RRC ID 49603
Author Chen H, Song Z, Ying S, Yang X, Wu W, Tan Q, Ju X, Wu W, Zhang X, Qu J, Wang Y.
Title Myeloid differentiation protein 2 induced retinal ischemia reperfusion injury via upregulation of ROS through a TLR4-NOX4 pathway.
Journal Toxicol Lett
Abstract Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Müller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Müller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury.
Volume 282
Pages 109-120
Published 2018-1-5
DOI 10.1016/j.toxlet.2017.10.018
PII S0378-4274(17)31441-8
PMID 29111459
MeSH Animals Apoptosis / drug effects Cell Survival / drug effects Chalcones / pharmacology Disease Models, Animal Ependymoglial Cells Humans Lymphocyte Antigen 96 / antagonists & inhibitors* Lymphocyte Antigen 96 / genetics Mice, Inbred C57BL Mice, Knockout NADPH Oxidase 4 / metabolism* Oxidative Stress / drug effects Reactive Oxygen Species / metabolism* Reperfusion Injury / metabolism* Retinal Diseases / metabolism* Signal Transduction Toll-Like Receptor 4 / metabolism* tert-Butylhydroperoxide / pharmacology
IF 3.499
Times Cited 2
Mice RBRC02388