Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β

Abstract

Background & Aims Overactivation of the innate immune response underlies many forms of liver injury including that caused by hepatotoxins. Recent studies have demonstrated that macrophage autophagy regulates innate immunity and resultant tissue inflammation. Although hepatocyte autophagy has been shown to modulate hepatic injury, little is known about the role of autophagy in hepatic macrophages during the inflammatory response to acute toxic liver injury. Our aim therefore was to determine whether macrophage autophagy functions to down regulate hepatic inflammation. Methods Mice with a LysM-CRE-mediated macrophage knockout of the autophagy gene ATG5 were examined for their response to toxin-induced liver injury from D-galactosamine/lipopolysaccharide (GalN/LPS). Results Knockout mice had increased liver injury from GalN/LPS as determined by significant increases in serum alanine aminotransferase, histological evidence of liver injury, positive terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, caspase activation and mortality as compared to littermate controls. Levels of proinflammatory tumor necrosis factor and interleukin (IL)-6 hepatic mRNA and serum protein were unchanged, but serum IL-1β was significantly increased in knockout mice. The increase in serum IL-1β was secondary to elevated hepatic caspase 1 activation and inflammasome-mediated cleavage of pro-IL-1β to its active form. Cultured hepatic macrophages from GalN/LPS-treated knockout mice had similarly increased IL-1β production. Dysregulation of IL-1β was the mechanism of increased liver injury as an IL-1 receptor antagonist prevented injury in knockout mice in concert with decreased neutrophil activation. Conclusions Macrophage autophagy functions to limit acute toxin-induced liver injury and death by inhibiting the generation of inflammasome-dependent IL-1β.

Function of Autophagy in Nonalcoholic Fatty Liver Disease

“…This mechanism of increased inflammation was specific for the liver as the decrease in macrophage autophagy failed to affect the extent of inflammation in adipose tissue. In addition, in a toxin-induced model of acute liver injury decreased macrophage autophagy also led to increased liver injury but secondary to toxicity from elevated amounts of IL-1β generated by increased inflammasome activation [54], similar to what had been reported in the intestinal inflammatory model [49]. Therefore in the fatty liver distinct mechanisms lead to over activation of the innate immune response in macrophages with defective autophagy.…”

A Mechanistic Review of Cell Death in Alcohol‐Induced Liver Injury

“…In rats that were fed with chronic ethanol diet for 8 weeks, it is found that alcohol-induced ER stress activates autophagy, which may promote chronic ethanol-induced fibrosis (Hernandez-Gea et al, 2013). In contrast to HSC, macrophage-specific autophagy-deficient mice are more susceptible to CCl 4 -induced fibrosis and endotoxin-induced liver injury (Lodder et al, 2015, Ilyas et al, 2015). Whether impaired macrophage autophagy would also exacerbate alcohol-induced liver injury remains to be determined.…”

Autophagy in macrophages regulates the inflammasome and protects against liver injury

“…In this issue of the Journal of Hepatology, Ilyas et al [9] demonstrated that macrophage autophagy inhibited inflammasome-mediated IL-1β generation and secretion to limit acute toxin-induced liver injury. To study the specific role of autophagy in macrophages, Ilyas et al generated a macrophage-specific knockout of the autophagy gene Atg5 by crossing the Atg5 floxed mice with LysM-Cre mice expressing a myeloid cell-specific Cre [9].…”

“…To study the specific role of autophagy in macrophages, Ilyas et al generated a macrophage-specific knockout of the autophagy gene Atg5 by crossing the Atg5 floxed mice with LysM-Cre mice expressing a myeloid cell-specific Cre [9]. To trigger acute liver injury in mice, Ilyas et al [9] injected mice with lipopolysaccharide (LPS) and D-galactosamine (GalN), which is a well-established animal model to induce acute liver injury mediated by macrophage-derived tumor necrosis factor-α (TNF-α). TNF-α induces hepatocyte apoptosis and liver injury through both the extrinsic and intrinsic apoptotic pathways [10] and promotes hepatic neutrophil recruitment and activation, which amplifies the apoptotic injury [11].…”

“…Similar to the LPS/GalN model, an enhanced IL-1-driven inflammatory response aggravated CCl 4 –induced liver injury in macrophage-specific Atg5 knockout mice [8]. While Ilyas et al [9] did not determine how loss of autophagy activates the Nalp3 inflammasome and caspase 1 in macrophages in response to LPS/GalN, it has been shown that toll-like receptor adaptor protein TRIF, macrophage K + efflux and reactive oxygen species (ROS) production but not NF-kB and p38 are required for caspase 1 activation and IL-1β generation in Atg16L-deficient macrophages [12]. It remains to be determined whether TRIF, K + efflux and ROS would also contribute to caspase-1 activation in LPS/GalN-treated macrophage-specific Atg5 knockout mice.…”