Kupffer cell diversity maintains liver function in alcohol-associated liver disease.

Background And Aims: Liver macrophages are heterogeneous and play an important role in alcohol-associated liver disease (ALD) but there is limited understanding of the functions of specific macrophage subsets in the disease. We used a Western diet alcohol (WDA) mouse model of ALD to examine the hepatic myeloid cell compartment by single cell RNAseq and targeted KC ablation to understand the diversity and function of liver macrophages in ALD.

Approach And Results: In the WDA liver, KCs and infiltrating monocytes/macrophages each represented about 50% of the myeloid pool.

Inflammatory macrophage to hepatocyte signals can be prevented by extracellular vesicle reprogramming.

Macrophage-derived extracellular vesicles (EVs) play key roles in intercellular communication. Within the liver, they have been linked to several inflammatory diseases including nonalcoholic fatty liver disease (NAFLD). In this study, we found that inflammatory macrophages cause injury to hepatocytes, in part by a cell-cell crosstalk phenomenon involving the secretion of EVs containing pro-inflammatory cargo.