Myeloperoxidase–Hepatocyte–Stellate Cell Cross Talk Promotes Hepatocyte Injury and Fibrosis in Experimental Nonalcoholic Steatohepatitis

Pulli, Benjamin; Ali, Muhammad; Iwamoto, Yoshiko; Zeller, Matthias W.G.; Schob, Stefan; Linnoila, Jenny; Chen, John W.

doi:10.1089/ars.2014.6108

Cited by 103 publications

(86 citation statements)

References 59 publications

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“…Activated hepatic stellate cells (myofibroblasts) are a major source of extracellular matrix production leading to progressive liver fibrosis (Fig. ) . There is a paucity of data on the role of neutrophils in bile duct injury in BA that warrants further research based on the findings that elastase and NETs correlated with rising bilirubin post‐HPE.…”

Section: Discussionmentioning

confidence: 99%

“…3). (41,42) There is a paucity of data on the role of neutrophils in bile duct injury in BA that warrants further research based on the findings that elastase and NETs correlated with rising bilirubin post-HPE. The small number of patients with BA analyzed in this study prohibits us from making any broad conclusions regarding the use of IL-8 as a biomarker of outcome in BA, and future studies should be appropriately powered in order to determine the accuracy of IL-8 as a biomarker of severity of disease.…”

Section: Discussionmentioning

confidence: 99%

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Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy

et al. 2019

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Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T‐ and B‐cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen‐DR isotype [HLA‐DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA‐DR + CD38 + NK cells and expression of NK cell activation markers CD69 and HLA‐DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)‐8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA‐DR + CD38 + NK cells and plasma IL‐8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL‐8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy

et al. 2019

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“…Activated neutrophil‐mediated oxidative stress results in a reduced capacity for nucleotide excision repair, which could further reduce DNA damage recognition and potentiate liver cancer development . Genetic or pharmacological elimination of MPO, NE, or proteinase 3 expression or activity diminishes HFD‐induced pathological changes in NASH …”

Section: Innate Immune Cellular Players In Nashmentioning

confidence: 99%

“…(23) Genetic or pharmacological elimination of MPO, NE, or proteinase 3 expression or activity diminishes HFDinduced pathological changes in NASH. (23,33,34)…”

Section: Neutrophilsmentioning

confidence: 99%

The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis

2019

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Inflammation and metabolic dysfunction are hallmarks of nonalcoholic steatohepatitis (NASH), which is one of the fastest‐growing liver diseases worldwide. Emerging evidence indicates that innate immune mechanisms are pivotal drivers of inflammation and other pathological manifestations observed in NASH, such as hepatosteatosis, insulin resistance (IR), and fibrosis. This robust innate immune reaction is intrinsic to the liver, which is an important immunological organ that contains a coordinated network of innate immune cells, including Kupffer cells (KCs), dendritic cells (DCs), and lymphocytes. Hepatocytes and liver sinusoidal endothelial cells (LSECs) are not formally innate immune cells, but they take on immune cell function when stressed. These cells can sense excess metabolites and bacterial products and translate those signals into immune responses and pathological hepatic changes during the development of NASH. In this review, we take a historical perspective in describing decades of research that aimed to identify the key molecular and cellular players in the innate immune system in the setting of NASH. Furthermore, we summarize the innate immune cells that are involved in the progression of NASH and illustrate how they sense disturbances in circulating metabolic factors by innate immune receptors and subsequently initiate the intercellular signaling cascades that lead to persistent inflammation and progression of hepatic complications.

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“…Work by both Pulli et al 5 and Novo et al 6 have shown that neutrophil-derived oxidative species can facilitate the recruitment of hepatic stellate cells, thereby activating profibrotic pathways. Neutrophils themselves have been shown to be involved in fibrosis through the secretion of interleukin (IL)-6 needed for the differentiation of T helper 17 cells,7 as well as being a direct source of IL-17 8.…”

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confidence: 99%

Take me to the liver: adipose tissue macrophages coordinate hepatic neutrophil recruitment

Pernes

Lancaster

Murphy

2018

Gut

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Myeloperoxidase–Hepatocyte–Stellate Cell Cross Talk Promotes Hepatocyte Injury and Fibrosis in Experimental Nonalcoholic Steatohepatitis

Abstract: Cumulatively, these findings demonstrate important cross talk between inflammatory myeloid cells, hepatocytes, and HSCs via MPO and establish MPO as part of a proapoptotic and profibrotic pathway of progression in NASH, as well as a potential therapeutic target to ameliorate this disease.

Cited by 103 publications

References 59 publications

Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy

Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy

The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis

Take me to the liver: adipose tissue macrophages coordinate hepatic neutrophil recruitment

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