Netting Liver Disease: Neutrophil Extracellular Traps in the Initiation and Exacerbation of Liver Pathology

Abstract

The liver plays a vital role in the immune system. Its unique position in the portal circulation and the architecture of the hepatic sinusoids, in combination with the wide-ranged population of immunocompetent cells, make the liver function as an immune filter. To aid in pathogen clearance, once challenged, the liver initiates the rapid recruitment of a wide variety of inflammatory cells, including neutrophils. These neutrophils, in conjunction with platelets, facilitate the release of neutrophil extracellular traps (NETs), which are web-like structures of decondensed nuclear DNA, histones, and neutrophil proteins. NETs function as both a physical and a chemical barrier, binding and killing pathogens circulating in the blood stream. In addition to their antimicrobial role, NETs also bind platelets, activate coagulation, and exacerbate host inflammatory response. This interplay between inflammation and coagulation drives microvascular occlusion, ischemia, and (sterile) damage in liver disease. Although direct clinical evidence of this interplay is scarce, preliminary studies indicate that NETs contribute to progression of liver disease and (thrombotic) complications. Here, we provide an overview of the pathological mechanisms of NETs in liver disease. In addition, we summarize clinical evidence for NETs in different disease etiologies and complications of liver disease and discuss the possible implications for the use of NETs as a diagnostic marker and a therapeutic target in liver disease.

Systemic inflammation and disorders of hemostasis in the AD-ACLF syndrome

“…Such processes include the generation of neutrophil extracellular traps that may be formed in response to activation of hemostasis, and activation of complement that is also known to communicate with the coagulation system. 2,10 Both of these processes have established roles in organ injury and their connection to the systemic inflammation hypothesis should not be overlooked.…”

NET-Mediated Pathogenesis of COVID-19: The Role of NETs in Hepatic Manifestations

“…Furthermore, the liver has been reported be the primary organ for bacterial sequestration which is thought to be fundamentally through the actions of two immune cells: Kupffer cells, the intrasinusoidal resting macrophages of the liver, through phagocytosis, and neutrophils, which are recruited to the liver in the setting of infection, via NET formation. 71,76 Indeed, apart from COVID, NETs have been well-established as key players in propagating liver injury in several pathologies, including alcohol-associated liver injury, portal hypertension in chronic liver disease, sepsis, liver transplantation, and even cancer. 10,18 Potential Role of NETs in COVID-Induced Endotheliopathy…”

Neutrophil Extracellular Trap-Driven Occlusive Diseases

“…In addition to their ability to bind and kill pathogens during innate immune responses, neutrophils and NETs participate in inflammatory and coagulatory responses in the circulatory system. So far, occlusions caused by NETs-associated thrombus formation have been linked to cancers [ 16 ], pre-eclampsia [ 63 ], renal ischemia-reperfusion injury [ 64 ], liver pathologies [ 65 ], and severe malaria [ 66 , 67 ].…”