Abstract
Excessive alcohol consumption induces intestinal dysbiosis of the gut microbiome and reduces gut epithelial integrity. This often leads to portal circulation-mediated translocation of gut-derived microbial products, such as lipopolysaccharide (LPS), to the liver, where these products engage Toll-like receptor 4 (TLR4) and initiate hepatic inflammation, which promotes alcoholic liver disease (ALD). Although the key self-destructive process of autophagy has been well-studied in hepatocytes, its role in macrophages during ALD pathogenesis remains elusive. Using WT and myeloid cell-specific autophagy-related 7 (Atg7) knockout (Atg7ΔMye) mice, we found that chronic ethanol feeding for 6 weeks plus LPS injection enhances serum alanine aminotransferase and IL-1β levels and augments hepatic C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) expression in WT mice, a phenotype that was further exacerbated in Atg7ΔMye mice. Atg7ΔMye macrophages exhibited defective mitochondrial respiration and displayed elevated mitochondrial reactive oxygen species production and inflammasome activation relative to WT cells. Interestingly, compared with WT cells, Atg7ΔMye macrophages also had a drastically increased abundance and nuclear translocation of interferon regulatory factor 1 (IRF1) after LPS stimulation. Mechanistically, LPS induced co-localization of IRF1 with the autophagy adaptor p62 and the autophagosome, resulting in subsequent IRF1 degradation. However, upon p62 silencing or Atg7 deletion, IRF1 started to accumulate in autophagy-deficient macrophages and translocated into the nucleus, where it induced CCL5 and CXCL10 expression. In conclusion, macrophage autophagy protects against ALD by promoting IRF1 degradation and removal of damaged mitochondria, limiting macrophage activation and inflammation.
Highlights
Excessive alcohol consumption induces intestinal dysbiosis of the gut microbiome and reduces gut epithelial integrity
Using WT and myeloid cell–specific autophagy-related 7 (Atg7) knockout (Atg7⌬Mye) mice, we found that chronic ethanol feeding for 6 weeks plus LPS injection enhances serum alanine aminotransferase and IL-1 levels and augments hepatic C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) expression in WT mice, a phenotype that was further exacerbated in Atg7⌬Mye mice
First we investigated whether autophagy is altered in liver macrophages during alcoholic liver disease (ALD) development
Summary
First we investigated whether autophagy is altered in liver macrophages during ALD development. Hepatic steatosis was dramatically increased in Atg7⌬Mye mice after ethanol and LPS co-administration (Fig. 2E) These results collectively demonstrate that macrophage autophagy inhibits liver injury and steatosis in mice after ALD is induced. B and C, liver macrophages from Atg7⌬Mye mice and ethanol-fed WT mice had a lower OCR relative to control diet–fed mice These results suggest that autophagy suppression by chronic ethanol feeding could be associated with compromised mitochondrial function. Macrophages deficient in TRIF, but not MyD88, abolished LPS-induced expression of CCL5 and CXCL10 (Fig. 5D) These results together suggest that, in addition to antagonizing NLRP3 inflammasome activation, macrophage autophagy inhibits CCL5 and CXCL10 production and may thereby further prevent alcohol-mediated liver injury, inflammation, and steatosis. LPS-induced CCL5 and CXCL10 production was significantly higher in p62-silenced macrophages relative to control cells (Fig. 7, C and D)
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