Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis

Abstract

Hepatocyte demise as well as signals released by stressed hepatocytes have been now recognized as important triggers of liver inflammation. While traditional concepts classically viewed hepatocyte cell death to occur by either a nonlytic, noninflammatory form (apoptosis), or lytic, proinflammatory nonregulated cell death (necrosis), recent studies have provided evidence for additional mechanisms that can contribute to both acute and chronic liver damage. Two novel forms of cell death, pyroptosis and necroptosis, are of particular importance as they are highly regulated and intrinsically proinflammatory. Additionally, stressed hepatocytes may also release signals to attract and activate monocytes into proinflammatory macrophages. In this review, the authors discuss recent developments supporting the role of novel triggers of liver inflammation in various forms of liver injury and their potential translational implications.

A narrative review of the role of necroptosis in liver disease: a double-edged sword

“…Thus, definitive identification of necroptosis requires affirmation by different detection methods and by detection of several kinds of signaling molecular, such as combining the biochemical and morphological tests. Up to now, immunohistochemistry and western blot analyses for phosphor-MLKL are considered acceptable methods to detect necroptosis (41,43).…”

Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS

“…Excessive formation of NAPQI consumes intracellular glutathione, binds to mitochondrial proteins, and impairs mitochondrial respiration, which subsequently gives rise to overwhelming mitochondrial oxidative stress that triggers signaling pathways through mitochondrial toxicity, eventually leading to cell death and sterile inflammation (2,3). Importantly, the excessive activation of immune cells, such as Kupffer cells (KCs) causes an inability to shut down the persistent activation of the inflammatory response, which results in tissue damage and disease progression (4)(5)(6)(7). Recent studies have shown that APAP displays dose-dependent toxicity in primary hepatocytes.…”

Mechanisms of nonalcoholic fatty liver disease and implications for surgery

“…Receptor interacting proteins (RIPs) are important cell stress sensors that activate the necroptotic pathway, and the formation of the "necroptosome," a complex containing RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL), leads to membrane lysis and pore formation. The cellular release of DAMPs due to cell membrane disruption is associated with the possible activation of the innate immune system and neighboring cells [21].…”