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; Won Il Jeong

doi:10.1038/s41467-017-02325-2

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, Won Il Jeong

* New professors

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

149 Citations (Scopus)

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⁺F4/80^low hepatic infiltrating macrophages, but not CD11b⁺F4/80^high 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 CD68^lowCD14^high 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.

Original language	English
Article number	2247
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02325-2
Publication status	Published - 2017 Dec 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NFR-2015R1A2A1A10055551), the Korea Mouse Phenotyping Project (NRF-2014 M3A9D5A01073556) of the Ministry of Science, ICT and Future Planning through the National Research Foundation, and the Intelligent Synthetic Biology Center of Global Frontier Project funded by the Ministry of Science, ICT & Future Planning (2011-0031955), Republic of Korea.

Publisher Copyright:
© 2017 The Author(s).

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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

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10.1038/s41467-017-02325-2

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Kim, S. Y., Jeong, J. M., Kim, S. J., Seo, W., Kim, M. H., Choi, W. M., Yoo, W., Lee, J. H., Shim, Y. R., Yi, H. S., Lee, Y. S., Eun, H. S., Lee, B. S., Chun, K., Kang, S. J., Kim, S. C., Gao, B., Kunos, G., Kim, H. M., & Jeong, W. I. (2017). Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. Nature communications, 8(1), Article 2247. https://doi.org/10.1038/s41467-017-02325-2

Kim, SY, Jeong, JM, Kim, SJ, Seo, W, Kim, MH, Choi, WM, Yoo, W, Lee, JH, Shim, YR, Yi, HS, Lee, YS, Eun, HS, Lee, BS, Chun, K, Kang, SJ, Kim, SC, Gao, B, Kunos, G, Kim, HM & Jeong, WI 2017, 'Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex', Nature communications, vol. 8, no. 1, 2247. https://doi.org/10.1038/s41467-017-02325-2

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title = "Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex",

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.",

author = "Kim, {So Yeon} and Jeong, {Jong Min} and Kim, {Soo Jin} and Wonhyo Seo and Kim, {Myung Ho} and Choi, {Won Mook} and Wonbeak Yoo and Lee, {Jun Hee} and Shim, {Young Ri} and Yi, {Hyon Seung} and Lee, {Young Sun} and Eun, {Hyuk Soo} and Lee, {Byung Seok} and Kwangsik Chun and Kang, {Suk Jo} and Kim, {Sun Chang} and Bin Gao and George Kunos and Kim, {Ho Min} and Jeong, {Won Il}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NFR-2015R1A2A1A10055551), the Korea Mouse Phenotyping Project (NRF-2014 M3A9D5A01073556) of the Ministry of Science, ICT and Future Planning through the National Research Foundation, and the Intelligent Synthetic Biology Center of Global Frontier Project funded by the Ministry of Science, ICT & Future Planning (2011-0031955), Republic of Korea. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Kim, So Yeon

AU - Jeong, Jong Min

AU - Kim, Soo Jin

AU - Seo, Wonhyo

AU - Kim, Myung Ho

AU - Choi, Won Mook

AU - Yoo, Wonbeak

AU - Lee, Jun Hee

AU - Shim, Young Ri

AU - Yi, Hyon Seung

AU - Lee, Young Sun

AU - Eun, Hyuk Soo

AU - Lee, Byung Seok

AU - Chun, Kwangsik

AU - Kang, Suk Jo

AU - Kim, Sun Chang

AU - Gao, Bin

AU - Kunos, George

AU - Kim, Ho Min

AU - Jeong, Won Il

N1 - Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NFR-2015R1A2A1A10055551), the Korea Mouse Phenotyping Project (NRF-2014 M3A9D5A01073556) of the Ministry of Science, ICT and Future Planning through the National Research Foundation, and the Intelligent Synthetic Biology Center of Global Frontier Project funded by the Ministry of Science, ICT & Future Planning (2011-0031955), Republic of Korea. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

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M1 - 2247

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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