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

被引：177

作者：

Kim, So Yeon ^{[1
]}

Jeong, Jong-Min ^{[1
]}

Kim, Soo Jin ^{[2
]}

Seo, Wonhyo ^{[1
]}

Kim, Myung-Ho ^{[2
]}

Choi, Won-Mook ^{[2
]}

Yoo, Wonbeak ^{[2
]}

Lee, Jun-Hee ^{[2
]}

Shim, Young-Ri ^{[1
]}

Yi, Hyon-Seung ^{[3
]}

Lee, Young-Sun ^{[4
]}

Eun, Hyuk Soo ^{[3
]}

Lee, Byung Seok ^{[3
]}

Chun, Kwangsik ^{[5
]}

Kang, Suk-Jo ^{[6
]}

Kim, Sun Chang ^{[6
,7
]}

Gao, Bin ^{[8
]}

Kunos, George ^{[8
]}

Kim, Ho Min ^{[2
]}

Jeong, Won-Il ^{[1
,2
]}

机构：

[1] Korea Adv Inst Sci & Technol, Biomed Sci & Engn Interdisciplinary Program, Lab Liver Res, Daejeon 34141, South Korea

[2] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon 34141, South Korea

[3] Chungnam Natl Univ, Sch Med, Dept Internal Med, Daejeon 35015, South Korea

[4] Korea Univ, Coll Med, Dept Internal Med, Seoul 08308, South Korea

[5] Chungnam Natl Univ, Sch Med, Dept Surg, Daejeon 35015, South Korea

[6] Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon 34141, South Korea

[7] Intelligent Synthet Biol Ctr, 373-1 Guseong Dong, Daejeon 34141, South Korea

[8] NIAAA, NIH, Bethesda, MD 20892 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

新加坡国家研究基金会;

关键词：

REACTIVE OXYGEN; NLRP3; INFLAMMASOME; ISOLATION STRESS; ADIPOSE-TISSUE; FATTY-ACIDS; NOX FAMILY; RECEPTOR; ACTIVATION; LIVER; EXPRESSION;

D O I：

10.1038/s41467-017-02325-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-1 beta 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.

引用

页数：15

共 52 条

[1] Macrophages Generate Reactive Oxygen Species in Response to Minimally Oxidized Low-Density Lipoprotein Toll-Like Receptor 4-and Spleen Tyrosine Kinase-Dependent Activation of NADPH Oxidase 2 [J].