Paradoxical Role of Matrix Metalloproteinases in Liver Injury and Regeneration after Sterile Acute Hepatic Failure

Abstract

Acetaminophen (APAP) poisoning is one of the leading causes of acute hepatic failure and liver transplantation is often the only lifesaving alternative. During the course of hepatocyte necrosis, an intense accumulation of neutrophils is often observed within the liver microenvironment. Despite the classic idea that neutrophil accumulation in tissues causes collateral tissue damage, there is a growing body of evidence showing that neutrophils can also orchestrate the resolution of inflammation. In this work, drug-induced liver injury was induced by oral administration of APAP and pharmacological intervention was made 12 h after this challenge. Liver injury and repair kinetics were evaluated by a novel combination of enzyme quantifications, ELISA, specific antagonists of neutrophil enzymes and confocal intravital microscopy. We have demonstrated that neutrophil infiltration is not only involved in injury amplification, but also in liver tissue repair after APAP-induced liver injury. In fact, while neutrophil depletion led to reduced hepatic necrosis during APAP poisoning, injury recovery was also delayed in neutropenic mice. The mechanisms underlying the neutrophil reparative role involved rapid degranulation and matrix metalloproteinases (MMPs) activity. Our data highlights the crucial role of neutrophils, in particular for MMPs, in the resolution phase of APAP-induced inflammatory response.

Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Gαi/o/ROS/p38 MAPK Signaling Pathway

“…This is in agreement with published studies demonstrating that neutrophil depletion by injection of Ly6G antibody markedly reduces chronic-binge ethanol feeding-induced liver injury and liver transplantation ischemia-reperfusion injury [8,38,39]. However, there are studies identifying the dual role for neutrophils in acetaminophen-induced acute liver injury, with neutrophil-mediated injury amplification early on, but exerting protective effects during the repair phase as depletion of neutrophils increases liver damage [40,41]. Also neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223 in CCl 4 -induced chronic liver injury [41].…”

Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD

“…In fact, a reliable gating strategy to differentially assess KCs and liver DCs is still under debate. 20 , 21 , 28 , 39 Importantly, an overt infiltration of neutrophils occurred at later time points (9 weeks), which was previously described as a key factor for enhanced collateral liver damage upon insults, 14 , 23 , 24 , 40 , 41 suggesting that such early alterations in these subpopulations may constitute a hallmark in the evolution from simple steatosis to steatohepatitis. However, it is reasonable to hypothesize that such overt neutrophil infiltration during NAFLD onset might also function as a backup strategy for bacterial clearance and phagocytosis while KCs are relatively absent.…”

More friend than foe: the emerging role of neutrophils in tissue repair

“…Intravital imaging revealed that neutrophils contributed to healing by phagocytosing debris and promoting vascular regrowth in part by making new sleeves for blood vessels to grow into (69). Along the same lines, a recent study identified a dual role for neutrophils in acetaminophen-induced acute liver injury, with neutrophil-mediated injury amplification early on, but protective effects during the repair phase, as depletion increased liver damage (111). The early phase may reflect killing and/or removal of injured cells that presents as increased injury but is required for repair.…”