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

• Published in: Nature communications Vol. 15; no. 1; pp. 5506 - 18
• Main Authors: Friedline, Randall H., Noh, Hye Lim, Suk, Sujin, Albusharif, Mahaa, Dagdeviren, Sezin, Saengnipanthkul, Suchaorn, Kim, Bukyung, Kim, Allison M., Kim, Lauren H., Tauer, Lauren A., Baez Torres, Natalie M., Choi, Stephanie, Kim, Bo-Yeon, Rao, Suryateja D., Kasina, Kaushal, Sun, Cheng, Toles, Benjamin J., Zhou, Chan, Li, Zixiu, Benoit, Vivian M., Patel, Payal R., Zheng, Doris X. T., Inashima, Kunikazu, Beaverson, Annika, Hu, Xiaodi, Tran, Duy A., Muller, Werner, Greiner, Dale L., Mullen, Alan C., Lee, Ki Won, Kim, Jason K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/95; 14/63; 38/77; 45/91; 59/57; 631/443/319/1642/137/773; 64/60; 692/4020/1503/1607/2750; 692/699/1503/1607/2750; 82/80; 96/106; Animals; Cirrhosis; Cytokines; Diet; Diet, High-Fat - adverse effects; Disease resistance; Fatty liver; Fatty Liver - metabolism; Fatty Liver - pathology; Fibrosis; Growth factors; Humanities and Social Sciences; Inflammation; Insulin; Insulin Resistance; Interferon gamma Receptor; Interferon-gamma - metabolism; Interleukin 12; Interleukin-12 - metabolism; Liver; Liver - metabolism; Liver - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Macrophages; Macrophages - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Myeloid cells; Obesity; Obesity - metabolism; Pathogenesis; Receptors, Interferon - genetics; Receptors, Interferon - metabolism; Science; Science (multidisciplinary); Signal Transduction; Therapeutic targets; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49633-y

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2 −/− ) 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-IFNγR2 −/− mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ 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 IFNγ-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 IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and playing a major role in the pathogenesis of metabolic liver disease.