NLRP3: a new therapeutic target in alcoholic liver disease

Abstract

The liver is in charge of a wide range of critical physiological processes and it plays an important role in activating the innate immune system which elicits the inflammatory events. Chronic ethanol exposure disrupts hepatic inflammatory mechanism and leads to the release of proinflammatory mediators such as chemokines, cytokines and activation of inflammasomes. The mechanism of liver fibrosis/cirrhosis involve activation of NLRP3 inflammasome, leading to the destruction of hepatocytes and subsequent metabolic dysregulation in humans. In addition, increasing evidence suggests that alcohol intake significantly modifies liver epigenetics, promoting the development of alcoholic liver disease (ALD). Epigenetic changes including histone modification, microRNA-induced genetic modulation, and DNA methylation are crucial in alcohol-evoked cell signaling that affects gene expression in the hepatic system. Though we are at the beginning stage without having the entire print of epigenetic signature, it is time to focus more on NLRP3 inflammasome and epigenetic modifications. Here we review the novel aspect of ALD pathology linking to inflammation and highlighting the role of epigenetic modification associated with NLRP3 inflammasome and how it could be a therapeutic target in ALD.

G-CSF increases calprotectin expression, liver damage and neuroinflammation in a murine model of alcohol-induced ACLF

“…Similar to the liver, we found increased neutrophil infiltration and calprotectin expression after G-CSF treatment, which was accompanied by increased p40phox expression and inflammasome activation. NLRP3 is known to play a central role in inflammasome activation and pyroptosis during alcohol-related liver disease ( de Carvalho Ribeiro and Szabo, 2022 ; Brahadeeswaran et al, 2023 ), nevertheless we cannot exclude contribution of additional pattern-recognition receptors in liver and/or brain of our alcohol-induced ACLF model. Specifically, microglia- and astrocyte-specific markers indicated increased microglia proliferation and reactive astrocytes after G-CSF treatment.…”

NLRP3 Inflammasome in Acute and Chronic Liver Diseases

“…ROS also promote the activation of the NLRP3 inflammasome via the NF-kB pathway, leading to the production of pro-inflammatory cytokines, e.g., TNF, IL-1β, and IL-8, which are upregulated in patients with alcohol-related liver damage [28] (Table 1). Upon binding to its receptor on the KCs, IL-1β acts as a mediator of liver inflammation, since it sustains the activation of resident macrophages and contributes to hepatitis and fibrosis [29,30].…”

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression

“…Alcohol-induced changes in histone modification enzyme expression and activity affect multiple innate and adaptive immunity cell populations [36][37][38][39][40][41][42]. Alcohol-induced epigenetic changes were described for several types of immune cells (e.g., granulocytes, macrophages, and T-lymphocytes) and are thought to promote exaggerated inflammatory responses in ALD.…”