. METHODS In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients. RESULTS CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels. CONCLUSIONS CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.
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Affiliation(s)
- Shoichi Kageyama
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Kentaro Kadono
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Hirofumi Hirao
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Kojiro Nakamura
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Takahiro Ito
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - David W. Gjertson
- Department of Biostatistics, UCLA School of Public Health University of California, Los Angeles, CA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
| | - Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
| | - Fady M. Kaldas
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Yuan Zhai
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
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10
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Hao C, Zhang J, Zhang F, Wu J, Cao H, Wang W. Mitochondrial DNA may act as a biomarker to predict donor-kidney quality. Clin Transplant 2021; 35:e14469. [PMID: 34448256 DOI: 10.1111/ctr.14469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 11/29/2022]
Abstract
Kidney transplantation is the best therapy for end-stage renal disease. Demand for kidney transplantation rises year-on-year, and the gap between kidney supply and demand remains large. To meet this clinical need, a gradual expansion in the supply of donors is required. However, clinics lack appropriate tools capable of quickly and accurately predicting post-transplant renal allograft function, and thus assess donor-kidney quality before transplantation. Mitochondrial DNA (mtDNA) is a key component of damage-associated molecular patterns (DAMPs) and plays an important part in ischemia-reperfusion injury (IRI), accelerating the progression of IRI by inducing inflammation and type I interferon responses. mtDNA is known to be closely involved in delayed graft function (DGF) and acute kidney injury (AKI) after transplantation. Thus, mtDNA is a potential biomarker able to predict post-transplant renal allograft function. This review summarizes mtDNA biology, the role mtDNA plays in renal transplantation, outlines advances in detecting mtDNA, and details mtDNA's able to predict post-transplant renal allograft function. We aim to elucidate the potential value of mtDNA as a biomarker in the prediction of IRI, and eventually provide help for predicting donor-kidney quality.
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Affiliation(s)
- Changzhen Hao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.,Institute of Urology, Capital Medical University, Beijing, China
| | - Jiandong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.,Institute of Urology, Capital Medical University, Beijing, China
| | - Feilong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.,Institute of Urology, Capital Medical University, Beijing, China
| | - Jiyue Wu
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.,Institute of Urology, Capital Medical University, Beijing, China
| | - Huawei Cao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.,Institute of Urology, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.,Institute of Urology, Capital Medical University, Beijing, China
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11
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Lai L, Zhang A, Yang B, Charles EJ, Kron IL, Yang Z. Plasmacytoid Dendritic Cells Mediate Myocardial Ischemia/Reperfusion Injury by Secreting Type I Interferons. J Am Heart Assoc 2021; 10:e020754. [PMID: 34325534 PMCID: PMC8475660 DOI: 10.1161/jaha.121.020754] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Background We previously demonstrated that ischemically injured cardiomyocytes release cell‐free DNA and HMGB1 (high mobility group box 1 protein) into circulation during reperfusion, activating proinflammatory responses and ultimately exacerbating reperfusion injury. We hypothesize that cell‐free DNA and HMGB1 mediate myocardial ischemia‐reperfusion injury by stimulating plasmacytoid dendritic cells (pDCs) to secrete type I interferon (IFN‐I). Methods and Results C57BL/6 and interferon alpha receptor‐1 knockout mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion (40′/60′ IR) before infarct size was evaluated by 2,3,5‐Triphenyltetrazolium chloride–Blue staining. Cardiac perfusate was acquired in ischemic hearts without reperfusion by antegrade perfusion of the isolated heart. Flow cytometry in pDC‐depleted mice treated with multiple doses of plasmacytoid dendritic cell antigen‐1 antibody via intraperitoneal injection demonstrated plasmacytoid dendritic cell antigen‐1 antibody treatment had no effect on conventional splenic dendritic cells but significantly reduced splenic pDCs by 60%. pDC‐depleted mice had significantly smaller infarct size and decreased plasma interferon‐α and interferon‐β compared with control. Blockade of the type I interferon signaling pathway with cyclic GMP‐AMP synthase inhibitor, stimulator of interferon genes antibody, or interferon regulatory factor 3 antibody upon reperfusion similarly significantly attenuated infarct size by 45%. Plasma levels of interferon‐α and interferon‐β were significantly reduced in cyclic GMP‐AMP synthase inhibitor‐treated mice. Infarct size was significantly reduced by >30% in type I interferon receptor monoclonal antibody–treated mice and interferon alpha receptor‐1 knockout mice. In splenocyte culture, 40′/0′ cardiac perfusate treatment stimulated interferon‐α and interferon‐β production; however, this effect disappeared in the presence of cyclic GMP‐AMP synthase inhibitor. Conclusions Type I interferon production is stimulated following myocardial ischemia by cardiogenic cell‐free DNA/HMGB1 in a pDC‐dependent manner, and subsequently activates type I interferon receptors to exacerbate reperfusion injury. These results identify new potential therapeutic targets to attenuate myocardial ischemia‐reperfusion injury.
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Affiliation(s)
- Lina Lai
- Department of Surgery University of Virginia Charlottesville VA.,Department of Pharmacology Changzhi Medical College Changzhi City Shanxi Province China
| | - Aimee Zhang
- Department of Surgery University of Virginia Charlottesville VA
| | - Boris Yang
- Department of Surgery University of Virginia Charlottesville VA
| | - Eric J Charles
- Department of Surgery University of Virginia Charlottesville VA
| | - Irving L Kron
- Department of Surgery University of Virginia Charlottesville VA
| | - Zequan Yang
- Department of Surgery University of Virginia Charlottesville VA
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12
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Fukuda D, Pham PT, Sata M. Emerging Roles of the Innate Immune System Regulated by DNA Sensors in the Development of Vascular and Metabolic Diseases. J Atheroscler Thromb 2021; 29:297-307. [PMID: 34248111 PMCID: PMC8894111 DOI: 10.5551/jat.rv17059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)—one of the most studied DNA sensors—recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.
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Affiliation(s)
- Daiju Fukuda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Phuong Tran Pham
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
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13
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Kim M, Huda MN, O'Connor A, Albright J, Durbin-Johnson B, Bennett BJ. Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross. Physiol Genomics 2021; 53:173-192. [PMID: 33818129 PMCID: PMC8424536 DOI: 10.1152/physiolgenomics.00140.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 12/28/2022] Open
Abstract
Mice have provided critical mechanistic understandings of clinical traits underlying metabolic syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content, which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.
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Affiliation(s)
- Myungsuk Kim
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
| | - M Nazmul Huda
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
| | - Annalouise O'Connor
- Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina
| | - Jody Albright
- Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina
| | | | - Brian J Bennett
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
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14
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Anti-interferon-α receptor 1 antibodies attenuate inflammation and organ injury following hemorrhagic shock. J Trauma Acute Care Surg 2020; 86:881-890. [PMID: 31009444 DOI: 10.1097/ta.0000000000002214] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hemorrhagic shock (HS) is a life-threatening condition resulting from rapid and significant loss of intravascular volume, leading to hemodynamic instability and death. Inflammation contributes to the multiple organ injury in HS. Type I interferons (IFNs), such as IFN-α and IFN-β, are a family of cytokines that regulate the inflammatory response through binding to IFN-α receptor (IFNAR) which consists of IFNAR1 and IFNAR2 chains. We hypothesized that type I IFNs provoke inflammation and worsen organ injury in HS. METHODS Male C57BL/6 mice (20-25 g) underwent hemorrhage by controlled bleeding via the femoral artery to maintain a mean arterial pressure of 27 ± 2.5 mm Hg for 90 minutes, followed by resuscitation for 30 minutes with two times shed blood volume of Ringer's lactate solution containing 1 mg/kg body weight of anti-IFNAR1 antibody (Ab) or control isotype-matched IgG (IgG). Blood and tissue samples were collected at 20 hours after the resuscitation for various analyses. RESULTS The expression of IFN-α and IFN-β mRNAs was significantly elevated in lungs and liver of the mice after HS. The IFNAR1-Ab treatment significantly decreased serum levels of organ injury markers lactate dehydrogenase and aspartate aminotransferase, as well as improved the integrity of lung and liver morphology, compared to the IgG control. The protein levels of proinflammatory cytokines TNF-α and IL-6, and mRNA expression of proinflammatory chemokines monocyte chemoattractant protein (MCP)-1, MCP-2, macrophage inflammatory protein 2 (MIP-2), and keratinocyte cytokine (KC) in the lungs of the HS mice were significantly decreased after treated with IFNAR1-Ab. Moreover, the myeloperoxidase activity and number of apoptotic cells in the lungs of HS mice treated with IFNAR1-Ab were decreased in comparison to the IgG control. CONCLUSION Administration of IFNAR1-Ab reduces inflammation and tissue injury. Thus, type I IFN signaling may be a potential therapeutic target for mitigating organ dysfunction in patients suffering from HS. STUDY TYPE Translational animal model.
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15
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Abstract
Ischemia/reperfusion (I/R) injury is a common occurrence resulting from acute mesenteric ischemia, traumatic or septic shock, burns, and surgical procedures that can lead to multiple organ failure and high mortality in critically ill patients. Mitochondria are often considered the cellular power factory via their capacity for ATP generation. Recently, mitochondria have been further identified as vital regulators of cell death, inflammation, and oxidative stress, all of which can aggravate I/R injury. Studies have indicated that mitochondrial DNA (mtDNA) damage leads to mitochondrial dysfunction and aggravates I/R injury. mtDNA is emerging as an agonist of the innate immune system that influences inflammatory pathology during I/R injury. In addition, when mtDNA is released into the cytoplasm, extracellular milieu, or circulation, it can activate multiple pattern-recognition receptors to trigger type I interferon and pro-inflammatory responses. Here, we review the emerging role of mtDNA in I/R injury to highlight novel mechanistic insights and discuss the pathophysiological relevance of mitochondrial biology.
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16
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Jassem W, Xystrakis E, Ghnewa YG, Yuksel M, Pop O, Martinez-Llordella M, Jabri Y, Huang X, Lozano JJ, Quaglia A, Sanchez-Fueyo A, Coussios CC, Rela M, Friend P, Heaton N, Ma Y. Normothermic Machine Perfusion (NMP) Inhibits Proinflammatory Responses in the Liver and Promotes Regeneration. Hepatology 2019; 70:682-695. [PMID: 30561835 DOI: 10.1002/hep.30475] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 10/01/2018] [Indexed: 12/21/2022]
Abstract
Liver transplantation (LT) is a successful treatment for patients with liver failure. However, organ shortage results in over 11% of patients losing their chance of a transplant attributed to liver decompensation (LD) and death. Ischemia/reperfusion injury (IRI) following conventional cold storage (CS) is a major cause of injury leading to graft loss after LT. Normothermic machine perfusion (NMP), a method of organ preservation, provides oxygen and nutrition during preservation and allows aerobic metabolism. NMP has recently been shown to enable improved organ utilization and posttransplant outcomes following a phase I and a phase III randomized trial. The aim of the present study is to assess the impact of NMP on reducing IRI and to define the underlying mechanisms. We transplanted and compared 12 NMP with 27 CS-preserved livers by performing gene microarray, immunoprofiling of hepatic lymphocytes, and immunochemistry staining of liver tissues for assessing necrosis, platelet deposition, and neutrophil infiltration, and the status of steatosis after NMP or CS prereperfusion and postreperfusion. Recipients receiving NMP grafts showed significantly lower peak aspartate aminotransferase (AST) levels than those receiving CS grafts. NMP altered gene-expression profiles of liver tissue from proinflammation to prohealing and regeneration. NMP also reduced the number of interferon gamma (IFN-γ) and interleukin (IL)-17-producing T cells and enlarged the CD4pos CD25high CD127neg FOXP3pos regulatory T cell (Treg) pool. NMP liver tissues showed less necrosis and apoptosis in the parenchyma and fewer neutrophil infiltration compared to CS liver tissues. Conclusion: Reduced IRI in NMP recipients was the consequence of the combination of inhibiting inflammation and promoting graft regeneration.
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Affiliation(s)
- Wayel Jassem
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom.,Transplantation Service, King's College Hospital, London, United Kingdom
| | - Emmanuel Xystrakis
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Yasmeen G Ghnewa
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Muhammed Yuksel
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Oltin Pop
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Marc Martinez-Llordella
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Yamen Jabri
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Xiaohong Huang
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Juan J Lozano
- Bioinformatics Platform, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain
| | - Alberto Quaglia
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
| | | | - Mohamed Rela
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom.,Transplantation Service, King's College Hospital, London, United Kingdom
| | - Peter Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Nigel Heaton
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom.,Transplantation Service, King's College Hospital, London, United Kingdom
| | - Yun Ma
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Science, King's College London, London, United Kingdom
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17
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Zhang X, Wu X, Hu Q, Wu J, Wang G, Hong Z, Ren J. Mitochondrial DNA in liver inflammation and oxidative stress. Life Sci 2019; 236:116464. [PMID: 31078546 DOI: 10.1016/j.lfs.2019.05.020] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023]
Abstract
The function of liver is highly dependent on mitochondria producing ATP for biosynthetic and detoxifying properties. Accumulating evidence indicates that most hepatic disorders are characterized by profound mitochondrial dysfunction. Mitochondrial dysfunction not only exhibits mitochondrial DNA (mtDNA) damage and depletion, but also releases mtDNA. mtDNA is a closed circular molecule encoding 13 of the polypeptides of the oxidative phosphorylation system. Extensive mtDNA lesions could exacerbate mitochondrial oxidative stress and subsequently cause damage to hepatocytes. When mtDNA leaves the confines of mitochondria to the cytosolic and extracellular environment, it can act as damage-associated molecular patterns (DAMPs) to trigger the inflammatory response through the Toll-like receptor 9, inflammasomes, and stimulator of interferon genes (STING) pathways and further exacerbate hepatocellular damage and even remote organs injury. In addition, mtDNA also plays a vital role in hepatitis B virus (HBV)-related liver injury and hepatocellular carcinoma (HCC). In this review, we describe mtDNA alterations during liver injury, focusing on the mechanisms of mtDNA-mediated liver inflammation and oxidative stress injury.
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Affiliation(s)
- Xufei Zhang
- Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China.
| | - Qiongyuan Hu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Jie Wu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Gefei Wang
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Zhiwu Hong
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China.
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- Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
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18
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Li W, Feng G, Gauthier JM, Lokshina I, Higashikubo R, Evans S, Liu X, Hassan A, Tanaka S, Cicka M, Hsiao HM, Ruiz-Perez D, Bredemeyer A, Gross RW, Mann DL, Tyurina YY, Gelman AE, Kagan VE, Linkermann A, Lavine KJ, Kreisel D. Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation. J Clin Invest 2019; 129:2293-2304. [PMID: 30830879 DOI: 10.1172/jci126428] [Citation(s) in RCA: 324] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
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Affiliation(s)
| | - Guoshuai Feng
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | | | - Inessa Lokshina
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | | | - Sarah Evans
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | - Xinping Liu
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | | | | | - Markus Cicka
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | | | | | - Andrea Bredemeyer
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | - Richard W Gross
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | - Douglas L Mann
- Department of Medicine, Washington University, Saint Louis, Missouri, USA
| | - Yulia Y Tyurina
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Andrew E Gelman
- Department of Surgery and.,Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA
| | - Valerian E Kagan
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Laboratory of Navigational Redox Lipidomics, I.M. Sechenov Moscow State Medical University, Moscow, Russia
| | - Andreas Linkermann
- Department of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany
| | - Kory J Lavine
- Department of Medicine, Washington University, Saint Louis, Missouri, USA.,Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA.,Department of Developmental Biology, Washington University, Saint Louis, Missouri, USA
| | - Daniel Kreisel
- Department of Surgery and.,Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA
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19
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Mihm S. Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver. Int J Mol Sci 2018; 19:ijms19103104. [PMID: 30309020 PMCID: PMC6213769 DOI: 10.3390/ijms19103104] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/21/2018] [Accepted: 10/08/2018] [Indexed: 02/07/2023] Open
Abstract
Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self-structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release—passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells—and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets.
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Affiliation(s)
- Sabine Mihm
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, 37075 Goettingen, Germany.
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20
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Liu BC, Sarhan J, Poltorak A. Host-Intrinsic Interferon Status in Infection and Immunity. Trends Mol Med 2018; 24:658-668. [PMID: 30060835 DOI: 10.1016/j.molmed.2018.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/31/2018] [Accepted: 06/07/2018] [Indexed: 01/09/2023]
Abstract
Most genetic ablations of interferon (IFN) signaling abolish both the experimentally induced IFN response and constitutive IFN, whose effects are well established in autoimmunity but understudied during infection. In host-pathogen interactions, most IFN-mediated responses are attributed to infection-driven IFN. However, IFNs confer their activity by regulating networks of interferon-stimulated genes (ISGs), a process that requires de novo transcription and translation of both IFN and downstream ISGs through feedback of IFN receptor signaling. Due to the temporal requirement for IFN activity, many rapid antimicrobial responses may instead result from pre-established IFN signature stemming from host-intrinsic processes. Addressing the permeating effects of constitutive IFN is therefore needed to accurately describe immunity as host intrinsic or pathogen induced.
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Affiliation(s)
- Beiyun C Liu
- Graduate Program in Immunology, Sackler School of Biomedical Sciences, Tufts University Boston, MA 02111, USA
| | - Joseph Sarhan
- Graduate Program in Immunology, Sackler School of Biomedical Sciences, Tufts University Boston, MA 02111, USA; Medical Scientist Training Program, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Alexander Poltorak
- Graduate Program in Immunology, Sackler School of Biomedical Sciences, Tufts University Boston, MA 02111, USA; Medical Scientist Training Program, Tufts University School of Medicine, Boston, MA 02111, USA; Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA.
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21
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Guan G, Shen Y, Yu Q, Liu H, Zhang B, Guo Y, Zhu X, Li Z, Rao W, Zhuang L, Zang Y. Down-regulation of IFIT3 protects liver from ischemia-reperfusion injury. Int Immunopharmacol 2018; 60:170-178. [DOI: 10.1016/j.intimp.2018.04.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 04/25/2018] [Accepted: 04/26/2018] [Indexed: 12/17/2022]
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22
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Rao J, Cheng F, Yang S, Zhai Y, Lu L. Ag-specific CD4 T cells promote innate immune responses in liver ischemia reperfusion injury. Cell Mol Immunol 2018; 16:98-100. [PMID: 29907880 DOI: 10.1038/s41423-018-0051-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 05/18/2018] [Indexed: 12/19/2022] Open
Affiliation(s)
- Jianhua Rao
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.,Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Feng Cheng
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shikun Yang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yuan Zhai
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.,Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Ling Lu
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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23
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Yang MQ, Du Q, Goswami J, Varley PR, Chen B, Wang RH, Morelli AE, Stolz DB, Billiar TR, Li J, Geller DA. Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury. Hepatology 2018; 67:1056-1070. [PMID: 29059701 PMCID: PMC5826835 DOI: 10.1002/hep.29605] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 10/06/2017] [Accepted: 10/16/2017] [Indexed: 12/11/2022]
Abstract
The role and regulators of extracellular vesicle (EV) secretion in hepatic ischemia/reperfusion (IR) injury have not been defined. Rab27a is a guanosine triphosphatase known to control EV release. Interferon regulatory factor 1 (IRF-1) is a transcription factor that plays an important role in liver IR and regulates certain guanosine triphosphatases. However, the relationships among IRF-1, Rab27a, and EV secretion are largely unknown. Here, we show induction of IRF-1 and Rab27a both in vitro in hypoxic hepatocytes and in vivo in warm IR and orthotopic liver transplantation livers. Interferon γ stimulation, IRF-1 transduction, or IR promoted Rab27a expression and EV secretion. Meanwhile, silencing of IRF-1 decreased Rab27a expression and EV secretion. Rab27a silencing decreased EV secretion and liver IR injury. Ten putative IRF-1 binding motifs in the 1,692-bp Rab27a promoter region were identified. Chromatin immunoprecipitation and electrophoretic mobility shift assay verified five functional IRF-1 binding motifs, which were confirmed by a Rab27a promoter luciferase assay. IR-induced EVs contained higher oxidized phospholipids (OxPL). OxPLs on the EV surface activated neutrophils through the toll-like receptor 4 pathway. OxPL-neutralizing E06 antibody blocked the effect of EVs and decreased liver IR injury. CONCLUSION These findings provide a novel mechanism by which IRF-1 regulates Rab27a transcription and EV secretion, leading to OxPL activation of neutrophils and subsequent hepatic IR injury. (Hepatology 2018;67:1056-1070).
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Affiliation(s)
- Mu-qing Yang
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
- Department of Surgery, Shanghai Tenth People’s Hospital, Tenth People’s Hospital of Tongji University, 301 Middle Yanchang Road, Shanghai 200072, People’s Republic of China
| | - Qiang Du
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Julie Goswami
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Patrick R. Varley
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Bin Chen
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Rong-hua Wang
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Adrian E. Morelli
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Donna B. Stolz
- Center of Biological Imaging, University of Pittsburgh, 3500 Terrace Street, BST S224, Pittsburgh, PA 15261
| | - Timothy R. Billiar
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
| | - Jiyu Li
- Department of Surgery, Shanghai Tenth People’s Hospital, Tenth People’s Hospital of Tongji University, 301 Middle Yanchang Road, Shanghai 200072, People’s Republic of China
| | - David A. Geller
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, W1507, Pittsburgh, PA 15261
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24
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Wieser V, Adolph TE, Grander C, Grabherr F, Enrich B, Moser P, Moschen AR, Kaser S, Tilg H. Adipose type I interferon signalling protects against metabolic dysfunction. Gut 2018; 67:157-165. [PMID: 28011892 DOI: 10.1136/gutjnl-2016-313155] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/28/2016] [Accepted: 12/02/2016] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD. DESIGN We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and β) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep ), adipocytes (Ifnar1Δat ), intestinal epithelial cells (Ifnar1ΔIEC ) or myelocytes (Ifnar1Δmyel ) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB). RESULTS Long chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver. CONCLUSIONS Our study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted.
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Affiliation(s)
- Verena Wieser
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Timon Erik Adolph
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Barbara Enrich
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Patrizia Moser
- Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria
| | - Alexander Rupert Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Susanne Kaser
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
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25
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Petta S, Valenti L, Tuttolomondo A, Dongiovanni P, Pipitone RM, Cammà C, Cabibi D, Di Marco V, Fracanzani AL, Badiali S, Nobili V, Fargion S, Grimaudo S, Craxì A. Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 2017; 66:1885-1893. [PMID: 28741298 DOI: 10.1002/hep.29395] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/01/2017] [Accepted: 07/20/2017] [Indexed: 12/13/2022]
Abstract
UNLABELLED The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). CONCLUSION The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885-1893).
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonino Tuttolomondo
- Sezione di Medicina Interna e Cardioangiologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Paola Dongiovanni
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Rosaria Maria Pipitone
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Daniela Cabibi
- Cattedra di Anatomia Patologica, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Sara Badiali
- Department of Surgery, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Valerio Nobili
- Hepatometabolic Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
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26
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Abstract
Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury.
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Affiliation(s)
- Takanori Konishi
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
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27
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Tian X, Sun H, Casbon AJ, Lim E, Francis KP, Hellman J, Prakash A. NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice. Front Immunol 2017; 8:1337. [PMID: 29163464 PMCID: PMC5671513 DOI: 10.3389/fimmu.2017.01337] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/03/2017] [Indexed: 02/06/2023] Open
Abstract
Sterile lung injury is an important clinical problem that complicates the course of severely ill patients. Interruption of blood flow, namely ischemia-reperfusion (IR), initiates a sterile inflammatory response in the lung that is believed to be maladaptive. The rationale for this study was to elucidate the molecular basis for lung IR inflammation and whether it is maladaptive or beneficial. Using a mouse model of lung IR, we demonstrate that sequential blocking of inflammasomes [specifically, NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)], inflammatory caspases, and interleukin (IL)-1β, all resulted in an attenuated inflammatory response. IL-1β production appeared to predominantly originate in conjunction with alveolar type 2 epithelial cells. Lung IR injury recruited unactivated or dormant neutrophils producing less reactive oxygen species thereby challenging the notion that recruited neutrophils are terminally activated. However, lung IR inflammation was able to limit or reduce the bacterial burden from subsequent experimentally induced pneumonia. Notably, inflammasome-deficient mice were unable to alter this bacterial burden following IR. Thus, we conclude that the NLRP3 inflammasome, through IL-1β production, regulates lung IR inflammation, which includes recruitment of dormant neutrophils. The sterile IR inflammatory response appears to serve an important function in inducing resistance to subsequent bacterial pneumonia and may constitute a critical part of early host responses to infection in trauma.
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Affiliation(s)
- Xiaoli Tian
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
| | - He Sun
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
| | - Amy-Jo Casbon
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, United States
| | - Edward Lim
- Preclinical Imaging, PerkinElmer, Hopkinton, MA, United States
| | - Kevin P Francis
- Preclinical Imaging, PerkinElmer, Hopkinton, MA, United States
| | - Judith Hellman
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States.,Division of Critical Care Medicine, Department of Anthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
| | - Arun Prakash
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
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28
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De Luna N, Suárez-Calvet X, Lleixà C, Diaz-Manera J, Olivé M, Illa I, Gallardo E. Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis. Sci Rep 2017; 7:8595. [PMID: 28819164 PMCID: PMC5561123 DOI: 10.1038/s41598-017-09309-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 07/25/2017] [Indexed: 12/21/2022] Open
Abstract
Dermatomyositis is an inflammatory myopathy characterized by symmetrical proximal muscle weakness and skin changes. Muscle biopsy hallmarks include perifascicular atrophy, loss of intramuscular capillaries, perivascular and perimysial inflammation and the overexpression of IFN-inducible genes. Among them, the retinoic-acid inducible gene 1 (RIG-I) is specifically overexpressed in perifascicular areas of dermatomyositis muscle. The aim of this work was to study if RIG-I expression may be modulated by hypoxia using an in vitro approach. We identified putative hypoxia response elements (HRE) in RIG-I regulatory regions and luciferase assays confirmed that RIG-I is a new HIF-inducible gene. We observed an increase expression of RIG-I both by Real time PCR and Western blot in hypoxic conditions in human muscle cells. Cell transfection with a constitutive RIG-I expression vector increased levels of phospho-IRF-3, indicating that RIG-I promotes binding of transcription factors to the enhancer sequence of IFN. Moreover, release of IFN-β was observed in hypoxic conditions. Finally, HIF-1α overexpression was confirmed in the muscle biopsies and in some RIG-I positive perifascicular muscle fibres but not in controls. Our results indicate that hypoxia triggers the production of IFN-I in vitro, and may contribute to the pathogenesis of DM together with other inflammatory factors.
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Affiliation(s)
- Noemí De Luna
- Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, (Barcelona) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Sant Pau, Spain
| | - Xavier Suárez-Calvet
- Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, (Barcelona) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Sant Pau, Spain
| | - Cinta Lleixà
- Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, (Barcelona) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Sant Pau, Spain
| | - Jordi Diaz-Manera
- Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, (Barcelona) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Sant Pau, Spain
| | - Montse Olivé
- Department of Pathology and Neuromuscular Unit, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
| | - Isabel Illa
- Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, (Barcelona) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Sant Pau, Spain.
| | - Eduard Gallardo
- Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, (Barcelona) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Sant Pau, Spain.
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Rani R, Tandon A, Wang J, Kumar S, Gandhi CR. Stellate Cells Orchestrate Concanavalin A-Induced Acute Liver Damage. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2008-2019. [PMID: 28710903 DOI: 10.1016/j.ajpath.2017.05.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/13/2017] [Accepted: 05/22/2017] [Indexed: 12/12/2022]
Abstract
Concanavalin A (ConA) causes immune cell-mediated liver damage, but the contribution of resident nonparenchymal cells (NPCs) is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, effects of ConA-conditioned HSC medium on hepatocytes were determined. ConA induced inflammation, sinusoidal congestion, and extensive midzonal hepatocyte death in control mice, which were strongly minimized in HSC-depleted mice. CD4 and natural killer T cells and neutrophils were markedly reduced in ConA-treated HSC-depleted mice compared with control mice. The increase in cytokines/chemokines of hepatic injury was much higher in ConA-treated control mice than in HSC-depleted mice. ConA-treated HSCs showed increased expression of interferon-β, tumor necrosis factor-α, and CXCL1, induced oxidative stress in hepatocytes, and caused hepatocyte apoptosis. ConA induced nuclear translocation of interferon-regulatory factor-1 (IRF1) in hepatocytes in vivo, and ConA/HSC induced a similar effect in cultured hepatocytes. IRF1-knockout mice were resistant to ConA-induced liver damage, and anti-interferon β antibody mitigated ConA/HSC-induced injury. In HSC-NPC co-culture, ConA-induced expression of inflammatory cytokines/chemokines was significantly augmented compared with NPCs alone. HSCs play an essential role in ConA-induced liver injury directly via the interferon-β/IRF1 axis, and by modulating properties of NPCs.
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Affiliation(s)
- Richa Rani
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ashish Tandon
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio
| | - Sudhir Kumar
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Chandrashekhar R Gandhi
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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30
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Abstract
Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver ischemia-reperfusion injury involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver ischemia-reperfusion injury in patients.
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31
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Sosa RA, Zarrinpar A, Rossetti M, Lassman CR, Naini BV, Datta N, Rao P, Harre N, Zheng Y, Spreafico R, Hoffmann A, Busuttil RW, Gjertson DW, Zhai Y, Kupiec-Weglinski JW, Reed EF. Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation. JCI Insight 2016; 1:e89679. [PMID: 27942590 DOI: 10.1172/jci.insight.89679] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.
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Affiliation(s)
| | | | | | | | | | | | - Ping Rao
- Department of Pathology and Laboratory Medicine
| | | | - Ying Zheng
- Department of Pathology and Laboratory Medicine
| | - Roberto Spreafico
- Department of Microbiology, Immunology, and Molecular Genetics, and.,Institute for Quantitative and Computational Biosciences, UCLA, California, USA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics, and.,Institute for Quantitative and Computational Biosciences, UCLA, California, USA
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32
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Jiang W, Liu G, Tang W. MicroRNA-182-5p Ameliorates Liver Ischemia-Reperfusion Injury by Suppressing Toll-Like Receptor 4. Transplant Proc 2016; 48:2809-2814. [DOI: 10.1016/j.transproceed.2016.06.043] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 06/06/2016] [Indexed: 12/21/2022]
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33
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Sun Q, Wang Q, Scott MJ, Billiar TR. Immune Activation in the Liver by Nucleic Acids. J Clin Transl Hepatol 2016; 4:151-7. [PMID: 27350945 PMCID: PMC4913071 DOI: 10.14218/jcth.2016.00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 02/24/2016] [Accepted: 03/07/2016] [Indexed: 12/17/2022] Open
Abstract
Viral infection in the liver, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, is a major health problem worldwide, especially in developing countries. The infection triggers a pro-inflammatory response in patients that is crucial for host defense. Recent studies have identified multiple transmembrane and cytosolic receptors that recognize pathogen-derived nucleic acids, and these receptors are essential for driving immune activation in the liver. In addition to sensing DNA/RNA from pathogens, these intracellular receptors can be activated by nucleic acids of host origin in response to sterile injuries. In this review, we discuss the expanding roles of these receptors in both immune and nonimmune cells in the liver.
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Affiliation(s)
- Qian Sun
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Melanie J. Scott
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Timothy R. Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- *Correspondence to: Timothy R. Billiar, Department of Surgery, University of Pittsburgh, Suite F1281, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Tel: +1-412-647-1749, Fax: +1-412-647-3247,
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34
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Zhang L, Xiang W, Wang G, Yan Z, Zhu Z, Guo Z, Sengupta R, Chen AF, Loughran PA, Lu B, Wang Q, Billiar TR. Interferon β (IFN-β) Production during the Double-stranded RNA (dsRNA) Response in Hepatocytes Involves Coordinated and Feedforward Signaling through Toll-like Receptor 3 (TLR3), RNA-dependent Protein Kinase (PKR), Inducible Nitric Oxide Synthase (iNOS), and Src Protein. J Biol Chem 2016; 291:15093-107. [PMID: 27226571 DOI: 10.1074/jbc.m116.717942] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Indexed: 12/19/2022] Open
Abstract
The sensing of double-stranded RNA (dsRNA) in the liver is important for antiviral defenses but can also contribute to sterile inflammation during liver injury. Hepatocytes are often the target of viral infection and are easily injured by inflammatory insults. Here we sought to establish the pathways involved in the production of type I interferons (IFN-I) in response to extracellular poly(I:C), a dsRNA mimetic, in hepatocytes. This was of interest because hepatocytes are long-lived and, unlike most immune cells that readily die after activation with dsRNA, are not viewed as cells with robust antimicrobial capacity. We found that poly(I:C) leads to rapid up-regulation of inducible nitric oxide synthase (iNOS), double-stranded RNA-dependent protein kinase (PKR), and Src. The production of IFN-β was dependent on iNOS, PKR, and Src and partially dependent on TLR3/Trif. iNOS and Src up-regulation was partially dependent on TLR3/Trif but entirely dependent on PKR. The phosphorylation of TLR3 on tyrosine 759 was shown to increase in parallel to IFN-β production in an iNOS- and Src-dependent manner, and Src was found to directly interact with TLR3 in the endosomal compartment of poly(I:C)-treated cells. Furthermore, we identified a robust NO/cGMP/PKG-dependent feedforward pathway for the amplification of iNOS expression. These data identify iNOS/NO as an integral component of IFN-β production in response to dsRNA in hepatocytes in a pathway that involves the coordinated activities of TLR3/Trif and PKR.
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Affiliation(s)
- Liyong Zhang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Wenpei Xiang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoliang Wang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Zhengzheng Yan
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Zhaowei Zhu
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Zhong Guo
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Rajib Sengupta
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Alex F Chen
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Patricia A Loughran
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and
| | - Ben Lu
- the Xiangya Third Hospital and Central South University School of Medicine, Changsha, China
| | - Qingde Wang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Timothy R Billiar
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213,
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35
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Donor Hepatic Steatosis Induce Exacerbated Ischemia-Reperfusion Injury Through Activation of Innate Immune Response Molecular Pathways. Transplantation 2016; 99:2523-33. [PMID: 26285018 DOI: 10.1097/tp.0000000000000857] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation after LT. METHODS Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: without steatosis (WS) of 5% or less (n = 13) and with steatosis (S) of 25% or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines evaluation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray average algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5%). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool. RESULTS Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circulating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time. CONCLUSIONS Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Preemptive strategies should consider it for safety usage of steatotic livers.
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36
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Wang H, Wang G, Zhang L, Zhang J, Zhang J, Wang Q, Billiar TR. ADAR1 Suppresses the Activation of Cytosolic RNA-Sensing Signaling Pathways to Protect the Liver from Ischemia/Reperfusion Injury. Sci Rep 2016; 6:20248. [PMID: 26832817 PMCID: PMC4735287 DOI: 10.1038/srep20248] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 12/29/2015] [Indexed: 12/21/2022] Open
Abstract
Excessive inflammation resulting from activation of the innate immune system significantly contributes to ischemia/reperfusion injury (IRI). Inflammatory reactions in both IRI and infections share the same signaling pathways evoked by danger/pathogen associated molecular pattern molecules. The cytosolic retinoid-inducible gene I(RIG-I)-like RNA receptor (RLR) RNA sensing pathway mediates type I IFN production during viral infection and the sensing of viral RNA is regulated by adenosine deaminase acting on RNA 1 (ADAR1). Using a model of liver IRI, we provide evidence that ADAR1 also regulates cytosolic RNA-sensing pathways in the setting of ischemic stress. Suppression of ADAR1 significantly enhanced inflammation and liver damage following IRI, which was accompanied by significant increases in type I IFN through cytosolic RNA-sensing pathways. In addition, knocking ADAR1 down in hepatocytes exaggerates inflammatory signaling to dsRNA or endotoxin and results in over production of type I IFN, which could be abolished by the interruption of RIG-I. Therefore, we identified a novel ADAR1-dependent protective contribution through which hepatocytes guard against aberrant cytosolic RLR-RNA-sensing pathway mediated inflammatory reaction in response to acute liver IR. ADAR1 protects against over activation of viral RNA-sensing pathways in non-infectious tissue stress.
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Affiliation(s)
- Hui Wang
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Guoliang Wang
- F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.,Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Liyong Zhang
- F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA
| | - Junbin Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jinxiang Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Qingde Wang
- F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA.,Third Xiangya Hospital, Central South University, Changsha, China 410083
| | - Timothy R Billiar
- F1281 UPMC Presbyterian Hospital, 200 Lothrop St, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA
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37
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WISP1 mediates hepatic warm ischemia reperfusion injury via TLR4 signaling in mice. Sci Rep 2016; 6:20141. [PMID: 26821752 PMCID: PMC4731767 DOI: 10.1038/srep20141] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 12/30/2015] [Indexed: 12/22/2022] Open
Abstract
Wnt-induced secreted protein-1 (WISP1) is an extracellular matrix protein that has been reported in cancer researches. Our previous studies on WISP1 implied it could be a harmful mediator in septic mice. However, its role in liver ischemia reperfusion (I/R) injury is unknown. This study investigated the effects of WISP1 on liver I/R damage. Male C57BL/6 wild-type mice were used to undergo 60 min segmental (70%) ischemia. WISP1 expression was measured after indicated time points of reperfusion. Anti-WISP1 antibody was injected intraperitoneally to mice. Toll-like receptor 4 (TLR4) knockout mice and TIR-domain-containing adaptor inducing interferon-β (TRIF) knockout mice were adopted in this study. WISP1 was significantly enhanced after 6 h of reperfusion when compared with sham treated mice and significantly decreased either by TLR4 knockout mice or TRIF knockout mice. Anti-WISP1 antibody significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), pathological changes and pro-inflammatory cytokine levels in the mice following I/R. Furthermore, significantly increased serum transaminase levels were found in C57 wild-type mice treated with recombinant WISP1 protein, but not found in TLR4 knockout or TRIF knockout mice subjected to liver I/R. Taken together, WISP1 might contribute to hepatic ischemia reperfusion injury in mice and possibly depends on TLR4/TRIF signaling.
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38
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Wang G, Wang H, Singh S, Zhou P, Yang S, Wang Y, Zhu Z, Zhang J, Chen A, Billiar T, Monga SP, Wang Q. ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:3224-37. [PMID: 26453800 PMCID: PMC4729276 DOI: 10.1016/j.ajpath.2015.08.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 07/15/2015] [Accepted: 08/11/2015] [Indexed: 12/18/2022]
Abstract
Adenosine deaminase acting on RNA 1 (ADAR1) is an essential protein for embryonic liver development. ADAR1 loss is embryonically lethal because of severe liver damage. Although ADAR1 is required in adult livers to prevent liver cell death, as demonstrated by liver-specific conditional knockout (Alb-ADAR1(KO)) mice, the mechanism remains elusive. We systematically analyzed Alb-ADAR1(KO) mice for liver damage. Differentiation genes and inflammatory pathways were examined in hepatic tissues from Alb-ADAR1(KO) and littermate controls. Inducible ADAR1 KO mice were used to validate regulatory effects of ADAR1 on inflammatory cytokines. We found that Alb-ADAR1(KO) mice showed dramatic growth retardation and high mortality because of severe structural and functional damage to the liver, which showed overwhelming inflammation, cell death, fibrosis, fatty change, and compensatory regeneration. Simultaneously, Alb-ADAR1(KO) showed altered expression of key differentiation genes and significantly higher levels of hepatic inflammatory cytokines, especially type I interferons, which was also verified by inducible ADAR1 knockdown in primary hepatocyte cultures. We conclude that ADAR1 is an essential molecule for maintaining adult liver homeostasis and, in turn, morphological and functional integrity. It inhibits the production of type I interferons and other inflammatory cytokines. Our findings may provide novel insight in the pathogenesis of liver diseases caused by excessive inflammatory responses, including autoimmune hepatitis.
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Affiliation(s)
- Guoliang Wang
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of General Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Wang
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Pei Zhou
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shengyong Yang
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Yujuan Wang
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Zhaowei Zhu
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jinxiang Zhang
- Department of General Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Alex Chen
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Cardiology, Center for Vascular Disease and Translational Medicine, Third Xiangya Hospital, Central South University, Changsha, China
| | - Timothy Billiar
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Cardiology, Center for Vascular Disease and Translational Medicine, Third Xiangya Hospital, Central South University, Changsha, China.
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Transection Speed and Impact on Perioperative Inflammatory Response - A Randomized Controlled Trial Comparing Stapler Hepatectomy and CUSA Resection. PLoS One 2015; 10:e0140314. [PMID: 26452162 PMCID: PMC4599945 DOI: 10.1371/journal.pone.0140314] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 09/23/2015] [Indexed: 12/27/2022] Open
Abstract
Background Parenchymal transection represents a crucial step during liver surgery and many different techniques have been described so far. Stapler resection is supposed to be faster than CUSA resection. However, whether speed impacts on the inflammatory response in patients undergoing liver resection (LR) remains unclear. Materials and Methods This is a randomized controlled trial including 40 patients undergoing anatomical LR. Primary endpoint was transection speed (cm2/min). Secondary endpoints included the perioperative change of pro- and anti-inflammatory cytokines, overall surgery duration, length of hospital stay, morbidity and mortality. Results Mean transection speed was significantly higher in patients undergoing stapler hepatectomy compared to CUSA resection (CUSA: 1 (0.4) cm2/min vs. Stapler: 10.8 (6.1) cm2/min; p<0.0001). Analyzing the impact of surgery duration on inflammatory response revealed a significant correlation between IL-6 levels measured at the end of surgery and the overall length of surgery (p<0.0001, r = 0.6188). Patients undergoing CUSA LR had significantly higher increase of interleukin-6 (IL-6) after parenchymal transection compared to patients with stapler hepatectomy in the portal and hepatic veins, respectively (p = 0.028; p = 0.044). C-reactive protein levels on the first post-operative day were significantly lower in the stapler cohort (p = 0.010). There was a trend towards a reduced overall surgery time in patients with stapler LR, especially in the subgroup of patients undergoing minor hepatectomies (p = 0.020). Conclusions Liver resection using staplers is fast, safe and suggests a diminished inflammatory response probably due to a decreased parenchymal transection time. Trial Registration ClinicalTrials.gov NCT01785212
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Zhang J, Zhang M, Zhang J, Xia Q. A Novel Mouse Model of Liver Ischemic/Reperfusion Injury and its Differences to the Existing Model. J INVEST SURG 2015. [PMID: 26204139 DOI: 10.3109/08941939.2014.983621] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Ischemia of the cephalad lobes (70% of liver mass) is a frequently employed mouse hepatic ischemia/reperfusion (I/R) model that does not involve outflow occlusion. This model produces results with relatively large variances. MATERIALS AND METHODS A novel model of ischemia of the left lateral lobe (35% of liver mass) that involves temporarily occluding the blood supply to the cephalad lobes to expel blood followed by occlusion of both the inflow and outflow of the left lateral lobe, was developed. Mice in the 35% (novel) and 70% (existing) model groups were subjected to I/R injury, and biochemical and histological analyses of blood and liver samples were performed. Tissue oxygen partial pressure (tPO2) measurements in the ischemic lobes were also performed to determine whether the hepatic tissue was in a stable hypoxic state. Statistical analyses of the biochemical results, histological scores, and tPO2 levels were performed from which coefficients of variation (CV) were calculated. RESULTS The CVs of the aminotransferase activities, histological scores, and tPO2 levels were much lower in the 35% group than those in the 70% group. The tPO2 measurements demonstrated that inflow occlusion in the 70% model did not result in a stable hypoxic state, even after the portal triads were ligated and severed, indicating that there was blood reflux from the vena cava, which would be responsible for the variations in results with the 70% I/R model. CONCLUSIONS The new 35% I/R model leads to reproducible results because both inflow and outflow of the ischemic lobe are occluded.
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Affiliation(s)
- Jianjian Zhang
- a Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai , China
| | - Ming Zhang
- a Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai , China
| | - Jianjun Zhang
- a Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai , China
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Tumor necrosis factor-related apoptosis-inducing ligand on NK cells protects from hepatic ischemia-reperfusion injury. Transplantation 2014; 97:1102-9. [PMID: 24804996 DOI: 10.1097/tp.0000000000000101] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) significantly contributes to graft dysfunction after liver transplantation. Natural killer (NK) cells are crucial innate effector cells in the liver and express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of hepatocyte cell death. Here, we investigated if TRAIL expression on NK cells contributes to hepatic IRI. METHODS The outcome after partial hepatic IRI was assessed in TRAIL-null mice and contrasted to C57BL/6J wild-type mice and after NK cell adoptive transfer in RAG2/common gamma-null mice that lack T, B, and NK cells. Liver IRI was assessed by histological analysis, alanine aminotransferase, hepatic neutrophil activation by myeloperoxidase activity, and cytokine secretion at specific time points. NK cell cytotoxicity and differentiation were assessed in vivo and in vitro. RESULTS Twenty-four hours after reperfusion, TRAIL-null mice exhibited significantly higher serum transaminases, histological signs of necrosis, neutrophil infiltration, and serum levels of interleukin-6 compared to wild-type animals. Adoptive transfer of TRAIL-null NK cells into immunodeficient RAG2/common gamma-null mice was associated with significantly elevated liver damage compared to transfer of wild-type NK cells. In TRAIL-null mice, NK cells exhibit higher cytotoxicity and decreased differentiation compared to wild-type mice. In vitro, cytotoxicity against YAC-1 and secretion of interferon gamma by TRAIL-null NK cells were significantly increased compared to wild-type controls. CONCLUSIONS These experiments reveal that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI through modulation of NK cell cytotoxicity and NK cell differentiation.
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Castellaneta A, Yoshida O, Kimura S, Yokota S, Geller DA, Murase N, Thomson AW. Plasmacytoid dendritic cell-derived IFN-α promotes murine liver ischemia/reperfusion injury by induction of hepatocyte IRF-1. Hepatology 2014; 60:267-77. [PMID: 24493010 PMCID: PMC4077928 DOI: 10.1002/hep.27037] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 01/29/2014] [Indexed: 12/25/2022]
Abstract
UNLABELLED Plasmacytoid dendritic cells (pDC) constitute the body's principal source of type I interferon (IFN) and are comparatively abundant in the liver. Among various cytokines implicated in liver ischemia and reperfusion (I/R) injury, type I IFNs have been described recently as playing an essential role in its pathogenesis. Moreover, type I IFNs have been shown to up-regulate hepatocyte expression of IFN regulatory factor 1 (IRF-1), a key transcription factor that regulates apoptosis and induces liver damage after I/R. Our aim was to ascertain the capacity of IFN-α released by liver pDC to induce liver damage through hepatic IRF-1 up-regulation after I/R injury. Our findings show that liver pDC mature and produce IFN-α in response to liver I/R. Liver pDC isolated after I/R induced elevated levels of IRF-1 production by hepatocytes compared with liver pDC isolated from sham-operated mice. Notably, hepatic IRF-1 expression was reduced significantly by neutralizing IFN-α. In vivo, IFN-α neutralization protected the liver from I/R injury by reducing hepatocyte apoptosis. This was associated with impaired expression of IRF-1 and proapoptotic molecules such as Fas ligand, its receptor (Fas) and death receptor 5, which are regulated by IRF-1. Furthermore, pDC-depleted mice failed to up-regulate hepatic IFN-α and displayed less liver injury associated with reduced levels of hepatic interleukin (IL)-6, tumor necrosis factor-α, and hepatocyte apoptosis after I/R compared with controls. CONCLUSION these data support the hypothesis that IFN-α derived from liver pDC plays a key role in the pathogenesis of liver I/R injury by enhancing apoptosis as a consequence of induction of hepatocyte IRF-1 expression.
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Affiliation(s)
- Antonino Castellaneta
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Osamu Yoshida
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Shoko Kimura
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Shinichiro Yokota
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - David A. Geller
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA,Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Noriko Murase
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Angus W. Thomson
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Abstract
PURPOSE OF REVIEW Ischemia and reperfusion injuries occur in multiple clinical settings and contribute to organ dysfunction/failures. Despite the innate inflammatory immune nature, T cells that are critically involved in the pathogenesis of ischemia reperfusion injury (IRI), include not only CD4+ T cells, but also CD8+ and γδT cells. This review focuses on questions of how putative Ag-specific T cells are involved, which include whether they function in an Ag-dependent manner; how they function, cytokine-mediated or costimulatory molecule-mediated mechanisms; and whether different T-cell subsets, Th1, Th17, regulatory T cell (Treg), are all involved and play distinctive roles? RECENT FINDINGS Specific T-cell populations, such as effector memory CD4 T cells, promote inflammatory immune activation by ischemia reperfusion independent of their adaptive properties, that is Ag-independently. They function by secreting cytokines and expressing costimulatory molecules to either promote or inhibit innate immune activation, or facilitate tissue repair/homeostasis, as exemplified by Th1, Th17 or Th2, Treg cells, respectively. SUMMARY T-cell-targeted therapies need to be refined with strategies to maximally eliminate the proinflammatory but spare the anti-inflammatory/immune regulatory properties of T cells, for future clinical application to ameliorate IRI.
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Dejager L, Vandevyver S, Ballegeer M, Van Wonterghem E, An LL, Riggs J, Kolbeck R, Libert C. Pharmacological inhibition of type I interferon signaling protects mice against lethal sepsis. J Infect Dis 2013; 209:960-70. [PMID: 24218508 DOI: 10.1093/infdis/jit600] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Current research on new therapeutic strategies for sepsis uses different animal models, such as the lipopolysaccharide-induced endotoxemia model and the cecal ligation and puncture (CLP) peritonitis model. By using genetic and pharmacologic inhibition of the type I interferon (IFN) receptor (IFNAR1), we show that type I IFN signaling plays a detrimental role in these sepsis models. Mortality after CLP was reduced even when type I IFN responses were blocked after the onset of sepsis. Our findings reveal that type I IFNs play an important detrimental role during sepsis by negatively regulating neutrophil recruitment. Reduced neutrophil influx likely occurs via the induction of the CXC motif chemokine 1. Moreover, human white blood cells exposed to heat-killed Pseudomonas aeruginosa secrete IFN-β and stimulate type I IFN signaling. We provide data that support pharmacologic inhibition of type I IFN signaling as a novel therapeutic treatment in severe sepsis.
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Affiliation(s)
- Lien Dejager
- Inflammation Research Center, Flanders Institute for Biotechnology
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45
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Ji H, Zhang Y, Liu Y, Shen XD, Gao F, Nguyen TT, Busuttil RW, Waschek JA, Kupiec-Weglinski JW. Vasoactive intestinal peptide attenuates liver ischemia/reperfusion injury in mice via the cyclic adenosine monophosphate-protein kinase a pathway. Liver Transpl 2013; 19:945-56. [PMID: 23744729 PMCID: PMC3775926 DOI: 10.1002/lt.23681] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 05/19/2013] [Indexed: 01/22/2023]
Abstract
Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.
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Affiliation(s)
- Haofeng Ji
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Yu Zhang
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA,Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuanxing Liu
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA,Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiu-da Shen
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Feng Gao
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Terry T. Nguyen
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - James A. Waschek
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
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Winterberg PD, Wang Y, Lin KM, Hartono JR, Nagami GT, Zhou XJ, Shelton JM, Richardson JA, Lu CY. Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI. Am J Physiol Renal Physiol 2013; 305:F164-72. [PMID: 23657854 PMCID: PMC3725662 DOI: 10.1152/ajprenal.00487.2012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Accepted: 05/05/2013] [Indexed: 01/01/2023] Open
Abstract
We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI-/-) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNβ and IFNαs: IFNβ expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNβ. We show by immunohistology and study of isolated cells that IFNβ is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2.
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Affiliation(s)
- Pamela D Winterberg
- Department of Pediatrics, Nephrology Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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47
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Datta G, Fuller BJ, Davidson BR. Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models. World J Gastroenterol 2013; 19:1683-98. [PMID: 23555157 PMCID: PMC3607745 DOI: 10.3748/wjg.v19.i11.1683] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/29/2012] [Accepted: 07/09/2012] [Indexed: 02/06/2023] Open
Abstract
Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery. Understanding the mechanisms of liver ischemia reperfusion injury (IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation, as well as expanding the potential pool of usable donor grafts. The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes, increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis. Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury. IRI involves a complex interplay between neutrophils, natural killer T-cells cells, CD4+ T cell subtypes, cytokines, nitric oxide synthases, haem oxygenase-1, survival kinases such as the signal transducer and activator of transcription, Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways. Transgenic animals, particularly genetic knockout models, have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies. Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein. This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI.
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48
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Ji H, Zhang Y, Shen X, Gao F, Huang CY, Abad C, Busuttil RW, Waschek JA, Kupiec-Weglinski JW. Neuropeptide PACAP in mouse liver ischemia and reperfusion injury: immunomodulation by the cAMP-PKA pathway. Hepatology 2013; 57:1225-37. [PMID: 22532103 PMCID: PMC3479352 DOI: 10.1002/hep.25802] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 04/17/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Hepatic ischemia and reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The immune system and the nervous system maintain extensive communication and mount a variety of integrated responses to danger signals through intricate chemical messengers. This study examined the function and potential therapeutic potential of neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) in a murine model of partial liver "warm" ischemia (90 minutes) followed by reperfusion. Liver IRI readily triggered the expression of intrinsic PACAP and its receptors, whereas the hepatocellular damage was exacerbated in PACAP-deficient mice. Conversely, PACAP27, or PACAP38 peptide monotherapy, which elevates intracellular cyclic adenosine monophosphate/protein kinase A (cAMP-PKA) signaling, protected livers from IRI, as evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. The liver protection rendered by PACAP peptides was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and selectively augmented hepatic interleukin (IL)-10 expression. Strikingly, PKA inhibition readily restored liver damage in otherwise IR-resistant, PACAP-conditioned mice. In vitro, PACAP treatment not only diminished macrophage tumor necrosis factor alpha/IL-6/IL-12 levels in a PKA-dependent manner, but also prevented necrosis and apoptosis in primary mouse hepatocyte cultures. CONCLUSION Our novel findings document the importance of PACAP-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to manage liver inflammation and IRI in transplant patients.
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Affiliation(s)
- Haofeng Ji
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Yu Zhang
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA,Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiuda Shen
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Feng Gao
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Cynthia Y. Huang
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Catalina Abad
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - James A. Waschek
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
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Loi P, Yuan Q, Torres D, Delbauve S, Laute MA, Lalmand MC, Pétein M, Goriely S, Goldman M, Flamand V. Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury. Hepatology 2013; 57:351-61. [PMID: 22911673 DOI: 10.1002/hep.26022] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 08/01/2012] [Indexed: 01/08/2023]
Abstract
UNLABELLED Interferon regulatory factor 3 (IRF3) is an important transcription factor in Toll-like receptor 4 (TLR4) signaling, a pathway that is known to play a critical role in liver ischemia-reperfusion injury. In order to decipher the involvement of IRF3 in this setting, we first compared the intensity of hepatic lesions in IRF3-deficient versus wildtype mice. We found increased levels of blood transaminases, enhanced liver necrosis, and more pronounced neutrophil infiltrates in IRF3-deficient mice. Neutrophil depletion by administration of anti-Ly6G monoclonal antibody indicated that neutrophils play a dominant role in the development of severe liver necrosis in IRF3-deficient mice. Quantification of cytokine genes expression revealed increased liver expression of interleukin (IL)-12/IL-23p40, IL-23p19 messenger RNA (mRNA), and IL-17A mRNA in IRF3-deficient versus wildtype (WT) mice, whereas IL-27p28 mRNA expression was diminished in the absence of IRF3. The increased IL-17 production in IRF3-deficient mice was functionally relevant, as IL-17 neutralization prevented the enhanced hepatocellular damages and liver inflammation in these animals. Evidence for enhanced production of IL-23 and decreased accumulation of IL-27 cytokine in M1 type macrophage from IRF3-deficient mice was also observed after treatment with lipopolysaccharide, a setting in which liver gamma-delta T cells and invariant natural killer T cells were found to be involved in IL-17A hyperproduction. CONCLUSION IRF3-dependent events downstream of TLR4 control the IL-23/IL-17 axis in the liver and this regulatory role of IRF3 is relevant to liver ischemia-reperfusion injury.
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Affiliation(s)
- Patrizia Loi
- Institut d'Immunologie Médicale, Université Libre de Bruxelles, Gosselies, Belgium
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50
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Zhang Y, Ji H, Shen X, Cai J, Gao F, Koenig KM, Batikian CM, Busuttil RW, Kupiec-Weglinski JW. Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia-reperfusion injury in mouse orthotopic liver transplantation. Am J Transplant 2013; 13:56-66. [PMID: 23137033 PMCID: PMC3535503 DOI: 10.1111/j.1600-6143.2012.04316.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 08/31/2012] [Indexed: 01/25/2023]
Abstract
Hepatic injury due to cold storage followed by reperfusion remains a major cause of morbidity and mortality after orthotopic liver transplantation (OLT). CD4 T cell TIM-1 signaling costimulates a variety of immune responses in allograft recipients. This study analyzes mechanisms by which TIM-1 affects liver ischemia-reperfusion injury (IRI) in a murine model of prolonged cold storage followed by OLT. Livers from C57BL/6 mice, preserved at 4°C in the UW solution for 20 h, were transplanted to syngeneic recipients. There was an early (1 h) increased accumulation of TIM-1+ activated CD4 T cells in the ischemic OLTs. Disruption of TIM-1 signaling with a blocking mAb (RMT1-10) ameliorated liver damage, evidenced by reduced sALT levels and well-preserved architecture. Unlike in controls, TIM-1 blockade diminished OLT expression of Tbet/IFN-γ, but amplified IL-4/IL-10/IL-22; abolished neutrophil and macrophage infiltration/activation and inhibited NF-κB while enhancing Bcl-2/Bcl-xl. Although adoptive transfer of CD4 T cells triggered liver damage in otherwise IR-resistant RAG(-/-) mice, adjunctive TIM-1 blockade reduced Tbet transcription and abolished macrophage activation, restoring homeostasis in IR-stressed livers. Further, transfer of TIM-1(Hi) CD4+, but not TIM-1(Lo) CD4+ T cells, recreated liver IRI in RAG(-/-) mice. Thus, TIM-1 expressing CD4 T cells are required in the mechanism of innate immune-mediated hepatic IRI in OLTs.
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Affiliation(s)
- Yu Zhang
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA,Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Haofeng Ji
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Xiuda Shen
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Jinzhen Cai
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA,Department of Transplantation, Tianjin First Center Hospital, Tianjin, China
| | - Feng Gao
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Kevin M. Koenig
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Christine M. Batikian
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA
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