Murine macrophage autophagy protects against alcohol-induced liver injury by degrading interferon regulatory factor 1 (IRF1) and removing damaged mitochondria

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 (Atg7^ΔMye) 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 Atg7^ΔMye mice. Atg7^ΔMye 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, Atg7^ΔMye 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.

Keywords: CC-chemokine ligand 10; CC-chemokine ligand 5; Toll-like receptor 4 (TLR4); alcohol; alcoholic liver disease; autophagy; chemokine; cytokine; dysbiosis; inflammasome; innate immunity; macrophage.