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

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)


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
Issue number1
Publication statusPublished - 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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