Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4–MD2 complex

So Yeon Kim, Jong-Min Jeong, Soo Jin Kim, Wonhyo Seo, Myung-Ho Kim, Won-Mook Choi, Wonbeak Yoo, Jun-Hee Lee, Young-Ri Shim, Hyon-Seung Yi, Young-Sun Lee, Hyuk Soo Eun, Byung Seok Lee, Kwangsik Chun, Suk-Jo Kang, Sun Chang Kim, Bin Gao, George Kunos, Ho Min Kim and Won-Il Jeong ()
Additional contact information
So Yeon Kim: Biomedical Science and Engineering Interdisciplinary Program, KAIST
Jong-Min Jeong: Biomedical Science and Engineering Interdisciplinary Program, KAIST
Soo Jin Kim: Graduate School of Medical Science and Engineering, KAIST
Wonhyo Seo: Biomedical Science and Engineering Interdisciplinary Program, KAIST
Myung-Ho Kim: Graduate School of Medical Science and Engineering, KAIST
Won-Mook Choi: Graduate School of Medical Science and Engineering, KAIST
Wonbeak Yoo: Graduate School of Medical Science and Engineering, KAIST
Jun-Hee Lee: Graduate School of Medical Science and Engineering, KAIST
Young-Ri Shim: Biomedical Science and Engineering Interdisciplinary Program, KAIST
Hyon-Seung Yi: Chungnam National University School of Medicine
Young-Sun Lee: Korea University College of Medicine
Hyuk Soo Eun: Chungnam National University School of Medicine
Byung Seok Lee: Chungnam National University School of Medicine
Kwangsik Chun: Chungnam National University School of Medicine
Suk-Jo Kang: Korea Advanced Institute of Science and Technology
Sun Chang Kim: Korea Advanced Institute of Science and Technology
Bin Gao: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
George Kunos: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Ho Min Kim: Graduate School of Medical Science and Engineering, KAIST
Won-Il Jeong: Biomedical Science and Engineering Interdisciplinary Program, KAIST

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor 4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b+F4/80low hepatic infiltrating macrophages, but not CD11b+F4/80high Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4–MD2 complex, palmitate binds a monomeric TLR4–MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68lowCD14high macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease.

Date: 2017
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DOI: 10.1038/s41467-017-02325-2

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