IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease

초록

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-gamma (IFN gamma) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFN gamma signaling in myeloid cells (Lyz-IFN gamma R2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFN gamma R2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFN gamma signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFN gamma-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH. Metabolic liver disease is highly prevalent in subjects with obesity and involves inflammation, insulin resistance, and fibrosis, leading to cirrhosis. Here, the authors show the IFN gamma-IL12 axis in regulating intercellular crosstalk in the liver and playing a major role in the pathogenesis of metabolic liver disease.

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