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; Jason K Kim

doi:10.1038/s41467-024-49633-y

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 BenoitPayal 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, Jason K Kim

Division of Immunology, Immunity to Infection and Respiratory Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	5506
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	29 Jun 2024
DOIs	https://doi.org/10.1038/s41467-024-49633-y
Publication status	Published - 1 Dec 2024

Keywords

Animals
Interferon-gamma/metabolism
Interleukin-12/metabolism
Male
Insulin Resistance
Obesity/metabolism
Mice
Fatty Liver/metabolism
Mice, Knockout
Macrophages/metabolism
Signal Transduction
Liver/metabolism
Mice, Inbred C57BL
Diet, High-Fat/adverse effects
Receptors, Interferon/metabolism
Interferon gamma Receptor
Liver Cirrhosis/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-49633-yLicence: CC BY

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Friedline, R. H., Noh, H. L., Suk, S., Albusharif, M., Dagdeviren, S., Saengnipanthkul, S., Kim, B., Kim, A. M., Kim, L. H., Tauer, L. A., Baez Torres, N. M., Choi, S., Kim, B.-Y., Rao, S. D., Kasina, K., Sun, C., Toles, B. J., Zhou, C., Li, Z., ... Kim, J. K. (2024). IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease. Nature Communications, 15(1), Article 5506. https://doi.org/10.1038/s41467-024-49633-y

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title = "IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease",

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.",

keywords = "Animals, Interferon-gamma/metabolism, Interleukin-12/metabolism, Male, Insulin Resistance, Obesity/metabolism, Mice, Fatty Liver/metabolism, Mice, Knockout, Macrophages/metabolism, Signal Transduction, Liver/metabolism, Mice, Inbred C57BL, Diet, High-Fat/adverse effects, Receptors, Interferon/metabolism, Interferon gamma Receptor, Liver Cirrhosis/metabolism",

author = "Friedline, {Randall H} and Noh, {Hye Lim} and Sujin Suk and Mahaa Albusharif and Sezin Dagdeviren and Suchaorn Saengnipanthkul and Bukyung Kim and Kim, {Allison M} and Kim, {Lauren H} and Tauer, {Lauren A} and {Baez Torres}, {Natalie M} and Stephanie Choi and Bo-Yeon Kim and Rao, {Suryateja D} and Kaushal Kasina and Cheng Sun and Toles, {Benjamin J} and Chan Zhou and Zixiu Li and Benoit, {Vivian M} and Patel, {Payal R} and Zheng, {Doris X T} and Kunikazu Inashima and Annika Beaverson and Xiaodi Hu and Tran, {Duy A} and Werner Muller and Greiner, {Dale L} and Mullen, {Alan C} and Lee, {Ki Won} and Kim, {Jason K}",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

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doi = "10.1038/s41467-024-49633-y",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

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Friedline, RH, Noh, HL, Suk, S, Albusharif, M, Dagdeviren, S, Saengnipanthkul, S, Kim, B, Kim, AM, Kim, LH, Tauer, LA, Baez Torres, NM, Choi, S, Kim, B-Y, Rao, SD, Kasina, K, Sun, C, Toles, BJ, Zhou, C, Li, Z, Benoit, VM, Patel, PR, Zheng, DXT, Inashima, K, Beaverson, A, Hu, X, Tran, DA, Muller, W, Greiner, DL, Mullen, AC, Lee, KW & Kim, JK 2024, 'IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease', Nature Communications, vol. 15, no. 1, 5506. https://doi.org/10.1038/s41467-024-49633-y

TY - JOUR

T1 - IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease

AU - Friedline, Randall H

AU - Noh, Hye Lim

AU - Suk, Sujin

AU - Albusharif, Mahaa

AU - Dagdeviren, Sezin

AU - Saengnipanthkul, Suchaorn

AU - Kim, Bukyung

AU - Kim, Allison M

AU - Kim, Lauren H

AU - Tauer, Lauren A

AU - Baez Torres, Natalie M

AU - Choi, Stephanie

AU - Kim, Bo-Yeon

AU - Rao, Suryateja D

AU - Kasina, Kaushal

AU - Sun, Cheng

AU - Toles, Benjamin J

AU - Zhou, Chan

AU - Li, Zixiu

AU - Benoit, Vivian M

AU - Patel, Payal R

AU - Zheng, Doris X T

AU - Inashima, Kunikazu

AU - Beaverson, Annika

AU - Hu, Xiaodi

AU - Tran, Duy A

AU - Muller, Werner

AU - Greiner, Dale L

AU - Mullen, Alan C

AU - Lee, Ki Won

AU - Kim, Jason K

PY - 2024/12/1

Y1 - 2024/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Interferon-gamma/metabolism

KW - Interleukin-12/metabolism

KW - Male

KW - Insulin Resistance

KW - Obesity/metabolism

KW - Mice

KW - Fatty Liver/metabolism

KW - Mice, Knockout

KW - Macrophages/metabolism

KW - Signal Transduction

KW - Liver/metabolism

KW - Mice, Inbred C57BL

KW - Diet, High-Fat/adverse effects

KW - Receptors, Interferon/metabolism

KW - Interferon gamma Receptor

KW - Liver Cirrhosis/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85197228969&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-49633-y

DO - 10.1038/s41467-024-49633-y

M3 - Article

C2 - 38951527

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5506

ER -

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

Abstract

Keywords

UN SDGs

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