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Retinal Ischemia/Reperfusion Injury Is Mediated by Toll-like Receptor 4 Activation of NLRP3 Inflammasomes
Qi, Yun1; Zhao, Min1; Bai, Yujing1; Huang, Lvzhen1; Yu, Wenzhen1; Bian, Zongmei2; Zhao, Mingwei1; Li, Xiaoxin1
关键词retina ischemia-reperfusion Toll-like receptor 4 inflammasomes IL-1 beta IL-18
刊名INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
2014-09-01
DOI10.1167/iovs.14-14380
55期:9页:5466-5475
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Ophthalmology
研究领域[WOS]Ophthalmology
关键词[WOS]PATTERN-RECOGNITION RECEPTORS ; INNATE IMMUNE ; ISCHEMIA ; DISEASE ; STROKE ; DAMAGE ; RESPONSES ; PLATFORM ; MODELS ; HEALTH
英文摘要

PURPOSE. Retinal ischemia/reperfusion (IR) is common in eye disorders. Pattern-recognition receptors (PRRs) are reported to initiate sterile inflammatory response. The role of PRRs in retinal IR injury is currently unknown. Thus, we investigated the expression and function of membrane and cytoplasmic PRRs during retinal IR.

METHODS. Retinal IR was induced in adult Brown Norway rats by clipping the retinal vessels for 30 minutes. RNA and proteins were extracted during the course of reperfusion, and the expression levels of the following proteins were determined: Toll-like receptor 2 (TLR2), TLR4, myeloid differentiation factor 88 (MyD88), TNF receptor-associated factor 6 (TRAF6), nuclear factor-kappa B (NF-kappa B), nucleotide-binding oligomerization domain-like receptor with pyrin domain protein 1 (NLRP1), NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, IL-1 beta, and IL-18. TLR4 expression in the retina was studied using immunohistochemistry. In addition, a TLR4 inhibitor was injected into the vitreous body as a therapeutic agent. After the treatment of TLR4 inhibitors, the levels of the above factors were evaluated, the apoptosis of cells in the retina, expression of cleaved-caspase-3 (c-casp-3), death of retinal ganglion cells, and the retina electroretinography was assessed.

RESULTS. After releasing the artery clamp, the retinal vessels were reperfused in 5 minutes. During the reperfusion, TLR4, MyD88, TRAF6, NF-kappa B, NLRP1, NLRP3, mature IL-1 beta, and IL-18 were upregulated, but not TLR2. In the IR model, TLR4 was highly expressed in ganglion cell and glia cell. Additionally, the inhibition of TLR4 significantly downregulated the activation of NLRP3, but not NLRP1, and the secretion of mature IL-1 beta and IL-18 also were inhibited. Moreover, the TLR4 inhibitor partially attenuated the injury of the retina, including alleviated retina apoptosis, downregulated c-casp-3 expression, rescued retinal ganglion cells death, and restored retina function.

CONCLUSIONS. These findings suggest that TLR4-signaling activation, triggered by damage-associated molecular patterns, regulates the activation of the NLRP3 inflammasomes and is responsible for the function of the retina in retinal IR injury.

语种英语
WOS记录号WOS:000343146900001
项目编号Z131102000413004 ; 2011CB510200 ; 81200690
资助机构Beijing Nova Program ; National Basic Research Program of China (973 Program) ; National Natural Science Foundation of China
引用统计
被引频次:30[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67212
专题北京大学第二临床医学院
北京大学第二临床医学院_眼科
作者单位1.Peking Univ, Peoples Hosp, Dept Ophthalmol,Key Lab Vis Loss & Restorat,Minis, Beijing Key Lab Diag & Therapy Retinal & Choroid, Beijing 100044, Peoples R China
2.Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA
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GB/T 7714
Qi, Yun,Zhao, Min,Bai, Yujing,et al. Retinal Ischemia/Reperfusion Injury Is Mediated by Toll-like Receptor 4 Activation of NLRP3 Inflammasomes[J]. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE,2014,55(9):5466-5475.
APA Qi, Yun.,Zhao, Min.,Bai, Yujing.,Huang, Lvzhen.,Yu, Wenzhen.,...&Li, Xiaoxin.(2014).Retinal Ischemia/Reperfusion Injury Is Mediated by Toll-like Receptor 4 Activation of NLRP3 Inflammasomes.INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE,55(9),5466-5475.
MLA Qi, Yun,et al."Retinal Ischemia/Reperfusion Injury Is Mediated by Toll-like Receptor 4 Activation of NLRP3 Inflammasomes".INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 55.9(2014):5466-5475.
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