TLR3 and TLR4 But not TLR2 are Involved in Vogt-Koyanagi- Harada Disease by Triggering Proinflammatory Cytokines Production Through Promoting the Production of Mitochondrial Reactive Oxygen Species

Author(s): L. Liang, X. Tan, Q. Zhou, Y. Tian, A. Kijlstra, P. Yang.

Journal Name: Current Molecular Medicine

Volume 15 , Issue 6 , 2015

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Abstract:

Vogt-Koyanagi-Harada (VKH) disease is considered to be an autoimmune disease possibly triggered by an abnormal response to infection. Activation of TLRs signaling pathways by microbial products can drive inflammatory responses and adaptive immunity. In the present study, we investigated the role of TLRs in the pathogenesis of VKH disease. We showed that the expression of TLR3 and TLR4, but not TLR2, was significantly increased in monocyte-derived macrophages (MDMs) from VKH patients with active uveitis compared to controls. VKH patients with active uveitis showed an elevated level of IL-1β, IL-6, IL-8, TNF-α and reactive oxygen species (ROS) in MDMs. IL-1β, IL-6, IL-8 and TNF-α production could be significantly upregulated and downregulated by a ROS activator or inhibitor, respectively. Downregulation of the NLRP3 inflammasome significantly inhibited the production of IL-1β but not IL-6, IL-8 and TNF-α. The phosphorylation levels of p38 and ERK1/2 were significantly higher in MDMs from active VKH patients compared to controls. Inhibition of p38 or ERK1/2 significantly decreased IL-1β, IL-6, IL-8 and TNF-α expression. These results suggest that the increased expression of TLR3/4 in MDMs may be involved in the pathogenesis of VKH disease by the induction of inflammatory cytokines which is mediated by enhanced production of ROS.

Keywords: Autoimmunity, NLRP3 inflammasome, reactive oxygen species, Toll-like receptors, Vogt-Koyanagi- Harada disease.

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Article Details

VOLUME: 15
ISSUE: 6
Year: 2015
Page: [529 - 542]
Pages: 14
DOI: 10.2174/1566524015666150731095611
Price: $58

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