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

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-1 beta was significantly increased in knockout mice. The increase in serum IL-1 beta was secondary to elevated hepatic caspase 1 activation and inflammasome-mediated cleavage of pro-IL-1 beta to its active form. Cultured hepatic macrophages from GalN/LPS-treated knockout mice had similarly increased IL-1 beta production. Dysregulation of IL-1 beta 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-1 beta. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.