TNF-α在視網(wǎng)膜神經(jīng)變性性疾病中的作用

謝芬高，宋慶磊，張希洲*

(三峽大學(xué) 1.人民醫(yī)院 宜昌市第一人民醫(yī)院 急救中心；2.醫(yī)學(xué)院 眼科學(xué)系，湖北 宜昌 443000)

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TNF-α在視網(wǎng)膜神經(jīng)變性性疾病中的作用

謝芬高1，宋慶磊2，張希洲1*

(三峽大學(xué) 1.人民醫(yī)院 宜昌市第一人民醫(yī)院 急救中心；2.醫(yī)學(xué)院 眼科學(xué)系，湖北 宜昌 443000)

視網(wǎng)膜神經(jīng)變性性疾病是引起視力下降的主要原因之一，TNF-α作為一種具有多效生物學(xué)活性的炎性細(xì)胞因子，與其受體結(jié)合后通過多種信號(hào)通路，在青光眼、缺血性視網(wǎng)膜病變、年齡相關(guān)性黃斑變性和色素性視網(wǎng)膜炎等視網(wǎng)膜神經(jīng)變性性疾病的病理生理過程中發(fā)揮重要作用。

腫瘤壞死因子-α；視力損傷；視網(wǎng)膜神經(jīng)變性性疾病

視力損傷是視網(wǎng)膜神經(jīng)變性性疾病常見臨床表現(xiàn)，業(yè)已證實(shí)腫瘤壞死因子-α(tumor necrosis factor-α，TNF-α)與視網(wǎng)膜神經(jīng)變性性疾病如青光眼、缺血性視網(wǎng)膜病變(ischemic retinopathy，IR)、年齡相關(guān)性黃斑變性(age-related macular degeneration，AMD)和色素性視網(wǎng)膜炎(retinitis pigmentosa，RP)等疾病的發(fā)生發(fā)展密切相關(guān)。TNF-α的表達(dá)產(chǎn)生炎性級(jí)聯(lián)反應(yīng)，誘導(dǎo)視網(wǎng)膜神經(jīng)節(jié)細(xì)胞(retinal ganglion cell，RGC)和光感受器細(xì)胞的凋亡/死亡而引起視力下降。本文就TNF-α在視網(wǎng)膜神經(jīng)變性性疾病中的作用進(jìn)行綜述。

1 TNF-α和其受體

腫瘤壞死因子因能使腫瘤細(xì)胞發(fā)生溶解壞死而得名，通常把由巨噬細(xì)胞釋放的腫瘤壞死因子稱為TNF-α，它具有促細(xì)胞增殖、分化、凋亡、致炎和抗腫瘤等作用，多由淋巴細(xì)胞、巨噬細(xì)胞、內(nèi)皮細(xì)胞和成纖維細(xì)胞等分泌[1]。成熟的TNF-α必須和受體結(jié)合才能發(fā)揮生物學(xué)效應(yīng)。

腫瘤壞死因子受體(tumor necrosis factor receptor，TNFR)包括TNFR1和TNFR2兩種受體，在中樞神經(jīng)系統(tǒng)的星狀細(xì)胞、膠質(zhì)細(xì)胞和神經(jīng)元等均有表達(dá)，視網(wǎng)膜作為腦組織的延續(xù)，其在視網(wǎng)膜組織中亦呈陽性表達(dá)。TNFR1包含死亡結(jié)構(gòu)域，直接誘導(dǎo)細(xì)胞凋亡，而TNFR2由于不含死亡結(jié)構(gòu)域，它的激活不直接參與細(xì)胞凋亡，通過腫瘤壞死因子受體相關(guān)因子 (tumor necrosis factor receptor associated factor，TRAF)增強(qiáng)TNFR1的功能[2]。TNF-α受體在組織中的分布密度以及靶細(xì)胞的不同狀態(tài)影響細(xì)胞對(duì)TNF-α的反應(yīng)性，多種機(jī)制與TNF-α的細(xì)胞毒作用相聯(lián)系，TNF-α通過核因子κB(nuclear factor kappa B，NF-κB)、c-Jun氨基末端激酶(JNK)以及依賴和不依賴含半胱氨酸的天冬氨酸蛋白水解酶(caspase)凋亡蛋白等信號(hào)通路調(diào)節(jié)細(xì)胞的生長(zhǎng)、分化與凋亡。TNF-α的釋放改變血流動(dòng)力學(xué)，調(diào)節(jié)IL- 6、細(xì)胞間黏附分子- 1(intercellular cell adhesion molecule- 1，ICAM- 1)和單核細(xì)胞趨化蛋白- 1(monocyte chemotactic protein 1，MCP- 1)等多種炎性因子的合成與釋放,促進(jìn)白細(xì)胞募集和浸潤，釋放多種細(xì)胞毒性物質(zhì)損傷細(xì)胞功能[3- 4]。TNFR的激活可以產(chǎn)生明顯的細(xì)胞毒作用，且少量的TNF-α與其受體結(jié)合就能通過沉默細(xì)胞生長(zhǎng)信號(hào)通路，引起RGC的凋亡[5]。谷氨酸鹽是體內(nèi)組織細(xì)胞代謝主要細(xì)胞毒物質(zhì)，TNF-α調(diào)節(jié)離子通道的活性，增加谷氨酸鹽的過度釋放，直接損傷RGC[6]。TNF-α與其受體結(jié)合是細(xì)胞內(nèi)重要的信號(hào)調(diào)節(jié)通路，作用機(jī)制如圖1所示[1,7]。

2 TNF-α和視網(wǎng)膜神經(jīng)變性性疾病

2.1 青光眼

RGC的凋亡和視神經(jīng)萎縮是青光眼的臨床病理特點(diǎn)，臨床病例研究和動(dòng)物實(shí)驗(yàn)均證實(shí)TNF-α的表達(dá)水平與青光眼的病理生理改變密切相關(guān)，TNF-α在眼壓升高的早期即開始表達(dá)，血清或眼內(nèi)組織中TNF-α含量的高低與RGC的凋亡程度呈正相關(guān)[8]。有研究發(fā)現(xiàn)玻璃體腔注射TNF-α不但直接誘導(dǎo)視神經(jīng)軸突的變性和RGC凋亡，還能激活上、下游預(yù)凋亡調(diào)節(jié)因子如神經(jīng)生長(zhǎng)因子前體(pro-form of nerve growth factor，proNGF)，誘導(dǎo)視網(wǎng)膜神經(jīng)元程序性凋亡[9]。使用藥物和TNF-α抗體抑制其活性和受體表達(dá)，可有效降低RGC凋亡的程度，對(duì)視網(wǎng)膜神經(jīng)纖維有較好的保護(hù)作用[10- 11]。

圖1 腫瘤壞死因子受體信號(hào)通路Fig 1 TNFR signal pathway

2.2 缺血性視網(wǎng)膜病變

視網(wǎng)膜血流灌注不足，引起組織細(xì)胞缺血缺氧，嚴(yán)重影響視力。視網(wǎng)膜缺血缺氧在糖尿病性視網(wǎng)膜病變、視網(wǎng)膜血管阻塞性疾病和早產(chǎn)兒視網(wǎng)膜病變等疾病的發(fā)展過程中起著重要的作用[12]。視網(wǎng)膜缺血再灌注激活巨噬細(xì)胞、小膠質(zhì)細(xì)胞和星狀細(xì)胞等合成TNF-α，并涉及多種信號(hào)傳導(dǎo)通路誘導(dǎo)細(xì)胞凋亡/死亡[13]。取RGC體外高血糖環(huán)境下培養(yǎng)，早期即大量死亡，細(xì)胞內(nèi)TNF-α表達(dá)增加和caspase- 3凋亡蛋白活性增強(qiáng)，啟動(dòng)caspase凋亡程序，加速RGC凋亡[14]。通過大鼠實(shí)驗(yàn)發(fā)現(xiàn)視網(wǎng)膜缺血再灌注損傷前吸入一氧化碳(carbon monoxide，CO)對(duì)RGC有明顯的保護(hù)作用，CO可以有效抑制TNF-α表達(dá)和caspase- 3凋亡蛋白活性，提高RGC細(xì)胞密度，調(diào)控部分依賴CO的caspase凋亡信號(hào)通路以及NF-κB信號(hào)通路抑制凋亡蛋白活性和炎性因子表達(dá)，延緩RGC的凋亡，對(duì)抗缺血性神經(jīng)元損傷[15]。

2.3 年齡相關(guān)性黃斑變性

AMD是以主要累及黃斑區(qū)視網(wǎng)膜(視網(wǎng)膜色素上皮、光感受器和脈絡(luò)膜)組織為主的一種嚴(yán)重不可逆的致盲性眼病。AMD分為干性和濕性兩種類型。干性AMD以視網(wǎng)膜色素上皮細(xì)胞和光感受器細(xì)胞進(jìn)行性變性凋亡以及視力損害較輕為特征，而濕性AMD以黃斑區(qū)脈絡(luò)膜下新生血管生成，黃斑出血和水腫，視力永久性下降甚至失明為臨床特點(diǎn)。

臨床病理學(xué)、流行病學(xué)和基因研究表明TNF-α與AMD的發(fā)生發(fā)展高度相關(guān)。視網(wǎng)膜色素上皮細(xì)胞(retinal pigment epithelium，RPE)及其連接復(fù)合體在視網(wǎng)膜與脈絡(luò)膜之間構(gòu)成一層上皮型外屏障，使視網(wǎng)膜組織液與脈絡(luò)膜組織液相隔離，TNF-α與其受體的結(jié)合調(diào)節(jié)RPE的黏附、趨化、遷移與增值，促進(jìn)RPE中凋亡因子的表達(dá)，破壞RPE的屏障功能，誘導(dǎo)光感受器細(xì)胞凋亡[16- 17]。血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor，VEGF)是眼內(nèi)新生血管發(fā)育、生長(zhǎng)和成熟的主要營養(yǎng)因子，TNF-α增加人RPE和脈絡(luò)膜成纖維細(xì)胞中VEGF-A與VEGF-C的分泌，加速脈絡(luò)膜新生血管的生成，導(dǎo)致黃斑區(qū)病變[18]。使用藥物下調(diào)TNF-α的表達(dá)，抑制新生血管的形成，減少炎性細(xì)胞的浸潤和募集，減輕組織細(xì)胞損傷，對(duì)AMD有明顯的治療作用[19]。

2.4 色素性視網(wǎng)膜炎

RP是以進(jìn)行性視桿、視錐細(xì)胞和色素上皮功能喪失為特征的遺傳性營養(yǎng)不良性疾病。在大部分RP的病理生理過程中最初表現(xiàn)為視桿細(xì)胞的變性和凋亡，繼而繼發(fā)視錐細(xì)胞營養(yǎng)不良、變性和萎縮，這也就是為什么患者早期臨床表現(xiàn)為夜盲和周邊視野損害的主要原因[20]。RP的發(fā)展過程中光感受器細(xì)胞變性和凋亡的分子機(jī)制可能為小膠質(zhì)細(xì)胞的激活，炎性因子涉及光感受器細(xì)胞的變性與凋亡。誘導(dǎo)鼠RP模型激活NF-κB信號(hào)通路，促進(jìn)小膠質(zhì)細(xì)胞釋放TNF-α，發(fā)現(xiàn)視錐、視桿細(xì)胞凋亡峰值與炎性因子表達(dá)高峰相一致[21]。在視紫紅質(zhì)合成利用障礙的RP模型中檢測(cè)到TNF-α基因表達(dá)上調(diào)，并與色素上皮細(xì)胞和光感受器細(xì)胞變性呈線性關(guān)系，TNF-α信號(hào)通路可能是RP發(fā)生發(fā)展過程中引起細(xì)胞凋亡的主要通路[22]。

3 結(jié)語和展望

視網(wǎng)膜神經(jīng)變性性疾病嚴(yán)重威脅患者視力，早期診斷及治療對(duì)降低致盲率尤為重要。TNF-α的研究已逐步走出腫瘤性疾病的范疇，其不僅誘導(dǎo)細(xì)胞凋亡，還參與細(xì)胞的遷移、分化與增值，以及組織的炎性反應(yīng)。TNF-α在視網(wǎng)膜神經(jīng)變性性疾病中發(fā)揮重要作用，抑制TNF-α表達(dá)可以減少炎性因子釋放，減輕組織炎性反應(yīng)，選擇TNF-α作為治療的靶點(diǎn)可能為治療這類疾病開啟新的篇章。

[1] Zhang Y, Li YW, Wang YX,etal. Remifentanil preconditioning alleviating brain damage of cerebral ischemia reperfusion rats by regulating the JNK signal pathway and TNF-α/TNFR1 signal pathway[J]. Mol Biol Rep, 2013,40:6997- 7006.

[2] Park KM, Bowers WJ. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction [J]. Cell Signal, 2010,22:977- 983.

[3] Wang Y, Li M, Xu Y,etal. Tumor necrosis factor-α regulates matrix metalloproteinase- 2 expression and cell migration via ERK pathway in rat glomerular mesangial cells[J]. J Neuroimmunol, Cell Biol Int, 2014,doi:10.1002/cbin.10298.

[4] Negrao R, Duarte D, Costa R,etal. Isoxanthohumol modulates angiogenesis and inflammation via vascular endothelial growth factor receptor, tumor necrosis factor alpha and nuclear factor kappa B pathways [J]. Biofactors, 2013,39:608- 622.

[5] Nelson CM, Ackerman KM, O’Hayer P,etal. Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Muller glia proliferation during zebrafish retinal regeneration[J]. J Neurosci,2013,33:6524- 6539.

[6] Al-Gayyar MM, Abdelsaid MA, Matragoon S,etal. Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity[J]. Br J Pharmacol, 2011,164: 170- 180.

[7] Al-Gayyar MM, Elsherbiny NM. Contribution of TNF-α to the development of retinal neurodegenerative disorders [J]. Eur Cytokine Netw, 2013,24:27- 36.

[8] Agarwal R, Agarwal P. Glaucomatous neurodegeneration: an eye on tumor necrosis factor-alpha[J]. Indian J Ophthalmol, 2012,60:255- 261.

[9] Ali TK, Al-Gayyar MM, Matragoon S,etal. Diabetes-inducedperoxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury[J]. Diabetologia, 2011,54:657- 668.

[10] Roh M, Zhang Y, Murakami Y,etal. Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-alpha), prevents retinal ganglion cell loss in a rat model of Glaucoma [J]. PLoS One,2012,7:e40065. doi: 10.1371/journal.pone.0040065.

[11] Koike A, Handa T, Zako M. Trabeculotomy in a Behcet’s disease patient one week after infliximab administration [J]. Case Report Ophthalmol,2012,3:151- 155.

[12] Husain S, Liou GI, Crosson CE. Opioid receptor activation: suppression of ischemia/reperfusion-induced production of TNF-alpha in the retina [J]. Invest Ophthalmol Vis Sci,2011,52:2577- 2583.

[13] Saxena S, Khanna VK, Pant AB,etal. Elevated tumor necrosis factor in serum is associated with increased retinal ischemia in proliferative eales’ disease[J]. Pathobiology,2011,78:261- 265.

[14] Costa GN, Vindeirinho J, Cavadas C,etal. Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose[J]. Mol Cell Neurosci, 2012,50:113- 123.

[15] Biermann J, Lagreze WA, Dimitriu C,etal. Preconditioning with inhalative carbon monoxide protects rat retinal ganglion cells from ischemia/reperfusion injury[J]. Invest Ophthalmol Vis Sci, 2010,51:3784- 3791.

[16] Klein R, Myers CE, Cruickshanks KJ,etal. Markers of inflammation, oxidative stress, and endothelial dysfunction and the 20-year cumulative incidence of early age-related macular degeneration: the beaver dam eye study[J]. JAMA Ophthalmol,2014,132:446- 455.

[17] Terasaki H, Kase S, Shirasawa M,etal. TNF-α decreases VEGF secretion in highly polarized RPE cells but increases it in non-polarized RPE cells related to crosstalk between JNK and NF-κB pathways[J]. PLoS One,2013,8:e69994.doi: 10.1371/journal.pone.0069994.

[18] Nagineni CN, Kommineni VK, William A,etal. Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration [J]. J Cell Physio,2012,227:116- 126.

[19] de Oliveira Dias JR, Rodrigues EB, Maia M,etal. Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy[J]. Br J Ophthalmol,2011,95:1631- 1637.

[20] Chizzolini M, Galan A, Milan E,etal. Good epidemiologic practice in retinitis pigmentosa: from phenotyping to biobanking [J]. Curr Genomics,2011,12:260- 266.

[21] Ozawa Y, Sasaki M, Takahashi N,etal. Neuroprotective effects of lutein in the retina[J]. Curr Pharm Des, 2012,18:51- 56.

[22] Kanan Y, Centola M, Bart F,etal. Analysis of genes differentially expressed during retinal degeneration in three mouse models [J]. Adv Exp Med Biol,2010,664:3- 13.

Role of TNF-α in retinal neural degeneration diseases

XIE Fen-gao1, SONG Qing-lei2, ZHANG Xi-zhou1*

(1.People’s Hospital of China Three Gorges University, Emergency Center, the First People’s Hospital of Yichang, 2.Dept. of Ophthalmology, School of Medicine, Three Gorges University, Yichang 443000, China)

Retinal neural degeneration diseases is one of the main causes of vision loss, TNF-α as an inflammatory cytokine with pleiotropic biological activity, after binding to its receptor by a variety of signaling pathways, may have play critical role in pathogenesis of retinal neural degeneration diseases including glaucoma, ischemic retinopathy, age-related macular degeneration and retinitis pigmentosa.

TNF-α; visual impairment; retinal neural degeneration diseases

2014- 05- 12

：2014- 07- 18

*通信作者(correspondingauthor)：41500474@qq.com

1001-6325(2015)02-0262-04

短篇綜述

R 774.1+3

：A