Flagellin-induced NADPH oxidase 4 activation is involved in atherosclerosis

Jinoh Kim, Misun Seo, Su Kyung Kim, Yun Soo Bae

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish
Article number25437
JournalScientific Reports
StatePublished - 5 May 2016

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant (No. 2012R1A5A1048236), by the Bio & Medical Technology Development Program (No. 2012M3A9B4028785), by Redoxomics grant (No. 2012M3A9C5048708) funded by Ministry of Science, ICT & Future Planning. We thank Dr. Christopher Chang (University of California at San Francisco) for PO-1.

Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.


Dive into the research topics of 'Flagellin-induced NADPH oxidase 4 activation is involved in atherosclerosis'. Together they form a unique fingerprint.

Cite this