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

Author

Listed:
  • 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
    Seoul National University)

  • Mahaa Albusharif

    (University of Massachusetts Chan Medical School)

  • Sezin Dagdeviren

    (University of Massachusetts Chan Medical School)

  • Suchaorn Saengnipanthkul

    (University of Massachusetts Chan Medical School
    Khon Kaen University)

  • Bukyung Kim

    (University of Massachusetts Chan Medical School
    Kosin University College of Medicine)

  • 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
    Soonchunhyang University College of Medicine)

  • 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
    University of Massachusetts Chan Medical School)

  • Alan C. Mullen

    (University of Massachusetts Chan Medical School)

  • Ki Won Lee

    (Seoul National University
    Seoul National University)

  • Jason K. Kim

    (University of Massachusetts Chan Medical School
    Seoul National University
    University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

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.

Suggested Citation

  • 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 Torre, 2024. "IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49633-y
    DOI: 10.1038/s41467-024-49633-y
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    References listed on IDEAS

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    1. InSug O-Sullivan & Wenwei Zhang & David H. Wasserman & Chong Wee Liew & Jonathan Liu & Jihye Paik & Ronald A. DePinho & Donna Beer Stolz & C. Ronald Kahn & Michael W. Schwartz & Terry G. Unterman, 2015. "FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    2. Anthony J. Filiano & Yang Xu & Nicholas J. Tustison & Rachel L. Marsh & Wendy Baker & Igor Smirnov & Christopher C. Overall & Sachin P. Gadani & Stephen D. Turner & Zhiping Weng & Sayeda Najamussahar , 2016. "Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour," Nature, Nature, vol. 535(7612), pages 425-429, July.
    3. David Bradley & Alan J. Smith & Alecia Blaszczak & Dharti Shantaram & Stephen M. Bergin & Anahita Jalilvand & Valerie Wright & Kathleen L. Wyne & Revati S. Dewal & Lisa A. Baer & Katherine R. Wright &, 2022. "Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. InSug O-Sullivan & Wenwei Zhang & David H. Wasserman & Chong Wee Liew & Jonathan Liu & Jihye Paik & Ronald A. DePinho & Donna Beer Stolz & C. Ronald Kahn & Michael W. Schwartz & Terry G. Unterman, 2015. "Erratum: FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization," Nature Communications, Nature, vol. 6(1), pages 1-3, November.
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