Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis

Windt, Dirk J. van der; Sud, Vikas; Zhang, Hongji; Varley, Patrick; Goswami, Julie; Yazdani, Hamza O.; Tohme, Samer; Loughran, Patricia; O’Doherty, Robert M.; Minervini, Marta Ida; Huang, Hai; Simmons, Richard L.; Tsung, Allan

doi:10.1002/hep.29914

Cited by 353 publications

(318 citation statements)

References 40 publications

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“…Markers of NETs are elevated in the serum of patients with NASH, and blockade of NET formation in mice protects mice from inflammation and NASH-driven HCC. (81) Another mechanism by which neutrophils can aggravate NASH is through human neutrophil peptides that induce cytokine and chemokine release during inflammation. Transgenic expression of human neutrophil peptide 1 in mice fed a NASH diet aggravated hepatic fibrosis through induction of hepatic stellate cell proliferation.…”

Section: Neutrophilsmentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.

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Section: Neutrophilsmentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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“…In several mouse models, NET formation has been demonstrated to be associated with tumor growth and/or metastasis (Fig. 4), e.g., NETs have been reported to enhance the growth of melanoma 139 , gastric cancer 140 , and hepatocellular cancer 141 . Moreover, cancer cells themselves are able to stimulate neutrophils to form NETs that facilitate cancer cell migration and invasion as shown in vitro and in vivo, indicating that they make use of a physiological host defense mechanism process to promote metastasis (Fig.…”

Section: The Formation Of Extracellular Dna Traps In Cancermentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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“…(85) Third, neutrophil extracellular traps (NETs) increase thrombin generation in a DNA-dependent way (86) and are increased in NASH. (87) However, neutrophils of patients with LC show a decreased ability to form NETs. (88) Thus, the increase of NETs is possibly due to decreased hepatic clearance.…”

Section: Phospholipids Cell-free Dna Neutrophil Extracellular Trapsmentioning

confidence: 99%

Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

et al. 2020

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In the setting of liver cirrhosis (LC), profound hemostatic changes occur, which affect primary hemostasis, coagulation, and fibrinolysis. They involve prohemorrhagic and prothrombotic alterations at each of these steps. Patients with cirrhosis exhibit multifactorial thrombocytopenia and in vitro thrombocytopathy, counterbalanced by increased von Willebrand factor. The resultant shift is difficult to assess, but overall these changes probably result in a rebalanced primary hemostasis. Concerning coagulation, the reduced activity of coagulation factors is counterbalanced by an increase in factor VIII (produced by liver sinusoidal endothelial cells), a decrease of the natural anticoagulants, and complex changes, including changes in circulating microparticles, cell-free DNA, and neutrophil extracellular traps. Overall, these alterations result in a procoagulant state. As for fibrinolysis, increased tissue-type and urokinase-type plasminogen activators, a relatively decreased plasminogen activator inhibitor 1, and decreased levels of thrombin-activatable fibrinolysis inhibitor and α2-antiplasmin are counterbalanced by decreased plasminogen and a decreased fibrin clot permeability. Whether and how these changes shift fibrinolysis remains to be determined. Overall, the current consensus is that in patients with cirrhosis, the hemostasis is shifted toward a procoagulant state. We review the published evidence for the concept of LC as a prothrombotic state, discuss discordant data, and highlight the impact of the underlying cause of LC on the resultant imbalance. (Hepatology 2020;71:2135-2148). Primary HemostasisChanges of primary hemostasis in patients with LC are shown in Table 1.Abbreviations: ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 repeats 13;Hepatology, June 2020 ZERMATTEN ET AL. 2136pRoHeMoRRHagIC CHaNgeS thrombocytopenia Thrombocytopenia (platelets <150 × 10 9 /L) occurs in up to 78% (1) of patients with LC, moderate thrombocytopenia (platelets 50-75 × 10 9 /L) occurs in approximately 13%, (2) and severe thrombocytopenia (platelets <50 × 10 9 /L) occurs in 1% to 2%. (3) Decreased production and increased clearance of platelets are both involved in LC-associated thrombocytopenia ( Fig. 1). Indeed, reticulated/immature platelets and glycocalicin (proteolytic extracellular fragment of glycoprotein 1b), which are markers of platelet production, are decreased in LC. (4) However, reticulated/ immature platelet fraction and glycocalicin index, which are markers of platelet turnover, are increased in patients with LC versus healthy donors (4,5) and in thrombocytopenic versus non-thrombocytopenic patients with LC. (4,6) Moreover, the mean platelet survival is decreased in LC, (7) indicating an increased platelet turnover. Differences across LC causes are possible. Indeed, reticulated platelets are increased in hepatitis C virus (HCV)-induced LC and decreased in alcohol-induced LC and hepatitis B virus (HBV)induced LC. (5) DeCReaSeD pRoDUCtIoN oF plateletSDecreased production is due to decre...

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Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis

Abstract: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).

Cited by 353 publications

References 40 publications

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

In vivo evidence for extracellular DNA trap formation

Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

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