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

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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.

Original languageEnglish
Article number2247
JournalNature communications
Volume8
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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ASJC Scopus subject areas

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

Cite this

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), [2247]. https://doi.org/10.1038/s41467-017-02325-2