Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β.
OBJECTIVE
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.
Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.
Ghulam
G
Ilyas
Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.
Enpeng
E
Zhao
Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.
Kun
K
Liu
Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States.
Yu
Y
Lin
Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States.
Lydia
L
Tesfa
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States.
Kathryn E
KE
Tanaka
Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States. Electronic address: mark.j.czaja@emory.edu.
Mark J
MJ
Czaja
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000401:mortality; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D053583:Interleukin-1beta / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000502:physiology
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins
Apoptosis; Galactosamine; Inflammasome; Innate immunity; Kupffer cell; Lipopolysaccharide; Macrophage