辅助T细胞17(Th17)与调节T细胞(Treg)在局灶性脑缺血损伤中作用及机制研究
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摘要
围术期脑缺血事件因其高死亡率(26%-60%)、高致残率越来越受到人们关注,尽管人们采取了多种救治方法,但效果仍不理想,究其原因是其发病机制未得到彻底阐明。但人们注意到:在局灶性脑缺血(focal cerebral ischemia,FCI)后一段时间里,脑损伤仍继续进行,并进一步加重,该损伤系缺血脑组织增强的局部炎性反应所致,故“炎性反应对缺血区脑组织的损伤要比缺血本身更严重”。提示:炎性反应状态的高低与脑组织神经功能损害程度关系密切,抑制“脑缺血后炎性反应”将成为脑缺血保护研究新的靶点。
近年发现,辅助T细胞17(Th17)与调节性T细胞(Treg)在机体多种炎性疾病发生、发展中扮演重要角色。因为,具有特异性表达转录因子RORγt的Th17细胞在自身免疫性疾病及过敏反应中发挥重要促炎作用,而Th17细胞的这些作用是通过其特异性释放细胞因子白介素17(IL-17)上调炎性因子“瀑布样释放”实现的。而特异性表达转录因子Foxp3的Treg细胞则通过直接接触或释放抗炎细胞因子(如IL-10和TGF-β1),维持免疫耐受,对抗炎性反应,同时,Treg细胞也可通过负性调控Thl7细胞的生成、功能及IL-17分泌发挥抗炎作用。因此,Th17与Treg细胞平衡状态在炎性免疫相关性疾病(自身免疫性疾病、中枢炎性疾病、器官移植等)的发展与预防中起着重要作用。
新近研究证实:Th17细胞在中枢神经系统炎性疾病中起着重要作用,如多发性硬化(MS)等,此外,还发现Th17细胞及IL-17与缺血性脑损伤关系密切。基于暂时性或永久性脑缺血时,脑组织损伤实质为“脑缺血后炎性反应导致的局部组织损伤”的事实,且机体炎性反应直接受免疫调控影响,故此,我们提出以下设想:
(1)脑缺血后可能存在Th17/ Treg细胞功能失衡,该失衡与脑缺血损伤同步、关联,此免疫调节失控进一步导致机体过度、过长的炎性反应的存在,致使脑损伤的进一步加重。
(2)通过对Th17、Treg细胞多层面免疫干预,维持Th17/ Treg细胞功能平衡,可能具有抑制缺血脑组织局部炎性反应状态及强度、减轻脑缺血后损伤的保护作用,并据此提出“脑缺血后免疫干预的脑保护预案”思路。
本研究系对上述第一步研究任务的完成,同时,也系2009年度国家自然科学基金面上项目资助项目(No.30872445)
目的:以昆明小鼠短暂性大脑中动脉栓塞模型(tMCAO)为基础,拟证实小鼠脑缺血后存在Th17/Treg细胞平衡关系破坏,此失衡状态与脑缺血后炎性损伤程度之间存在同步、相关关系,为进一步揭示脑缺血后炎性损伤机制,开拓缺血性脑损伤治疗的新领域提供思路。
方法:70只昆明小鼠随机分为模型组(n=60)和假手术组(sham,n=10),模型组又分为6h、12h、24h、48h、72h及5d六个亚组(n=10/亚组)。采用腔内线栓法建立小鼠tMCAO模型;通过检测脑梗死容积及神经功能缺陷评分(NDS)观察缺血后脑组织损伤程度;通过免疫荧光染色观察Th17细胞在脑组织中的侵润;并应用流式细胞分析、ELISA、Western blot分别检测Th17及Treg细胞比率、相关细胞因子及特异性转录因子RORγt和Foxp3蛋白的变化。
结果:脑缺血再灌注后,脑组织水肿加重,梗死容积增大,48h[(44.4±3.2)%]时达峰值,而后有所减小;神经功能学评分逐渐降低,神经功能逐渐恢复,5 d(2.2±0.45)较6 h(4.6±0.55)明显提高(P<0.05);流式细胞分析发现,Th17细胞百分率在缺血后开始逐渐增多,24h时达最大值[(0.70±0.10)%,p<0.05,vs sham and 5d],而5d[(0.30±0.10)%]时又恢复至正常水平。与脑损伤程度变化一致;Treg细胞表现出相反变化,缺血后细胞数量逐渐减少,24h[(0.9±0.29)%]时处于低谷,近乎消失,而后逐渐升高,在5d[(3.2±0.49)%,p<0.05]时恢复甚至超过正常水平;Th17及Treg相关细胞因子缺血后的变化趋势与Th17细胞及Treg细胞相一致,但脑及血清中IL-17A却表现出随缺血时间延长而逐渐增多的趋势,在5d时达最大值(脑,77.9±5.11 pg/ml;血清,29.44±3.06 pg/ml);Treg细胞特异性转录因子Foxp3与Treg细胞比率变化一致,而Th17细胞特异性转录因子RORγt却无明显变化;另外,通过免疫荧光染色我们观察到缺血坏死脑组织周边存在Th17细胞。
结论:脑缺血后小鼠体内确实存在着Th17/Treg细胞平衡关系破坏,Th17及Treg相关炎性细胞因子缺血后的变化趋势与Th17细胞及Treg细胞比率变化相一致,两者与缺血脑组织损伤程度具有明显相关关系,初步认为:脑缺血后Th17/Treg细胞功能状态失衡,系通过免疫调控失控,放大、加重脑缺血局部炎性反应程度,参与脑缺血损伤的发展过程,纠正和维持Th17/Treg细胞平衡关系有望成为治疗脑缺血损伤的新靶点。
Perioperative cerebral ischemia with high mortality rates(26%-60%)and high disability rates is paid more attention by people. Although several measures being taken, the therapeutic protective effect of cerebral ischemia (CI) was still less, mainly due to the pathogenesis of CI remains unclear. However, it was found that, after CI, the brain damage is deteriorated gradually and the local in-flammatory response is more obvious simultaneously, which playing a main important role in cerebral injury may be more worse than by cerebral ischemia its-self. How to inhibiting inflammatory response after CI has become a new target for study to protect ischemic cerebral injury.
Recently, help T 17 cell (Th17) and regulatory T cell (Treg) were found that they play important roles in process of several inflammatory diseases. Th17 cells expressing retinoic acid-related orphan receptorγt (RORγt) take a critical effect in the development of autoimmunity and allergic reactions by producing IL-17,that up-regulates rate of releasing inflammatory cytokines to injury cere- bral tissue.
Meanwhile, Treg cells expressing the forkhead/winged helix transcription factor (Foxp3) have anti-inflammatory properties and maintain tolerance against self components by contact-dependent suppression or releasing an-ti-inflammatory cytokines [such as interleukin (IL)-10 and transforming growth factor (TGF)-β1]. Therefore, the balance between Th17 and Treg cells play an important role in the treatment and prevention of inflammatory diseases (au-toimmune diseases, CNS’s inflammatory diseases, transplant organ rejection).
It was recently reported that Th17 cell get a great role in the formation and development of inflammatory disease in central nervous system (CNS), such as Multiple Sclerosis (MS). Otherwise, Th17 & IL-17 were demonstrated that there are co- relationships with cerebral ischemia. The transient or permanent cerebral ischemia, the corn of fact, would be“the injury of cerebral ischemia is led by inflammatory response after CI”.
Depending upon above fact ,We firstly present our hypothesized in the world that:
(1) There may be an imbalance of Treg/Th17 cells existing after CI, which appears and change with ischemic cerebral injury simultaneously, and this un-control of immunological regulation by imbalance of Treg/Th17 cells would amplify the degree of inflammatory response and delay its time course, which aggravate ischemic cerebral injury.
(2) Recovering the balance of Th17/Treg cells by immune interference at different levels for Th17 or IL-17 or Treg may inhibit inflammatory response after CI and reduce the extent of ischemic cerebral injury. The goal of our study would be approval a new immune interference thought to prevent ischemic ce-rebral injury.
Our research project was paid attention and supported by National Natural Science Foundation of China (NSFC, No.30872445). This report is our study for first part of the project.
Objective:On the model of transient middle cerebral artery occlusion (tMCAO) in mice, this study was determined to confirm an imbalance of Th17/Treg existing after transient cerebral ischemia in mice, and there is a rela-tionship between Th17/Treg imbalance and ischemic brain injury, which explore the inflammatory regulation mechanism following cerebral ischemia. That would present a new therapy method for stroke patient.
Methods:70 mice were randomly divided into experimental (n=60) and sham (n=10) groups. And former were divided into six subgroups by assessing time points after surgical manipulation: They were 6 h (n=10), 12 h (n=10), 24 h (n=10), 48h (n=10), 72h (n=10) and 5 days (n=10). The model of tMCAO was established by modified monofilament method;Neurologic deficit score (NDS) was performed at every time points after tMCAO, after then sacrificed mice and measured the volume of cerebral infarction by tetrazolium chloride staining (TTC);the infiltration of Th17 cells in brain was observed by immunofluores-cence;Th17/Treg functions including cell frequencies, related cytokine secretion and key transcription factors (RORγt or Foxp3) at different levels were inves-tigated by flow cytometric (FCM) analysis, enzyme-linked immunosorbent assay (ELISA) and Western blot.
Results:After cerebral ischemia, brain edema became worse and brain infarcted area enlarged gradually, and the peaks were at 48h[(44.4±3.2)%], and then the brain infarcted area slightly reduced; Neurological function improved gradually when being compared 5d (2.2±0.45, P<0.05) with 6h after CI, (4.6±0.55); FCM analysis indicated the tendency that the frequencies of Th17 cells began to increase gradually following cerebral ischemia, and appeared the maximum at 24h [(0.70±0.10) %, p<0.05, vs sham and 5d], and then it was re-turned to normal level. This tendency was consistent with that of cerebral ische-mia extent. The frequencies of Treg cells, in contrast, firstly began to reduce slowly, and arrived at the minimum level at 24h [(0.9±0.29) %], almost disap-pear, After 24h, the frequencies of Treg cells recovered step by step, At 5d ,it was near normal level or even exceeded in certain mice[(3.2±0.49) %,p<0.05]; Meanwhile, most cytokines related with Th17 and Treg cells were showed to the similar change tendency with frequencies of Th17 or Treg. But, surprisingly, IL-17A increased gradually from 6h to 5d in brain or blood serum, and arrived at the maximum at 5d (brain, 77.9±5.11pg/ml; blood serum, 29.44±3.06 pg/ml); The change tendency of Foxp3 that Treg special transcription factor was in ac-cordence with that of Treg cells frequencies, while there was no obvious change for Th17 special transcription factor RORγt; In addition, the infiltration of Th17 cells in ischemic brain hemisphere was observed by immunofluorescence, but not in contralateral hemisphere.
Conclusion:It is sure that Th17/Treg functional imbalance exists in mice after transient cerebral ischemia. The change tendency of associated cytokines is consistent with that of Th17 and Treg cells. Those change tendencies are closely associated with extent of cerebral injury. So we thought that Th17/Treg cells imbalance may play an important role in the progress of ischemic cerebral injury. Correcting and maintaining Th17/Treg function balance will become a new the-rapeutic target for ischemic cerebral injury.
近年发现,辅助T细胞17(Th17)与调节性T细胞(Treg)在机体多种炎性疾病发生、发展中扮演重要角色。因为,具有特异性表达转录因子RORγt的Th17细胞在自身免疫性疾病及过敏反应中发挥重要促炎作用,而Th17细胞的这些作用是通过其特异性释放细胞因子白介素17(IL-17)上调炎性因子“瀑布样释放”实现的。而特异性表达转录因子Foxp3的Treg细胞则通过直接接触或释放抗炎细胞因子(如IL-10和TGF-β1),维持免疫耐受,对抗炎性反应,同时,Treg细胞也可通过负性调控Thl7细胞的生成、功能及IL-17分泌发挥抗炎作用。因此,Th17与Treg细胞平衡状态在炎性免疫相关性疾病(自身免疫性疾病、中枢炎性疾病、器官移植等)的发展与预防中起着重要作用。
新近研究证实:Th17细胞在中枢神经系统炎性疾病中起着重要作用,如多发性硬化(MS)等,此外,还发现Th17细胞及IL-17与缺血性脑损伤关系密切。基于暂时性或永久性脑缺血时,脑组织损伤实质为“脑缺血后炎性反应导致的局部组织损伤”的事实,且机体炎性反应直接受免疫调控影响,故此,我们提出以下设想:
(1)脑缺血后可能存在Th17/ Treg细胞功能失衡,该失衡与脑缺血损伤同步、关联,此免疫调节失控进一步导致机体过度、过长的炎性反应的存在,致使脑损伤的进一步加重。
(2)通过对Th17、Treg细胞多层面免疫干预,维持Th17/ Treg细胞功能平衡,可能具有抑制缺血脑组织局部炎性反应状态及强度、减轻脑缺血后损伤的保护作用,并据此提出“脑缺血后免疫干预的脑保护预案”思路。
本研究系对上述第一步研究任务的完成,同时,也系2009年度国家自然科学基金面上项目资助项目(No.30872445)
目的:以昆明小鼠短暂性大脑中动脉栓塞模型(tMCAO)为基础,拟证实小鼠脑缺血后存在Th17/Treg细胞平衡关系破坏,此失衡状态与脑缺血后炎性损伤程度之间存在同步、相关关系,为进一步揭示脑缺血后炎性损伤机制,开拓缺血性脑损伤治疗的新领域提供思路。
方法:70只昆明小鼠随机分为模型组(n=60)和假手术组(sham,n=10),模型组又分为6h、12h、24h、48h、72h及5d六个亚组(n=10/亚组)。采用腔内线栓法建立小鼠tMCAO模型;通过检测脑梗死容积及神经功能缺陷评分(NDS)观察缺血后脑组织损伤程度;通过免疫荧光染色观察Th17细胞在脑组织中的侵润;并应用流式细胞分析、ELISA、Western blot分别检测Th17及Treg细胞比率、相关细胞因子及特异性转录因子RORγt和Foxp3蛋白的变化。
结果:脑缺血再灌注后,脑组织水肿加重,梗死容积增大,48h[(44.4±3.2)%]时达峰值,而后有所减小;神经功能学评分逐渐降低,神经功能逐渐恢复,5 d(2.2±0.45)较6 h(4.6±0.55)明显提高(P<0.05);流式细胞分析发现,Th17细胞百分率在缺血后开始逐渐增多,24h时达最大值[(0.70±0.10)%,p<0.05,vs sham and 5d],而5d[(0.30±0.10)%]时又恢复至正常水平。与脑损伤程度变化一致;Treg细胞表现出相反变化,缺血后细胞数量逐渐减少,24h[(0.9±0.29)%]时处于低谷,近乎消失,而后逐渐升高,在5d[(3.2±0.49)%,p<0.05]时恢复甚至超过正常水平;Th17及Treg相关细胞因子缺血后的变化趋势与Th17细胞及Treg细胞相一致,但脑及血清中IL-17A却表现出随缺血时间延长而逐渐增多的趋势,在5d时达最大值(脑,77.9±5.11 pg/ml;血清,29.44±3.06 pg/ml);Treg细胞特异性转录因子Foxp3与Treg细胞比率变化一致,而Th17细胞特异性转录因子RORγt却无明显变化;另外,通过免疫荧光染色我们观察到缺血坏死脑组织周边存在Th17细胞。
结论:脑缺血后小鼠体内确实存在着Th17/Treg细胞平衡关系破坏,Th17及Treg相关炎性细胞因子缺血后的变化趋势与Th17细胞及Treg细胞比率变化相一致,两者与缺血脑组织损伤程度具有明显相关关系,初步认为:脑缺血后Th17/Treg细胞功能状态失衡,系通过免疫调控失控,放大、加重脑缺血局部炎性反应程度,参与脑缺血损伤的发展过程,纠正和维持Th17/Treg细胞平衡关系有望成为治疗脑缺血损伤的新靶点。
Perioperative cerebral ischemia with high mortality rates(26%-60%)and high disability rates is paid more attention by people. Although several measures being taken, the therapeutic protective effect of cerebral ischemia (CI) was still less, mainly due to the pathogenesis of CI remains unclear. However, it was found that, after CI, the brain damage is deteriorated gradually and the local in-flammatory response is more obvious simultaneously, which playing a main important role in cerebral injury may be more worse than by cerebral ischemia its-self. How to inhibiting inflammatory response after CI has become a new target for study to protect ischemic cerebral injury.
Recently, help T 17 cell (Th17) and regulatory T cell (Treg) were found that they play important roles in process of several inflammatory diseases. Th17 cells expressing retinoic acid-related orphan receptorγt (RORγt) take a critical effect in the development of autoimmunity and allergic reactions by producing IL-17,that up-regulates rate of releasing inflammatory cytokines to injury cere- bral tissue.
Meanwhile, Treg cells expressing the forkhead/winged helix transcription factor (Foxp3) have anti-inflammatory properties and maintain tolerance against self components by contact-dependent suppression or releasing an-ti-inflammatory cytokines [such as interleukin (IL)-10 and transforming growth factor (TGF)-β1]. Therefore, the balance between Th17 and Treg cells play an important role in the treatment and prevention of inflammatory diseases (au-toimmune diseases, CNS’s inflammatory diseases, transplant organ rejection).
It was recently reported that Th17 cell get a great role in the formation and development of inflammatory disease in central nervous system (CNS), such as Multiple Sclerosis (MS). Otherwise, Th17 & IL-17 were demonstrated that there are co- relationships with cerebral ischemia. The transient or permanent cerebral ischemia, the corn of fact, would be“the injury of cerebral ischemia is led by inflammatory response after CI”.
Depending upon above fact ,We firstly present our hypothesized in the world that:
(1) There may be an imbalance of Treg/Th17 cells existing after CI, which appears and change with ischemic cerebral injury simultaneously, and this un-control of immunological regulation by imbalance of Treg/Th17 cells would amplify the degree of inflammatory response and delay its time course, which aggravate ischemic cerebral injury.
(2) Recovering the balance of Th17/Treg cells by immune interference at different levels for Th17 or IL-17 or Treg may inhibit inflammatory response after CI and reduce the extent of ischemic cerebral injury. The goal of our study would be approval a new immune interference thought to prevent ischemic ce-rebral injury.
Our research project was paid attention and supported by National Natural Science Foundation of China (NSFC, No.30872445). This report is our study for first part of the project.
Objective:On the model of transient middle cerebral artery occlusion (tMCAO) in mice, this study was determined to confirm an imbalance of Th17/Treg existing after transient cerebral ischemia in mice, and there is a rela-tionship between Th17/Treg imbalance and ischemic brain injury, which explore the inflammatory regulation mechanism following cerebral ischemia. That would present a new therapy method for stroke patient.
Methods:70 mice were randomly divided into experimental (n=60) and sham (n=10) groups. And former were divided into six subgroups by assessing time points after surgical manipulation: They were 6 h (n=10), 12 h (n=10), 24 h (n=10), 48h (n=10), 72h (n=10) and 5 days (n=10). The model of tMCAO was established by modified monofilament method;Neurologic deficit score (NDS) was performed at every time points after tMCAO, after then sacrificed mice and measured the volume of cerebral infarction by tetrazolium chloride staining (TTC);the infiltration of Th17 cells in brain was observed by immunofluores-cence;Th17/Treg functions including cell frequencies, related cytokine secretion and key transcription factors (RORγt or Foxp3) at different levels were inves-tigated by flow cytometric (FCM) analysis, enzyme-linked immunosorbent assay (ELISA) and Western blot.
Results:After cerebral ischemia, brain edema became worse and brain infarcted area enlarged gradually, and the peaks were at 48h[(44.4±3.2)%], and then the brain infarcted area slightly reduced; Neurological function improved gradually when being compared 5d (2.2±0.45, P<0.05) with 6h after CI, (4.6±0.55); FCM analysis indicated the tendency that the frequencies of Th17 cells began to increase gradually following cerebral ischemia, and appeared the maximum at 24h [(0.70±0.10) %, p<0.05, vs sham and 5d], and then it was re-turned to normal level. This tendency was consistent with that of cerebral ische-mia extent. The frequencies of Treg cells, in contrast, firstly began to reduce slowly, and arrived at the minimum level at 24h [(0.9±0.29) %], almost disap-pear, After 24h, the frequencies of Treg cells recovered step by step, At 5d ,it was near normal level or even exceeded in certain mice[(3.2±0.49) %,p<0.05]; Meanwhile, most cytokines related with Th17 and Treg cells were showed to the similar change tendency with frequencies of Th17 or Treg. But, surprisingly, IL-17A increased gradually from 6h to 5d in brain or blood serum, and arrived at the maximum at 5d (brain, 77.9±5.11pg/ml; blood serum, 29.44±3.06 pg/ml); The change tendency of Foxp3 that Treg special transcription factor was in ac-cordence with that of Treg cells frequencies, while there was no obvious change for Th17 special transcription factor RORγt; In addition, the infiltration of Th17 cells in ischemic brain hemisphere was observed by immunofluorescence, but not in contralateral hemisphere.
Conclusion:It is sure that Th17/Treg functional imbalance exists in mice after transient cerebral ischemia. The change tendency of associated cytokines is consistent with that of Th17 and Treg cells. Those change tendencies are closely associated with extent of cerebral injury. So we thought that Th17/Treg cells imbalance may play an important role in the progress of ischemic cerebral injury. Correcting and maintaining Th17/Treg function balance will become a new the-rapeutic target for ischemic cerebral injury.
引文
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