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

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...

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Detalles Bibliográficos
Autores principales: Kim, So Yeon, Jeong, Jong-Min, Kim, Soo Jin, Seo, Wonhyo, Kim, Myung-Ho, Choi, Won-Mook, Yoo, Wonbeak, Lee, Jun-Hee, Shim, Young-Ri, Yi, Hyon-Seung, Lee, Young-Sun, Eun, Hyuk Soo, Lee, Byung Seok, Chun, Kwangsik, Kang, Suk-Jo, Kim, Sun Chang, Gao, Bin, Kunos, George, Kim, Ho Min, Jeong, Won-Il
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740170/
https://www.ncbi.nlm.nih.gov/pubmed/29269727
http://dx.doi.org/10.1038/s41467-017-02325-2
Descripción
Sumario: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(low)CD14(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.