title: Myeloid differentiation protein 2-dependent mechanisms in retinal ischemia-reperfusion injury.
abstract: Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigment epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Ren
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Tao
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Huaicheng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Gaozhi
authors.initials: G
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: wuwencan118@163.com.
authors.forename: Wencan
authors.initials: W
authors.lastname: Wu
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: szmeyes@126.com.
authors.forename: Zongming
authors.initials: Z
authors.lastname: Song
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: yi.wang1122@wmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D047188:Chalcones / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D012164:Retinal Diseases / Q000188:drug therapy / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C000603962:1-(3,4-dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one; D047188:Chalcones; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Apoptosis; HMGB-1; Inflammation; MD2; Retinal ischemia-reperfusion injury; TLR4