Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome

Magar Ghazarian; Xavier S Revelo; Mark K Nøhr; Helen Luck; Kejing Zeng; Helena Lei; Sue Tsai; Stephanie A Schroer; Yoo Jin Park; Melissa Hui Yen Chng; Lei Shen; June Ann D'Angelo; Peter Horton; William C Chapman; Diane Brockmeier; Minna Woo; Edgar G Engleman; Oyedele Adeyi; Naoto Hirano; Tianru Jin; Adam J Gehring; Shawn Winer; Daniel A Winer

doi:10.1126/sciimmunol.aai7616

Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome

Magar Ghazarian, Xavier S Revelo, Mark K Nøhr, Helen Luck, Kejing Zeng, Helena Lei, Sue Tsai, Stephanie A Schroer, Yoo Jin Park, Melissa Hui Yen Chng, Lei Shen, June Ann D'Angelo, Peter Horton, William C Chapman, Diane Brockmeier, Minna Woo, Edgar G Engleman, Oyedele Adeyi, Naoto Hirano, Tianru JinAdam J Gehring, Shawn Winer, Daniel A Winer

44 Citationer (Scopus)

Abstract

Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8⁺ T cell subsets, which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8⁺ T cells represent a dominant intrahepatic immune cell population that is linked to glucose dysregulation. Accumulation and activation of these cells are supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice up-regulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFN protein, whereas IFNR1^−/− mice or CD8-specific IFNR1^−/− chimeric mice are protected from disease. IFNR1 inhibitors improve metabolic parameters in mice, whereas CD8⁺ T cells and IFN-I responses correlate with NAFLD in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

Originalsprog	Engelsk
Artikelnummer	eaai7616
Bogserie	Advances in Immunology
Vol/bind	2
Udgave nummer	10
ISSN	0065-2776
DOI	https://doi.org/10.1126/sciimmunol.aai7616
Status	Udgivet - 21 apr. 2017
Udgivet eksternt	Ja

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10.1126/sciimmunol.aai7616

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Ghazarian, M., Revelo, X. S., Nøhr, M. K., Luck, H., Zeng, K., Lei, H., Tsai, S., Schroer, S. A., Park, Y. J., Chng, M. H. Y., Shen, L., D'Angelo, J. A., Horton, P., Chapman, W. C., Brockmeier, D., Woo, M., Engleman, E. G., Adeyi, O., Hirano, N., ... Winer, D. A. (2017). Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome. Advances in Immunology, 2(10), Artikel eaai7616. https://doi.org/10.1126/sciimmunol.aai7616

Ghazarian, M, Revelo, XS, Nøhr, MK, Luck, H, Zeng, K, Lei, H, Tsai, S, Schroer, SA, Park, YJ, Chng, MHY, Shen, L, D'Angelo, JA, Horton, P, Chapman, WC, Brockmeier, D, Woo, M, Engleman, EG, Adeyi, O, Hirano, N, Jin, T, Gehring, AJ, Winer, S & Winer, DA 2017, 'Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome', Advances in Immunology, bind 2, nr. 10, eaai7616. https://doi.org/10.1126/sciimmunol.aai7616

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title = "Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome",

abstract = "Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets, which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population that is linked to glucose dysregulation. Accumulation and activation of these cells are supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice up-regulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFN protein, whereas IFNR1−/− mice or CD8-specific IFNR1−/− chimeric mice are protected from disease. IFNR1 inhibitors improve metabolic parameters in mice, whereas CD8+ T cells and IFN-I responses correlate with NAFLD in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.",

author = "Magar Ghazarian and Revelo, {Xavier S} and N{\o}hr, {Mark K} and Helen Luck and Kejing Zeng and Helena Lei and Sue Tsai and Schroer, {Stephanie A} and Park, {Yoo Jin} and Chng, {Melissa Hui Yen} and Lei Shen and D'Angelo, {June Ann} and Peter Horton and Chapman, {William C} and Diane Brockmeier and Minna Woo and Engleman, {Edgar G} and Oyedele Adeyi and Naoto Hirano and Tianru Jin and Gehring, {Adam J} and Shawn Winer and Winer, {Daniel A}",

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doi = "10.1126/sciimmunol.aai7616",

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AU - Ghazarian, Magar

AU - Revelo, Xavier S

AU - Nøhr, Mark K

AU - Luck, Helen

AU - Zeng, Kejing

AU - Lei, Helena

AU - Tsai, Sue

AU - Schroer, Stephanie A

AU - Park, Yoo Jin

AU - Chng, Melissa Hui Yen

AU - Shen, Lei

AU - D'Angelo, June Ann

AU - Horton, Peter

AU - Chapman, William C

AU - Brockmeier, Diane

AU - Woo, Minna

AU - Engleman, Edgar G

AU - Adeyi, Oyedele

AU - Hirano, Naoto

AU - Jin, Tianru

AU - Gehring, Adam J

AU - Winer, Shawn

AU - Winer, Daniel A

PY - 2017/4/21

Y1 - 2017/4/21

N2 - Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets, which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population that is linked to glucose dysregulation. Accumulation and activation of these cells are supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice up-regulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFN protein, whereas IFNR1−/− mice or CD8-specific IFNR1−/− chimeric mice are protected from disease. IFNR1 inhibitors improve metabolic parameters in mice, whereas CD8+ T cells and IFN-I responses correlate with NAFLD in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

AB - Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets, which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population that is linked to glucose dysregulation. Accumulation and activation of these cells are supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice up-regulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFN protein, whereas IFNR1−/− mice or CD8-specific IFNR1−/− chimeric mice are protected from disease. IFNR1 inhibitors improve metabolic parameters in mice, whereas CD8+ T cells and IFN-I responses correlate with NAFLD in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

U2 - 10.1126/sciimmunol.aai7616

DO - 10.1126/sciimmunol.aai7616

M3 - Journal article

C2 - 28567448

SN - 0065-2776

VL - 2

JO - Advances in Immunology

JF - Advances in Immunology

IS - 10

M1 - eaai7616

ER -

Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome

Abstract

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