小胶质细胞的激活和抑制在大鼠视网膜光损伤模型中的作用研究
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摘要
第一部分:视网膜小胶质细胞在大鼠视网膜光损伤模型中的作用
选用成年雄性SD大鼠,予缝线开睑,1%阿托品扩瞳,经24h暗适应后,放入光照箱中接受24 h强度为2500Lux的宽谱蓝光照射。在光照后的3d、7d、14d应用光镜、TUNEL染色、透射电镜观察实验大鼠视网膜组织结构的改变及细胞凋亡情况;应用闪光ERG评价视网膜功能。结果显示:光照后视网膜光感受器的内外节破坏,外核层排列紊乱,核质固缩,核层逐渐变薄,14d时减少达60.09%;光照后1d,外核层出现大量TUNEL(+)细胞,进一步经透射电镜证实光感受器的死亡方式为凋亡;光照后14d,视网膜功能显著下降,OdB光照强度不能诱导出Photic-ERG波形;模型眼出现与视网膜色素变性相似的以凋亡为特征的光感受器变性。
在成功建立了大鼠视网膜光损伤模型后,我们又进一步研究了实验性视网膜光损伤模型中小胶质细胞的迁移、活化及其与光感受器凋亡的关系。光照后2h、6h、1d、3d、7d、14d,采用免疫荧光染色观察两组大鼠视网膜OX42(+)细胞(小胶质细胞)的形态改变、迁移活动,并对视网膜外层的TUNEL(+)细胞和OX42(+)细胞分别计数并绘制时间变化曲线,分析两者的关系,同时用ED1抗体寻找可能的血源性巨噬细胞;用透射电镜观察进入光感受器层的小胶质细胞的吞噬行为;用Real-time PCR和Western-blot法对光照后视网膜胶质源性致炎因子及神经毒性物质IL-1βmRNA及蛋白表达变化进行定量分析。
结果显示:光照后2h视网膜外核层即可见TUNEL(+)细胞,1d时达高峰,3d后逐渐减少;光照后6h视网膜外核层开始出现少量OX42(+)细胞,逐渐增多并于3d时达高峰,7d后渐消失,从时间变化曲线可见OX42(+)细胞的迁移高峰落后并紧随凋亡高峰;视网膜铺片中见OX42(+)细胞由呈小细胞体和细的分支突触的静息形态转变为肥大细胞体的激活形态;强光照射上调了视网膜IL-1βmRNA及蛋白的表达,其时间变化趋势同小胶质细胞的激活和迁移趋势基本一致;透射电镜显示进入外核层的小胶质细胞吞噬了光感受器的外节膜盘;光照后的晚期由于血视网膜屏障的破坏,极少量的血源性巨噬细胞向视网膜外层浸润。
本部分的研究发现视网膜光损伤模型中光感受器的凋亡诱导了小胶质细胞向外层的迁移、活化及吞噬行为的发生,并伴有胶质源性神经毒性物质IL-1β的上调,提示小胶质细胞在加速光感受器变性过程中发挥着重要的作用。
第二部分:纳洛酮对脂多糖诱导的视网膜小胶质细胞激活的影响
原代培养并分离纯化视网膜小胶质细胞,利用脂多糖(LPS)建立体外激活模型,分为接受不同浓度(-)-naloxone及其异构体(+)-naloxone预处理的实验组和对照组,采用OX42免疫荧光染色观察naloxone对LPS激活的视网膜小胶质细胞形态的影响;用酶联免疫吸附试验检测naloxone对LPS激活的小胶质细胞分泌IL-1β的影响;用MTT比色法观察naloxone对LPS激活的小胶质细胞增殖的影响。
实验结果显示:LPS活化的小胶质细胞呈典型的激活形态,表现为胞体显著增大,胞膜突起变粗、皱褶,OX42阳性染色明显增强,呈“水母状”,1μM的(-)-naloxone及其异构体(+)-naloxone预处理30min则显著抑制了LPS引起的此种形态学变化,表现为更接近于对照组的轻度激活形态;此外naloxone预处理能显著减少LPS引起的小胶质细胞释放IL-1β的增多,从量效曲线上看,naloxone对LPS引起的小胶质细胞释放IL-1β的抑制作用呈一定的剂量依赖性和时间依赖性,以1μM、12h效果最为明显,且异构体具有等效性;MTT比色法显示0.25μM～1.25μM naloxone对≤100ng/ml LPS处理的小胶质细胞的数量无明显影响。
本部分的研究发现naloxone能够有效抑制LPS活化的视网膜小胶质细胞的形态变化及IL-1β的产生;一定浓度下的naloxone对LPS活化的小胶质细胞的增殖无明显影响,提示功能抑制;naloxone及其异构体对抑制活化的小胶质细胞的形态变化及IL-1β的产生具有等效性,提示其抑制作用可能与阿片受体无关。
第三部分:纳洛酮对视网膜光损伤模型中光感受器变性的神经保护作用
SD大鼠接受2500Lux的宽谱蓝光照射24h制成光损伤模型。实验组大鼠于光照前2d接受不同剂量naloxone腹腔注射直至光照后2周,而对照组则接受等量的PBS腹腔注射。用组织学和视觉电生理的方法来评价naloxone对光照引起的光感受器变性的神经保护作用;用TUNEL染色观察naloxone对光照后光感受器凋亡的影响;用免疫荧光染色观察视网膜OX42(+)细胞(小胶质细胞)的迁移活动,用Western-blot来检测光照后视网膜IL-1β蛋白含量的变化。
结果显示PBS治疗组在光照后的14d,视网膜外核层显著变薄,而接受1mg/dnaloxone腹腔注射的实验组无论是上方或下方的视网膜其外核层厚度都得到了较好的保留,后极部尤其明显。Naloxone的神经保护作用显示了良好的剂量依赖性,其中又以1mg/day效果最为理想;而在相同的时间点,naloxone治疗组其ERG最大混合反应的a波、b波振幅较光照前自身基线水平的下降程度均较对照组低;免疫荧光染色显示naloxone处理组迁移入外核层的小胶质细胞数较对照组明显减少,而视网膜IL-1β蛋白水平在两组间的差异也与此吻合;TUNEL染色显示naloxone能够减少光照后3～7d光感受器的凋亡。
本部分的研究发现naloxone能够延缓强光照射引起的后期光感受器的变性过程,其机理可能在于抑制了视网膜小胶质细胞的活化。
Part One:The role of retinal microglia in rat photic-injury model
Sprague-Dawley rats accepted dark-adaptation for 24 h prior to blue light exposure of 24 h at 2.5 Klux.At 3d,7d and 14d after exposure to light,HE staining, TUNEL staining and transmission electron microscopy were used to observe the changes of retinal histology and apoptosis of photoreceptors.Dark-adapted flash ERG was used to evaluate the retinal funciton.The results showed that the inner and outer segment of photoreceptors were destroied,the outer nuclear layer(ONL) was disarranged and thinned with 60.09%reduction at 14d after exposure to light.There were a large amount of TUNEL(+) apoptotic cells in the ONL at 1d which was confirmed by transmission electron microscopy.Both a- and b-wave amplitude were significantly reduced 14d after light exposure.
After successfully established the rat photic-injury model,we further explore the migration,activation of retinal microglia and its relationship with photoreceptor apoptosis in our model.At 2h、6h、1d、3d、7d、14d after light exposure,OX42 immunostaining was used to label the migration and activation of microglia,ED1 antibody was used to label possible blood-borne macrophages.The number of TUNEL(+) and OX42(+) cells in the outer retina were counted and a Time-Num curve were established.Electron micrographic image was used to observe the phagocytization of microglia.Real-time PCR and Western-blot were used to evaluate the retinal IL-1βmRNA and protein level.
The results showed that TUNEL(+) cells were noted in the ONL as early as 2h, and their presence were noticeably increased to reach the peak at 1d but declined at 3d. In contrast,OX42(+) cells assumed a more ameboid configuration were seen in the ONL at 6h and their presence increased significantly at 1d and 3d,so as the retinal IL-1βmRNA and protein expression.Electron micrography showed that microglia migrating into the ONL phagocytized the ROS disc of photoreceptors.The possibility of invasion of circulating macrophages cannot be excluded because a few ED1(+) cells were observed in the superior region at 7d.
Hence the conclusions are that activation and migration of retinal microglia,as well as expression of microglia-derived toxic factor(IL-1β),coincides with photoreceptor apopotosis and migrated microglia phagocytized the ROS disc of photoreceptors,suggesting activated microglia play a major role in the further degeneration ofphotoreceptors after exposure to intense light.
Part Two:The effect of naloxone stereoisomers on LPS-activated retinal microglia
Primary cultured and purified retinal microglia were activated by LPS after pretreatment with diverse concentrations of(-)-naloxone and its isomer(+)-naloxone. OX42 immunostaining was used to observe the effect of naloxone on LPS-induced morphological changes of microglia;ELISA assay was used to evaluate the effect of naloxone on LPS-stimulated release of IL-1β;MTT assay was used to observe the proliferation of microglia.
The results showed that following treatment with LPS,the microglia became activated with a greatly enlarged cell body and the characteristic shapes of activation; naloxone significantly inhibited the LPS-induced morphological change as demonstrated by the return of the OX-42(+) cells to the morphology of untreated cells. In addition to preventing the activation of microglia,naloxone significantly inhibited the production and release of IL-1βand this inhibition was dose-and time-related as illustrated by the Dose-Effect curve with the 1μM、12h showed the best effect. Naloxone and its isomer were equally effective in inhibiting the LPS-induced activation of microglia.MTT results showed that 0.25μM～1.25μM naloxone had no influence on the proliferation of microglia treated by≤100ng/ml LPS.
Hence the conclusions are naloxone can functionally inhibit LPS-induced activation of retinal microglia and the release of IL-1β.Both naloxone stereoisomers were equally effective indicating that the possible mechanisim of action may be unrelated to the opioid system.
Part Three:Naloxone has neuroprotective effects against light-induced photoreceptor degeneration through inhibiting retinal microglial activation
SD rats were exposed to intense blue light for 24h.Daily intraperitoneal injection of naloxone or PBS as control was given 2 days before exposure to light and continued for 2 weeks.Apoptotic cells were detected by the TUNEL assay,and anti-OX42 antibody was used to label retinal microglia.Western-blot was applied to evaluate the retinal IL-1βprotein level.Retinal histology and ERG were also performed to evaluate the effects of naloxone on the light-induced photoreceptor degeneration.
Similar to the morphological findings in the untreated control animals,the thickness of the ONL was markedly reduced in the PBS-treated group at 14d after photic injury.In contrast,treatment with 1 mg/day of naloxone provided significant protection of photoreceptors against photic injury in both the superior and inferior quadrants of the retina,especially in the posterior area.The extent of restoration of ONL thickness by naloxone was dose-related,with the maximum effect seen in the 1 mg/day group.Naloxone-treated group showed significantly less loss of a- and b-wave amplitudes when compared with the PBS-treated group.Compared to the control,the number of microglia in the outer retina was significantly decreased in the naloxone-treated group at 3d,so as the retinal IL-1βprotein level.TUNEL assay showed that treatment with naloxone(1mg/day) showed significantly fewer TUNEL-positive cells at 3 and 7 days,but not at 1d post light exposure.
Hence the conclusions are that systemic infusion of naloxone significantly reduced the further photoreceptor cell apoptosis after initial direct light-induced damage possibly through inhibiting the activation of microglia.
选用成年雄性SD大鼠,予缝线开睑,1%阿托品扩瞳,经24h暗适应后,放入光照箱中接受24 h强度为2500Lux的宽谱蓝光照射。在光照后的3d、7d、14d应用光镜、TUNEL染色、透射电镜观察实验大鼠视网膜组织结构的改变及细胞凋亡情况;应用闪光ERG评价视网膜功能。结果显示:光照后视网膜光感受器的内外节破坏,外核层排列紊乱,核质固缩,核层逐渐变薄,14d时减少达60.09%;光照后1d,外核层出现大量TUNEL(+)细胞,进一步经透射电镜证实光感受器的死亡方式为凋亡;光照后14d,视网膜功能显著下降,OdB光照强度不能诱导出Photic-ERG波形;模型眼出现与视网膜色素变性相似的以凋亡为特征的光感受器变性。
在成功建立了大鼠视网膜光损伤模型后,我们又进一步研究了实验性视网膜光损伤模型中小胶质细胞的迁移、活化及其与光感受器凋亡的关系。光照后2h、6h、1d、3d、7d、14d,采用免疫荧光染色观察两组大鼠视网膜OX42(+)细胞(小胶质细胞)的形态改变、迁移活动,并对视网膜外层的TUNEL(+)细胞和OX42(+)细胞分别计数并绘制时间变化曲线,分析两者的关系,同时用ED1抗体寻找可能的血源性巨噬细胞;用透射电镜观察进入光感受器层的小胶质细胞的吞噬行为;用Real-time PCR和Western-blot法对光照后视网膜胶质源性致炎因子及神经毒性物质IL-1βmRNA及蛋白表达变化进行定量分析。
结果显示:光照后2h视网膜外核层即可见TUNEL(+)细胞,1d时达高峰,3d后逐渐减少;光照后6h视网膜外核层开始出现少量OX42(+)细胞,逐渐增多并于3d时达高峰,7d后渐消失,从时间变化曲线可见OX42(+)细胞的迁移高峰落后并紧随凋亡高峰;视网膜铺片中见OX42(+)细胞由呈小细胞体和细的分支突触的静息形态转变为肥大细胞体的激活形态;强光照射上调了视网膜IL-1βmRNA及蛋白的表达,其时间变化趋势同小胶质细胞的激活和迁移趋势基本一致;透射电镜显示进入外核层的小胶质细胞吞噬了光感受器的外节膜盘;光照后的晚期由于血视网膜屏障的破坏,极少量的血源性巨噬细胞向视网膜外层浸润。
本部分的研究发现视网膜光损伤模型中光感受器的凋亡诱导了小胶质细胞向外层的迁移、活化及吞噬行为的发生,并伴有胶质源性神经毒性物质IL-1β的上调,提示小胶质细胞在加速光感受器变性过程中发挥着重要的作用。
第二部分:纳洛酮对脂多糖诱导的视网膜小胶质细胞激活的影响
原代培养并分离纯化视网膜小胶质细胞,利用脂多糖(LPS)建立体外激活模型,分为接受不同浓度(-)-naloxone及其异构体(+)-naloxone预处理的实验组和对照组,采用OX42免疫荧光染色观察naloxone对LPS激活的视网膜小胶质细胞形态的影响;用酶联免疫吸附试验检测naloxone对LPS激活的小胶质细胞分泌IL-1β的影响;用MTT比色法观察naloxone对LPS激活的小胶质细胞增殖的影响。
实验结果显示:LPS活化的小胶质细胞呈典型的激活形态,表现为胞体显著增大,胞膜突起变粗、皱褶,OX42阳性染色明显增强,呈“水母状”,1μM的(-)-naloxone及其异构体(+)-naloxone预处理30min则显著抑制了LPS引起的此种形态学变化,表现为更接近于对照组的轻度激活形态;此外naloxone预处理能显著减少LPS引起的小胶质细胞释放IL-1β的增多,从量效曲线上看,naloxone对LPS引起的小胶质细胞释放IL-1β的抑制作用呈一定的剂量依赖性和时间依赖性,以1μM、12h效果最为明显,且异构体具有等效性;MTT比色法显示0.25μM～1.25μM naloxone对≤100ng/ml LPS处理的小胶质细胞的数量无明显影响。
本部分的研究发现naloxone能够有效抑制LPS活化的视网膜小胶质细胞的形态变化及IL-1β的产生;一定浓度下的naloxone对LPS活化的小胶质细胞的增殖无明显影响,提示功能抑制;naloxone及其异构体对抑制活化的小胶质细胞的形态变化及IL-1β的产生具有等效性,提示其抑制作用可能与阿片受体无关。
第三部分:纳洛酮对视网膜光损伤模型中光感受器变性的神经保护作用
SD大鼠接受2500Lux的宽谱蓝光照射24h制成光损伤模型。实验组大鼠于光照前2d接受不同剂量naloxone腹腔注射直至光照后2周,而对照组则接受等量的PBS腹腔注射。用组织学和视觉电生理的方法来评价naloxone对光照引起的光感受器变性的神经保护作用;用TUNEL染色观察naloxone对光照后光感受器凋亡的影响;用免疫荧光染色观察视网膜OX42(+)细胞(小胶质细胞)的迁移活动,用Western-blot来检测光照后视网膜IL-1β蛋白含量的变化。
结果显示PBS治疗组在光照后的14d,视网膜外核层显著变薄,而接受1mg/dnaloxone腹腔注射的实验组无论是上方或下方的视网膜其外核层厚度都得到了较好的保留,后极部尤其明显。Naloxone的神经保护作用显示了良好的剂量依赖性,其中又以1mg/day效果最为理想;而在相同的时间点,naloxone治疗组其ERG最大混合反应的a波、b波振幅较光照前自身基线水平的下降程度均较对照组低;免疫荧光染色显示naloxone处理组迁移入外核层的小胶质细胞数较对照组明显减少,而视网膜IL-1β蛋白水平在两组间的差异也与此吻合;TUNEL染色显示naloxone能够减少光照后3～7d光感受器的凋亡。
本部分的研究发现naloxone能够延缓强光照射引起的后期光感受器的变性过程,其机理可能在于抑制了视网膜小胶质细胞的活化。
Part One:The role of retinal microglia in rat photic-injury model
Sprague-Dawley rats accepted dark-adaptation for 24 h prior to blue light exposure of 24 h at 2.5 Klux.At 3d,7d and 14d after exposure to light,HE staining, TUNEL staining and transmission electron microscopy were used to observe the changes of retinal histology and apoptosis of photoreceptors.Dark-adapted flash ERG was used to evaluate the retinal funciton.The results showed that the inner and outer segment of photoreceptors were destroied,the outer nuclear layer(ONL) was disarranged and thinned with 60.09%reduction at 14d after exposure to light.There were a large amount of TUNEL(+) apoptotic cells in the ONL at 1d which was confirmed by transmission electron microscopy.Both a- and b-wave amplitude were significantly reduced 14d after light exposure.
After successfully established the rat photic-injury model,we further explore the migration,activation of retinal microglia and its relationship with photoreceptor apoptosis in our model.At 2h、6h、1d、3d、7d、14d after light exposure,OX42 immunostaining was used to label the migration and activation of microglia,ED1 antibody was used to label possible blood-borne macrophages.The number of TUNEL(+) and OX42(+) cells in the outer retina were counted and a Time-Num curve were established.Electron micrographic image was used to observe the phagocytization of microglia.Real-time PCR and Western-blot were used to evaluate the retinal IL-1βmRNA and protein level.
The results showed that TUNEL(+) cells were noted in the ONL as early as 2h, and their presence were noticeably increased to reach the peak at 1d but declined at 3d. In contrast,OX42(+) cells assumed a more ameboid configuration were seen in the ONL at 6h and their presence increased significantly at 1d and 3d,so as the retinal IL-1βmRNA and protein expression.Electron micrography showed that microglia migrating into the ONL phagocytized the ROS disc of photoreceptors.The possibility of invasion of circulating macrophages cannot be excluded because a few ED1(+) cells were observed in the superior region at 7d.
Hence the conclusions are that activation and migration of retinal microglia,as well as expression of microglia-derived toxic factor(IL-1β),coincides with photoreceptor apopotosis and migrated microglia phagocytized the ROS disc of photoreceptors,suggesting activated microglia play a major role in the further degeneration ofphotoreceptors after exposure to intense light.
Part Two:The effect of naloxone stereoisomers on LPS-activated retinal microglia
Primary cultured and purified retinal microglia were activated by LPS after pretreatment with diverse concentrations of(-)-naloxone and its isomer(+)-naloxone. OX42 immunostaining was used to observe the effect of naloxone on LPS-induced morphological changes of microglia;ELISA assay was used to evaluate the effect of naloxone on LPS-stimulated release of IL-1β;MTT assay was used to observe the proliferation of microglia.
The results showed that following treatment with LPS,the microglia became activated with a greatly enlarged cell body and the characteristic shapes of activation; naloxone significantly inhibited the LPS-induced morphological change as demonstrated by the return of the OX-42(+) cells to the morphology of untreated cells. In addition to preventing the activation of microglia,naloxone significantly inhibited the production and release of IL-1βand this inhibition was dose-and time-related as illustrated by the Dose-Effect curve with the 1μM、12h showed the best effect. Naloxone and its isomer were equally effective in inhibiting the LPS-induced activation of microglia.MTT results showed that 0.25μM～1.25μM naloxone had no influence on the proliferation of microglia treated by≤100ng/ml LPS.
Hence the conclusions are naloxone can functionally inhibit LPS-induced activation of retinal microglia and the release of IL-1β.Both naloxone stereoisomers were equally effective indicating that the possible mechanisim of action may be unrelated to the opioid system.
Part Three:Naloxone has neuroprotective effects against light-induced photoreceptor degeneration through inhibiting retinal microglial activation
SD rats were exposed to intense blue light for 24h.Daily intraperitoneal injection of naloxone or PBS as control was given 2 days before exposure to light and continued for 2 weeks.Apoptotic cells were detected by the TUNEL assay,and anti-OX42 antibody was used to label retinal microglia.Western-blot was applied to evaluate the retinal IL-1βprotein level.Retinal histology and ERG were also performed to evaluate the effects of naloxone on the light-induced photoreceptor degeneration.
Similar to the morphological findings in the untreated control animals,the thickness of the ONL was markedly reduced in the PBS-treated group at 14d after photic injury.In contrast,treatment with 1 mg/day of naloxone provided significant protection of photoreceptors against photic injury in both the superior and inferior quadrants of the retina,especially in the posterior area.The extent of restoration of ONL thickness by naloxone was dose-related,with the maximum effect seen in the 1 mg/day group.Naloxone-treated group showed significantly less loss of a- and b-wave amplitudes when compared with the PBS-treated group.Compared to the control,the number of microglia in the outer retina was significantly decreased in the naloxone-treated group at 3d,so as the retinal IL-1βprotein level.TUNEL assay showed that treatment with naloxone(1mg/day) showed significantly fewer TUNEL-positive cells at 3 and 7 days,but not at 1d post light exposure.
Hence the conclusions are that systemic infusion of naloxone significantly reduced the further photoreceptor cell apoptosis after initial direct light-induced damage possibly through inhibiting the activation of microglia.
引文
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[9]Stence N,Waite M,Dailey ME.Dynamics of microglial activation:a confocal time-lapse analysis in hippocampal slices.Glia[J].2001;33(3):256-266.
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[17]Mainster MA:Light and macular degeneration:a biophysical and clinical perspective.Eye[J].1987;1(Pt 2):304-310.
[18]Wenzel A,Grimm C,Samardzija M,et al.Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration.Progress in Retinal and Eye Research[J].2005;24:275-306.
[19]Wu J,Seregard S,Algvere PV.Photochemical Damage of the Retina.Surv Ophthalmol[J].2006;51(5):461-481.
[20]LaVail MM,Unoki K,Yasumura D,et al.Multiple growth factors,cytokines,and neurotrophins rescue photoreceptors from the damaging effects of constant light.Proc Natl Acad Sci U S A[J].1992;89(23):11249-11253.
[21]Noell WK,Walker VS,Kang KS,et al.Retinal damage by light in rats.IInvest Ophthalmol Vis Sci[J].1966;5:450-473.
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[23]王凤期,何守志,黄靖香,等.氩激光对培养的牛视网膜色素上皮细胞损伤的扫描电镜观察.眼科研究[J].2004;22:37-39.
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