title: Flagellin-induced NADPH oxidase 4 activation is involved in atherosclerosis.
abstract: It is widely accepted that bacterial infection-mediated inflammation facilitates development of atherosclerosis by activating toll-like receptor (TLR) signaling system. We reasoned that NADPH oxidases (Nox), required for TLR-mediated inflammatory response, are involved in atherogenesis. Here, we show that the activation of Nox4 through TLR5 regulates the inflammation of the endothelium and in atherogenesis. Flagellin-induced interaction between the COOH region of Nox4 and the TIR domain of TLR5 led to H2O2 generation, which in turn promoted the secretion of pro-inflammatory cytokines including IL-8, as well as the expression of ICAM-1 in human aortic endothelial cells (HAECs). Knockdown of the Nox4 in HAECs resulted in attenuated expressions of IL-8 and ICAM-1 leading to a reduction in the adhesion and trans-endothelial migration of monocytes. Challenge of recombinant FliC (rFliC) to the ApoE KO mice with high-fat diet (HFD) resulted in significantly increased atherosclerotic plaque sizes compared to the saline-injected mice. However, an injection of rFliC into the Nox4ApoE DKO mice with HFDs failed to generate atherosclerotic plaque, suggesting that Nox4 deficiency resulted in significant protections against rFliC-mediated atherogenesis. We conclude that TLR5-dependent Nox4 activation and subsequent H2O2 generation play critical roles for the development of atherosclerosis.
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Jinoh
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Misun
authors.initials: M
authors.lastname: Seo
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Su Kyung
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
mesh_terms: D000818:Animals; D001011:Aorta; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005408:Flagellin / Q000009:adverse effects*; D055786:Gene Knockout Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D000074663:NADPH Oxidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; C573420:ICAM1 protein, human; D016209:Interleukin-8; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D018799:Intercellular Adhesion Molecule-1; D005408:Flagellin; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; C498910:NOX4 protein, human