|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|
|WOS标题词||Science & Technology|
|关键词[WOS]||PATTERN-RECOGNITION RECEPTORS ; INNATE IMMUNE ; ISCHEMIA ; DISEASE ; STROKE ; DAMAGE ; RESPONSES ; PLATFORM ; MODELS ; HEALTH|
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.
|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|
|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
|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.|