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Background: One mechanism underlying the development of alcoholic liver disease is overactivation of the innate immune response. Recent investigations indicate that the lysosomal pathway of autophagy down-regulates the inflammatory state of hepatic macrophages, suggesting that macrophage autophagy may regulate innate immunity in alcoholic liver disease. The function of macrophage autophagy in the development of alcoholic liver disease was examined in studies employing mice with a myeloid-specific decrease in autophagy., Methods: Littermate control and Atg5 Δmye mice lacking Atg5-dependent myeloid autophagy were administered a Lieber-DeCarli control (CD) or ethanol diet (ED) alone or together with lipopolysaccharide (LPS) and examined for the degree of liver injury and inflammation., Results: Knockout mice with decreased macrophage autophagy had equivalent steatosis but increased mortality and liver injury from ED alone. Increased liver injury and hepatocyte death also occurred in Atg5 Δmye mice administered ED and LPS in association with systemic inflammation as indicated by elevated serum levels of proinflammatory cytokines. Hepatic macrophage and neutrophil infiltration were unaffected by decreased autophagy, but levels of proinflammatory cytokine gene induction were significantly increased in the livers but not adipose tissue of knockout mice treated with ED and LPS. Inflammasome activation was increased in ED/LPS-treated knockout mice resulting in elevated interleukin (IL)-1β production. Increased IL-1β promoted alcoholic liver disease as liver injury was decreased by the administration of an IL-1 receptor antagonist., Conclusions: Macrophage autophagy functions to prevent liver injury from alcohol. This protection is mediated in part by down-regulation of inflammasome-dependent and inflammasome-independent hepatic inflammation. Therapies to increase autophagy may be effective in this disease through anti-inflammatory effects on macrophages., (© 2019 by the Research Society on Alcoholism.)

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., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.

Wong LL, Tanaka K, Lau L, Komura S. Pre-transplant treatment of hepatocellular carcinoma: assessment of tumor necrosis in explanted livers. Clin Transplant 2004: 18: 227–234. © Blackwell Munksgaard, 2004 Although liver transplantation (LT) is likely the most effective therapy for localized hepatocellular cancer (HCC), limited donor livers have resulted in prolonged waiting times for transplant. Pre-transplant therapy such as transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) may be needed to sustain patients who are waiting. Records, imaging studies, and pathology to identify tumor necrosis on 15 explanted livers with HCC were reviewed. Forty-nine nodules were removed from 15 explanted livers. Five nodules in three livers that received no pre-transplant therapy were excluded from the study. Of the remaining 44 nodules in 12 patients, 29 (66%) had 75% or more tumor necrosis. Fifteen nodules in five patients had <75% necrosis and these were due to local/non-local recurrences or perhaps suboptimal treatment with RFA, TACE or cisplatin gel injection. Mean waiting time for LT was 162.5 d. Nine of 13 patients had a different number of nodules when listed as were seen at explant, although stage changed in only three patients. One patient died 48 months post-LT (recurrent HCC), while the remaining patients are alive 2–55 months post-LT. We conclude that pre-transplant treatments for HCC are generally effective in achieving tumor necrosis. Factors involved in eventual extent of HCC seen at LT may include adequacy of treatment, accuracy of imaging techniques, local/non-local recurrences, and time waiting for transplant. We now need to determine if tumor necrosis can allow patients to wait longer for transplant and eventually affect long-term outcome. [ABSTRACT FROM AUTHOR]