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

Randall H. Friedline, Hye Lim Noh, Sujin Suk, Mahaa Albusharif, Sezin Dagdeviren, Suchaorn Saengnipanthkul, Bukyung Kim, Allison M. Kim, Lauren H. Kim, Lauren A. Tauer, Natalie M. Baez Torres, Stephanie Choi, Bo-Yeon Kim, Suryateja D. Rao, Kaushal Kasina, Cheng Sun, Benjamin J. Toles, Chan Zhou, Zixiu Li, Vivian M. Benoit, Payal R. Patel, Doris X. T. Zheng, Kunikazu Inashima, Annika Beaverson, Xiaodi Hu, Duy A. Tran, Werner Muller, Dale L. Greiner, Alan C. Mullen, Ki Won Lee and Jason K. Kim ()
Additional contact information
Randall H. Friedline: University of Massachusetts Chan Medical School
Hye Lim Noh: University of Massachusetts Chan Medical School
Sujin Suk: University of Massachusetts Chan Medical School
Mahaa Albusharif: University of Massachusetts Chan Medical School
Sezin Dagdeviren: University of Massachusetts Chan Medical School
Suchaorn Saengnipanthkul: University of Massachusetts Chan Medical School
Bukyung Kim: University of Massachusetts Chan Medical School
Allison M. Kim: University of Massachusetts Chan Medical School
Lauren H. Kim: University of Massachusetts Chan Medical School
Lauren A. Tauer: University of Massachusetts Chan Medical School
Natalie M. Baez Torres: University of Massachusetts Chan Medical School
Stephanie Choi: University of Massachusetts Chan Medical School
Bo-Yeon Kim: University of Massachusetts Chan Medical School
Suryateja D. Rao: University of Massachusetts Chan Medical School
Kaushal Kasina: University of Massachusetts Chan Medical School
Cheng Sun: University of Massachusetts Chan Medical School
Benjamin J. Toles: University of Massachusetts Chan Medical School
Chan Zhou: Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School
Zixiu Li: Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School
Vivian M. Benoit: University of Massachusetts Chan Medical School
Payal R. Patel: University of Massachusetts Chan Medical School
Doris X. T. Zheng: University of Massachusetts Chan Medical School
Kunikazu Inashima: University of Massachusetts Chan Medical School
Annika Beaverson: University of Massachusetts Chan Medical School
Xiaodi Hu: University of Massachusetts Chan Medical School
Duy A. Tran: University of Massachusetts Chan Medical School
Werner Muller: University of Manchester
Dale L. Greiner: University of Massachusetts Chan Medical School
Alan C. Mullen: University of Massachusetts Chan Medical School
Ki Won Lee: Seoul National University
Jason K. Kim: University of Massachusetts Chan Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49633-y

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