Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury

Abstract

Polymorphonuclear leukocytes (neutrophils) are essential in the defense against invading microorganisms, tissue trauma or any inciting inflammatory signals. Hepatic infiltration of neutrophils is an acute response to recent or ongoing liver injury, hepatic stress or unknown systemic inflammatory signals. Once neutrophils reach the liver, they can cause mild-to-severe tissue damage and consequent liver failure. For neutrophils to appear in the liver, neutrophils have to undergo systemic activation (priming) by inflammatory mediators such as cytokines, chemokines, complement factors, immune complexes, opsonized particles and other biologically active molecules, e.g., platelet activating factor. Neutrophils accumulated in the hepatic microvasculature (sinusoids and postsinusoidal venules) can extravasate (transmigrate) into the hepatic parenchyma if they receive a signal from distressed cells. Transmigration can be mediated by a chemokine gradient established towards the hepatic parenchyma and generally involves orchestration by adhesion molecules on neutrophils (β 2 integrins) and on endothelial cells (intracellular adhesion molecules, ICAM-1). After transmigration, neutrophils adhere to distressed hepatocytes through their β 2 integrins and ICAM-1 expressed on hepatocytes. Neutrophil contact with hepatocytes mediate oxidative killing of hepatocytes by initiation of respiratory burst and neutrophil degranulation leading to hepatocellular oncotic necrosis. Neutrophil-mediated liver injury has been demonstrated in a variety of diseases and chemical/drug toxicities. Relevant examples are discussed in this review.

Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure

“…Excessive neutrophil infiltration and activation can have adverse effects. Consistent with previous studies [35], our findings suggest that injection of D-Gal/LPS increase the migration of neutrophils, elevate their oxidative burst levels, enhance hepatic MPO activity, and upregulate MDA expression. These effects were downregulated by BMSCs.…”

Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure

“…Excessive neutrophil infiltration and activation can have adverse effects. Consistent with previous studies [35], our findings suggest that injection of D-Gal/LPS increase the migration of neutrophils, elevate their oxidative burst levels, enhance hepatic MPO activity, and upregulate MDA expression. These effects were downregulated by BMSCs.…”

Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury

“…Thus, although the production of IL‐6 by Kupffer cells immediately after ligation is beneficial, we speculate that long‐term production by iMNPs is detrimental. Furthermore, in accordance with previous reports, we speculate that the elevated production of MIP2 and KC by iMNPs and the resultant accumulation of neutrophils in the livers of BDL mice are also detrimental .…”

Inhibition of CCl4-induced liver inflammation and fibrosis by a NEU3 inhibitor

“…Compared to control (oil) mice, there was no significant treatment-induced difference in the numbers of CLEC4F positive Kupffer cells ( S5A–S5C Fig ) or CD3 T cells ( S5D–S5F Fig ), and there were no significant differences between male and female mice. As previously observed [ 62 – 64 ], compared to control mice, there was an increase in the number of neutrophils in the CCl 4 treated mice, but this increase was only significant in females ( Fig 3A–3C and S6 Fig ). Comparing CCl 4 and CCl 4 +2AP treated mice, there was a reduction in the number of S100A8/MRP8 positive cells in the CCl 4 +2AP treated female, but not male mice ( Fig 3A–3C and S6 Fig ).…”

Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure

“…Excessive neutrophil infiltration and activation can have adverse effects. Consistent with previous studies [35], our findings suggest that injection of D-Gal/LPS increase the migration of neutrophils, elevate their oxidative burst levels, enhance hepatic MPO activity, and upregulate MDA expression. These effects were downregulated by BMSCs.…”

Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury

“…Thus, although the production of IL‐6 by Kupffer cells immediately after ligation is beneficial, we speculate that long‐term production by iMNPs is detrimental. Furthermore, in accordance with previous reports, we speculate that the elevated production of MIP2 and KC by iMNPs and the resultant accumulation of neutrophils in the livers of BDL mice are also detrimental .…”

Inhibition of CCl4-induced liver inflammation and fibrosis by a NEU3 inhibitor

“…Compared to control (oil) mice, there was no significant treatment-induced difference in the numbers of CLEC4F positive Kupffer cells ( S5A–S5C Fig ) or CD3 T cells ( S5D–S5F Fig ), and there were no significant differences between male and female mice. As previously observed [ 62 – 64 ], compared to control mice, there was an increase in the number of neutrophils in the CCl 4 treated mice, but this increase was only significant in females ( Fig 3A–3C and S6 Fig ). Comparing CCl 4 and CCl 4 +2AP treated mice, there was a reduction in the number of S100A8/MRP8 positive cells in the CCl 4 +2AP treated female, but not male mice ( Fig 3A–3C and S6 Fig ).…”

Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure

“…Excessive neutrophil infiltration and activation can have adverse effects. Consistent with previous studies [35], our findings suggest that injection of D-Gal/LPS increase the migration of neutrophils, elevate their oxidative burst levels, enhance hepatic MPO activity, and upregulate MDA expression. These effects were downregulated by BMSCs.…”

Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury

“…Thus, although the production of IL‐6 by Kupffer cells immediately after ligation is beneficial, we speculate that long‐term production by iMNPs is detrimental. Furthermore, in accordance with previous reports, we speculate that the elevated production of MIP2 and KC by iMNPs and the resultant accumulation of neutrophils in the livers of BDL mice are also detrimental .…”

Inhibition of CCl4-induced liver inflammation and fibrosis by a NEU3 inhibitor

“…Compared to control (oil) mice, there was no significant treatment-induced difference in the numbers of CLEC4F positive Kupffer cells ( S5A–S5C Fig ) or CD3 T cells ( S5D–S5F Fig ), and there were no significant differences between male and female mice. As previously observed [ 62 – 64 ], compared to control mice, there was an increase in the number of neutrophils in the CCl 4 treated mice, but this increase was only significant in females ( Fig 3A–3C and S6 Fig ). Comparing CCl 4 and CCl 4 +2AP treated mice, there was a reduction in the number of S100A8/MRP8 positive cells in the CCl 4 +2AP treated female, but not male mice ( Fig 3A–3C and S6 Fig ).…”