The Role of Neutrophils as a Driver in Hepatic Ischemia-Reperfusion Injury and Cancer Growth

Abstract

The innate immune system plays an essential role in the response to sterile inflammation and its association with liver ischemia and reperfusion injury (IRI). Liver IRI often manifests during times of surgical stress such as cancer surgery or liver transplantation. Following the initiation of liver IRI, stressed hepatocytes release damage-associated molecular patterns (DAMPs) which promote the infiltration of innate immune cells which then initiate an inflammatory cascade and cytokine storm. Upon reperfusion, neutrophils are among the first cells that infiltrate the liver. Within the liver, neutrophils play an important role in fueling tissue damage and tumor progression by promoting the metastatic cascade through the formation of Neutrophil Extracellular Traps (NETs). NETs are composed of web-like DNA structures containing proteins that are released in response to inflammatory stimuli in the environment. Additionally, NETs can aid in mediating liver IRI, promoting tumor progression, and most recently, in mediating early graft rejection in liver transplantation. In this review we aim to summarize the current knowledge of innate immune cells, with a focus on neutrophils, and their role in mediating IRI in mouse and human diseases, including cancer and transplantation. Moreover, we will investigate the interaction of Neutrophils with varying subtypes of other cells. Furthermore, we will discuss the role and different treatment modalities in targeting Neutrophils and NETs to prevent IRI.

Isosteviol plays a protective role on hepatic ischemia and reperfusion injury in mice through MAPK/NF-κB signaling pathway

“…KCs extensively gathered at the injury site during I/R and produced a large number of oxygen free radicals, which induced oxidative stress and caused liver injury [21] . Activated KCs cells signi cantly increased the release of pro-in ammatory cytokines, including TNF-α, IL-1β and IL-6, and also promoted the recruitment and adhesion of neutrophils to the hepatic sinuses, especially TNF-α plays an important role in this process [22][23][24] . In the past decades, liver endothelial injury as the initial factor leading to hepatic I/R injury that has been widely recognized by researchers.…”

“…The I/R pathological process includes the occurrence of apoptosis. The reduction of neutrophils release will also reduce the release of cytokine, thus reducing cell death [24] . Studies have con rmed that TNF-α promotes the occurrence of both pro-apoptotic and anti-apoptotic signals [8] .…”

The role of extracellular traps in ischemia reperfusion injury

“…As drivers, neutrophils play an important role in the early stages of liver I/R and are the major amplifiers of liver IRI. Neutrophils are also major contributors to the acute rejection associated with liver transplantation ( 133 , 134 ). The formation of NETs plays some role in driving liver IRI ( 135 ).…”

Dapsone Lowers Neutrophil to Lymphocyte Ratio and Mortality in COVID-19 Patients Admitted to the ICU

“…That underlying triggering signaling remains unaffected by dapsone [ 15 , 16 , 17 ]. It was on this basis that dapsone has seen ancillary use in treating various cancers such as glioblastoma and others where neutrophils participate in growth facilitation [ 18 , 19 , 20 , 21 ].…”

“…Neutrophils, although essential for defense against infections, also participate in tissue destruction when their activity becomes overly exuberant, as occurs in human pathological inflammatory states for which dapsone is used such as bullous pemphigoid, Behcet’s disease, dermatitis herpetiformis, etc. [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”