ER stress induces NLRP3 inflammasome activation and hepatocyte death

Abstract

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

Metformin attenuates ER stress–induced mitochondrial dysfunction

“…The THAP-induced ER stress increases cardiac injury through augmentation of the CHOP expression and inflammation. 42 …”

Inflammasome Priming in Sterile Inflammatory Disease

“…However, misfolded proteins can also lead to endoplasmic reticulum (ER) stress intracellularly [108] , which could trigger signal 1 for NLRP3 activation [109] , perhaps via damaged mitochondria and ROS [110] . S100A8/A9 proteins and HMGB1 are also molecules released by dead or dying cells downstream of an accumulation of misfolded proteins, and these also have the capacity to prime the inflammasome, as shown using peripheral blood mononuclear cells in vitro [111] and in mouse models [112] .…”

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

“…Potassium efflux, mitochondria dysfunction, and lysosomal disruption have been reported to mediate the activation of NLRP3, leading to the hypothesis that this inflammasome is a guardian of cellular integrity (11,12). In addition to detecting mitochondrial perturbations, NLRP3 was found to be activated by endoplasmic reticulum (ER) stress in different tissues including macrophages (13,14), liver (15), and insulin-producing β cells (16,17). Inflammasome activation may therefore contribute to the lowgrade inflammation (parainflammation) that characterizes stressed or malfunctioning cells, hence promoting adaptation and restoration of tissue function (18).…”