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敲低NLRP12对高眼压大鼠RGCs的保护作用及其抑制细胞焦亡的机制
宋伟琼
何芳
杜玲芳
谭华霞
刘丹
作者及单位信息
·
DOI： 10.3760/cma.j.cn115989-20211021-00572
Protective effect of NLRP12 knockdown on retinal damage in rats with ocular hypertension and its mechanism of inhibiting cell pyroptosis
Song Weiqiong
He Fang
Du Lingfang
Tan Huaxia
Liu Dan
Authors Info & Affiliations
Song Weiqiong
Department of Ophthalmology, The First People's Hospital of Chenzhou, Chenzhou 423000, China
He Fang
Department of Ophthalmology, The First People's Hospital of Chenzhou, Chenzhou 423000, China
Du Lingfang
Department of Ophthalmology, The First People's Hospital of Chenzhou, Chenzhou 423000, China
Tan Huaxia
Department of Ophthalmology, The First People's Hospital of Chenzhou, Chenzhou 423000, China
Liu Dan
Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410078, China
·
DOI： 10.3760/cma.j.cn115989-20211021-00572
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摘要

目的探讨敲低NOD样受体家族热蛋白结构域12(NLRP12)对高眼压大鼠视网膜神经节细胞(RGCs)炎症因子水平和视网膜损伤的影响及其机制。

方法选取70只SPF级成年雄性SD大鼠，采用随机数字表法分为对照组、高眼压组、高眼压+小干扰RNA阴性对照(siNC)组、高眼压+siNLRP12组和高眼压+siNLRP12+重组大鼠caspase-1(rrcaspase-1)组，每组14只。其中对照组仅接受右眼结膜切口处理，其他各组均采用巩膜外静脉烧灼法建立大鼠右眼高眼压模型；高眼压+siNC组、高眼压+siNLRP12组和高眼压+siNLRP12+rrcaspase-1组建立高眼压模型后分别给予尾静脉注射siNC、siNLRP12和siNLRP12+rrcaspase-1试剂。巩膜外静脉烧灼术后1 d、1周、2周、3周，测量大鼠右眼眼压；巩膜外静脉烧灼术后3周，采用苏木精－伊红染色法观察各组大鼠视网膜结构，计数各组RGCs数量。将RGCs分为对照组、rrcaspase-1组、siNC+rrcaspase-1组、siNLRP12+rrcaspase-1组，其中rrcaspase-1组、siNC+rrcaspase-1组、siNLRP12+rrcaspase-1组分别采用rrcaspase-1、siNC+rrcaspase-1和siNLRP12+rrcaspase-1处理细胞24 h，对照组不予处理。采用Western blot法检测RGCs和大鼠视网膜组织中NLRP12、caspase-1、cleaved-caspase-1蛋白表达水平；采用酶联免疫吸附测定法检测大鼠血清或细胞培养物上清中肿瘤坏死因子α(TNF-α)及白细胞介素1β(IL-1β)浓度。

结果与对照组比较，术后1、2、3周高眼压组眼压高于对照组，差异均有统计学意义(均 P<0.05)。对照组视网膜各层组织清晰，RGCs呈单层排列，高眼压组和高眼压+siNC组RGCs层松散，视网膜内丛状层变薄。高眼压+siNLRP12组视网膜内丛状层较高眼压组增厚，高眼压+siNLRP12组和高眼压+siNLRP12+rrcaspase-1组RGCs层松散。对照组、高眼压组、高眼压+siNC组、高眼压+siNLRP12组和高眼压+siNLRP12+rrcaspase-1组RGCs数量分别为(119.31±23.25)、(89.19±16.98)、(88.87±13.92)、(109.33±10.25)和(92.89±12.58)个，总体比较差异有统计学意义( F＝201.932， P<0.001)，其中高眼压组、高眼压+siNC组、高眼压+siNLRP12组和高眼压+siNLRP12+rrcaspase-1组RGCs数量少于对照组，高眼压+siNLRP12组RGCs数量多于高眼压+siNC组，高眼压+siNLRP12+rrcaspase-1组RGCs数量少于高眼压+siNLRP12组，差异均有统计学意义(均 P<0.05)。高眼压组、高眼压+siNC组、高眼压+siNLRP12组和高眼压+siNLRP12+rrcaspase-1组大鼠视网膜组织中caspase-1和cleaved-caspase-1蛋白相对表达量及TNF-α和IL-1β浓度较对照组升高，高眼压+siNLRP12组较高眼压+siNC组降低，高眼压+siNLRP12+rrcaspase-1组较高眼压+siNLRP12组升高，差异均有统计学意义(均 P<0.05)。rrcaspase-1组、siNC+rrcaspase-1组RGCs中caspase-1和cleaved-caspase-1蛋白相对表达量较对照组增加，siNLRP12+rrcaspase-1组NLRP12、caspase-1和cleaved-caspase-1蛋白相对表达量较对照组降低，rrcaspase-1组、siNC+rrcaspase-1组、siNLRP12+rrcaspase-1组TNF-α和IL-1β相对质量浓度较对照组升高，siNLRP12+rrcaspase-1组NLRP12、caspase-1和cleaved-caspase-1蛋白相对表达量及TNF-α和IL-1β相对质量浓度较siNC+rrcaspase-1组降低，差异均有统计学意义(均 P<0.05)。

结论敲低NLRP12可通过抑制caspase-1激活改善高眼压引发的炎症反应和视网膜损伤。

青光眼;高眼压;视网膜神经节细胞;NOD样受体家族热蛋白结构域12;半胱天冬酶1;细胞焦亡
ABSTRACT

ObjectiveTo investigate the effect and mechanism of NOD-like receptor family pyrin domain containing 12 (NLRP12) knockdown on inflammatory factor levels and retinal injury in retinal ganglion cells (RGCs) of rats with high intraocular pressure.

MethodsSeventy SPF adult male SD rats were selected and randomized into control group, high intraocular pressure (IOP) group, high IOP+ small interfering RNA negative control (siNC) group, high IOP+ siNLRP12 group and high IOP+ siNLRP12+ recombinant rat caspase-1 (rrcaspase-1) group, with 14 rats in each group.Rats in the control group were only treated with conjunctival incision in the right eye, and ocular hypertension model was established in the other four groups with external scleral vein cauterization.High IOP+ siNC group, high IOP+ siNLRP12 group and high IOP+ siNLRP12+ rrcaspase-1 group were injected with siNC, siNLRP12 and siNLRP12+ rrcaspase-1 reagent via the tail vein, respectively.The IOP of the right eye was measured at 1 day, 1, 2 and 3 weeks after the operation.Three weeks after the operation, the retinal structure was observed by hematoxylin-eosin staining, and the number of RGCs in each group was counted.RGCs were divided into control group, rrcaspase-1 group, siNC+ rrcaspase-1 group, siNLRP12+ rrcaspase-1 group.The cells in rrcaspase-1 group, siNC+ rrcaspase-1 group and siNLRP12+ rrcaspase-1 group were treated with rrcaspase-1, siNC+ rrcaspase-1 and siNLRP12+ rrcaspase-1 reagent for 24 hours, respectively.No treatment was given to the control group.The expression levels of NLRP12, caspase-1 and cleaved-caspase-1 proteins in RGCs and retinal tissue were detected by Western blot.The concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat serum or cell culture supernatant were detected by enzyme-linked immunosorbent assay.The study protocol was approved by the Animal Ethics Committee of the First People's Hospital of Chenzhou (No.2020086).

ResultsCompared with control group, the IOP was higher in high IOP group at 1, 2 and 3 weeks after cauterization, and the differences were statistically significant (all at P<0.05). The retinal tissue was clear with the RGCs in a single layer arrangement in the control group.In the high IOP group and the high IOP+ siNC group, the RGCs layer was loose and the inner plexiform layer was thin.The inner plexiform layer was thickened in high IOP+ siNLRP12 group compared with high IOP group, and the RGCs layer was loose in the high IOP+ siNLRP12 group and the high IOP+ siNLRP12+ rrcaspase-1 group.The number of RGCs in control group, high IOP group, high IOP+ siNC group, high IOP+ siNLRP12 group and high IOP+ siNLRP12+ rrcaspase-1 group was 119.31±23.25, 89.19±16.98, 88.87±13.92, 109.33±10.25 and 92.89±12.58, respectively, showing a statistically significant overall difference ( F=201.932, P<0.001). The number of RGCs was lower in the high IOP group, high IOP+ siNC group, high IOP+ siNLRP12 group and high IOP+ siNLRP12+ rrcaspase-1 group than the control group, higher in the high IOP+ siNLRP12 group than the high IOP+ siNC group, and lower in the high IOP+ siNLRP12+ rrcaspase-1 group than the high IOP+ siNLRP12 group, and the differences were statistically significant (all at P<0.05). The relative expressions of caspase-1 and cleaved-caspase-1 proteins and the concentrations of TNF-α and IL-1β in the retinal tissue were higher in high IOP group, high IOP+ siNC group, high IOP+ siNLRP12 group and high IOP+ siNLRP12+ rrcaspase-1 group than control group, higher in high IOP+ siNLRP12 group than high IOP+ siNC group, and higher in high IOP+ siNLRP12+ rrcaspase-1 group than high IOP+ siNLRP12 group (all at P<0.05). Relative expression levels of caspase-1 and cleaved-caspase-1 protein were increased in rrcaspase-1 group and siNC+ rrcaspase-1 group compared with control group, and relative expression levels of NLRP12, caspase-1 and cleaved-caspase-1 protein were decreased in siNLRP12+ rrcaspase-1 group compared with control group (all at P<0.05). The relative mass concentrations of TNF-α and IL-1β were increased in rrcaspase-1 group, siNC+ rrcaspase-1 group and siNLRP12+ rrcaspase-1 group compared with the control group (all at P<0.05). Relative expression levels of NLRP12, caspase-1 and cleaved-caspase-1 proteins and relative mass concentrations of TNF-α and IL-1β in siNLRP12+ rrcaspase-1 group were lower than those in siNC+ rrcaspase-1 group (all at P<0.05).

ConclusionsKnockdown of NLRP12 can reduce the inflammatory response and retinal injury induced by high IOP by inhibiting the activation of caspase-1.

Glaucoma;Ocular hypertension;Retinal ganglion cells;NLRP12 protein;Caspase-1;Pyroptosis
He Fang, Email: mocdef.qabq221414627
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引用本文

宋伟琼,何芳,杜玲芳,等. 敲低NLRP12对高眼压大鼠RGCs的保护作用及其抑制细胞焦亡的机制[J]. 中华实验眼科杂志,2023,41(02)：110-118.

DOI:10.3760/cma.j.cn115989-20211021-00572

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视网膜神经节细胞(retinal ganglion cells，RGCs)死亡是青光眼致盲或视野缺损的潜在病理机制 [ 1 ]。年龄是青光眼的主要危险因素，而目前认为眼压升高是关键的可变危险因素 [ 2 , 3 ]。而且，通过手术或药物降低眼压可将视网膜损伤和渐进性视野丧失的发生率降低近一半 [ 3 ]，从而确立了降低眼压是治疗青光眼的有效方法。高眼压会导致细胞毒性因子和退化因子的产生。其中肿瘤坏死因子α(tumor necrosis factor-α，TNF-α)是一种促炎细胞因子，在青光眼患者和青光眼模型大鼠的视盘中检测到TNF-α及其受体表达升高，而且TNF-α介导了高眼压对RGCs的细胞毒性作用 [ 4 ]。研究发现，NOD样受体家族热蛋白结构域12(NOD-like receptors family pyrin domain containing 12，NLRP12)在调节自身炎症性疾病中发挥重要作用 [ 5 , 6 ]。Caspase-1介导的细胞焦亡在促进促炎细胞因子表达方面具有关键作用 [ 7 ]。NLRP12可以通过激活caspase-1诱发神经节细胞焦亡和白细胞介素1β(interleukin-1β，IL-1β)成熟，促进青光眼的RGCs死亡和神经炎症 [ 7 ]。然而，在高眼压中NLRP12能否通过激活caspase-1调控RGCs炎症及阻断NLRP12/caspase-1信号对高眼压环境下视网膜损伤是否具有改善作用尚不清楚。本研究拟探讨高眼压造成大鼠RGCs损伤的炎性机制，研究敲低NLRP12对RGCs的影响及其作用机制，为青光眼视神经损伤的治疗提供新的思路。
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何芳，Email： mocdef.qabq221414627
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宋伟琼：参与论文选题、研究设计、实验实施、数据采集和分析、论文撰写；何芳：参与论文选题、研究设计、实验实施、数据采集和统计分析、文章内容的审核和定稿；杜玲芳：参与论文选题、研究设计、实验实施、对文章智力性内容修改和定稿；谭华霞：参与数据采集；刘丹：参与数据收集和统计分析

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湖南省自然科学基金科卫联合项目 (2019JJ80012)
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