RORγt+IL-17+ neutrophils play a critical role in hepatic ischemia–reperfusion injury

Tan, Zhongming; Jiang, Runqiu; Wang, Xuehao; Wang, Youjing; Lü, Ling; Liu, Qianghui; Zheng, Song Guo; Sun, Beicheng; Ryffel, Bernhard

doi:10.1093/jmcb/mjs065

Cited by 59 publications

(52 citation statements)

References 12 publications

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“…However, Gr-1 hi neutrophils represent the major source of IL-17A among the cells infiltrating the liver 24 h after CCl 4 injection. The upregulation of transcription factor RORgt in neutrophils suggests that neutrophils express the Th17 transcription factor, and hence enabling those cells to produce IL-17A, which is consistent with our previous findings in hepatic ischemia/ reperfusion injury (20). Therefore, IL-17A-expressing neutrophils potentially exhibit an autoamplification effect.…”

Section: Discussionsupporting

confidence: 90%

“…Liver mononuclear cells were isolated from mice 24 h after the CCl4 challenge as described previously (20). In brief, liver mononuclear cells were collected and plated at 1 3 10 5 /ml and restimulated at 6 h in vitro with phorbol 12-myristate 13-acetate (50 ng/ml) and ionomycin (750 ng/ ml) in complete medium (IMDM supplemented with 5% RT-PCR analysis for IL-1b, IL-6, IL-17A, TGF-b, and a-SMA mRNA Total RNA of the frozen liver samples was extracted with TRIzol reagent (Invitrogen) and quantified.…”

Section: Liver Mononuclear Cell Isolation and Flow Cytometry Analysismentioning

confidence: 99%

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IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

Tan

Qian

Jiang

et al. 2013

The Journal of Immunology

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272

208

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Liver fibrosis is a severe, life-threatening clinical condition resulting from nonresolving hepatitis of different origins. IL-17A is critical in inflammation, but its relation to liver fibrosis remains elusive. We find increased IL-17A expression in fibrotic livers from HBV-infected patients undergoing partial hepatectomy because of cirrhosis-related early-stage hepatocellular carcinoma in comparison with control nonfibrotic livers from uninfected patients with hepatic hemangioma. In fibrotic livers, IL-17A immunoreactivity localizes to the inflammatory infiltrate. In experimental carbon tetrachloride–induced liver fibrosis of IL-17RA–deficient mice, we observe reduced neutrophil influx, proinflammatory cytokines, hepatocellular necrosis, inflammation, and fibrosis as compared with control C57BL/6 mice. IL-17A is produced by neutrophils and T lymphocytes expressing the Th17 lineage–specific transcription factor Retinoic acid receptor–related orphan receptor γt. Furthermore, hepatic stellate cells (HSCs) isolated from naive C57BL/6 mice respond to IL-17A with increased IL-6, α-smooth muscle actin, collagen, and TGF-β mRNA expression, suggesting an IL-17A–driven fibrotic process. Pharmacologic ERK1/2 or p38 inhibition significantly attenuated IL-17A–induced HSC activation and collagen expression. In conclusion, IL-17A+ Retinoic acid receptor–related orphan receptor γt+ neutrophils and T cells are recruited into the injured liver driving a chronic, fibrotic hepatitis. IL-17A–dependent HSC activation may be critical for liver fibrosis. Thus, blockade of IL-17A could potentially benefit patients with chronic hepatitis and liver fibrosis.

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Section: Discussionsupporting

confidence: 90%

Section: Liver Mononuclear Cell Isolation and Flow Cytometry Analysismentioning

confidence: 99%

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

Tan

Qian

Jiang

et al. 2013

The Journal of Immunology

Self Cite

272

208

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“…16 In IL-1R1 and IL-17A deficient mice, hepatic I/R injury and neutrophil recruitment were attenuated. 17 A study of human liver damage identified a neutrophil elastase inhibitor that had therapeutic potential, and this inhibitor was associated with a reduced release of high mobility group box protein 1 and reduced IL-6 levels. 18 Additionally, an MMP-9 knockout model of liver I/R demonstrated reduced liver damage, and this reduction was associated with decreased neutrophil transmigration through the liver sinusoids.…”

Section: Neutrophils In the Defense Against Infectionmentioning

confidence: 99%

The role of neutrophils in the development of liver diseases

et al. 2014

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Liver disease encompasses a wide variety of liver conditions, including liver failure, liver cirrhosis and a spectrum of acute and chronic hepatitis, such as alcoholic, fatty, drug, viral and chronic hepatitis. Liver injury is a primary causative factor in liver disease; generally, these factors include direct liver damage and immune-mediated liver injury. Neutrophils (also known as neutrophilic granulocytes or polymorphonuclear leukocytes (PMNs)) are the most abundant circulating white blood cell type in humans, and PMNs are a major innate immune cell subset. Inappropriate activation and homing of neutrophils to the microvasculature contributes to the pathological manifestations of many types of liver disease. This review summarizes novel concepts of neutrophil-mediated liver injury that are based on current clinical and animal model studies.

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“…Liver mononuclear cells (MNCs) were isolated as described (10). Briefly, mouse livers were removed and pressed through a 100-mm cell strainer (BD), suspended in RPMI 1640 medium (Life Technologies, BRL), and centrifuged at 50 3 g for 5 min.…”

Section: Liver Mononuclear Cell Preparationmentioning

confidence: 99%

Survival and Inflammation Promotion Effect of PTPRO in Fulminant Hepatitis Is Associated with NF-κB Activation

Jiang

Chen

Hou

et al. 2014

The Journal of Immunology

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Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A–induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α–induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3β/β-catenin cascade. Increased β-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced β-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3β/β-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.

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RORγt+IL-17+ neutrophils play a critical role in hepatic ischemia–reperfusion injury

Cited by 59 publications

References 12 publications

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

The role of neutrophils in the development of liver diseases

Survival and Inflammation Promotion Effect of PTPRO in Fulminant Hepatitis Is Associated with NF-κB Activation

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