小脑顶核调节免疫系统功能的中枢和外周途径
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摘要
目的：
我们实验室以前的研究表明小脑顶核可参与调节淋巴细胞功能。由于小脑与免疫系统之间没有直接的结构上的联系，因此探讨小脑调节免疫功能的途径和机制对于更好地理解小脑的免疫调节功能具有重要的意义。下丘脑是中枢神经系统中重要的免疫调节中枢。为此，本研究一方面进一步揭示小脑顶核至下丘脑的神经投射路径及性质；另一方面，在上述研究的基础上分别研究小脑顶核至下丘脑γ-氨基丁酸（γ-aminobutyric acid, GABA）能和谷氨酸能神经投射对淋巴细胞功能的影响，以探讨小脑顶核调节免疫功能的中枢和外周途径，进一步拓宽和加深对小脑神经免疫调节的认识和理解。
方法：
1.单侧小脑顶核内微量注射葡聚糖-德克萨斯红（Texas red dextran amine,TRDA），顺行追踪顶核至下丘脑的神经投射路径及终止部位。单侧下丘脑外侧区（lateral hypothalamic area, LHA）内微量注射逆行追踪剂红色荧光金（Fluoro-Ruby,FR），结合GABA和谷氨酸免疫荧光组织化学染色，进一步确定顶核至下丘脑投射的性质。
2.双侧小脑顶核内微量注射GABA降解酶—GABA转氨酶的抑制剂氨已烯酸（vigabatrin, VGB）或GABA合成酶—谷氨酸脱羧酶的抑制剂3-巯基丙酸（3-mercaptopropionic acid,3-MP），并以未作任何处理的空白大鼠和双侧小脑顶核注射等量生理盐水的大鼠作为对照。注射后第3天，用羧基荧光素琥珀酰亚胺酯（carboxyl fluorescein succinimidyl ester, CFSE）和抗CD3抗体流式双标技术检测T淋巴细胞对刀豆蛋白A（concanavalin A, Con A）刺激的增殖反应；用酶联免疫吸附法（enzyme-linked immunosorbent assay, ELISA）检测血清中抗绵羊红细胞（sheep redblood cells, SRBC）特异性IgM抗体水平；动物于第6天加强注射药物，3天后用CAM/EH-1流式双标技术检测脾脏自然杀伤（natural killer, NK）细胞杀伤肿瘤靶细胞YAC-1的活性。在检测淋巴细胞功能的同时，用FR逆行追踪结合GABA免疫组化染色检测顶核至LHA投射中GABA能神经元数目的变化，并用高效液相色谱法（highperformance liquid chromatography, HPLC）检测下丘脑中GABA的含量变化。
3.大鼠用小牛血清白蛋白（bovine serum albumin, BSA）进行免疫。免疫后第3天，双侧小脑顶核内微量注射谷氨酸合成酶—谷氨酰胺酶的抑制剂6-重氮-5-氧代-L-正亮氨酸（6-diazo-5-oxo-L-norleucine, DON），同时双侧LHA或丘脑腹外侧核（ventrolateral thalamic nuclei, VL）内微量注射谷氨酸膜转运体抑制剂苏式-3-羟基天冬氨酸（D,L-threo-β-hydroxyaspartic acid, THA）。动物饲养3天，用抗CD3，CD4，CD8，CD45RA和NKR-P1A抗体标记流式检测外周血中T细胞及其亚群，B细胞和NK细胞的百分比变化；用CD3/CD25和CD3/CFSE流式双标技术分别检测肠系膜淋巴结T细胞对Con A刺激的活化和增殖能力；用real-time PCR法检测淋巴结T细胞中细胞因子IL-2，IFN-γ，IL-4，IL-5，IL-10，TGF-β，IL-22，IL-17mRNA的表达及用ELISA法检测细胞培养上清中细胞因子IL-2，IFN-γ，IL-4，IL-10，TGF-β，IL-22，IL-17的水平。此外，大鼠B细胞抗BSA IgM和IgG抗体生成能力及脾脏NK细胞的杀伤活性也分别用ELISA法及流式细胞术进行检测。在检测上述淋巴细胞功能的同时，同样用FR逆行追踪结合谷氨酸免疫组化染色检测顶核至LHA投射中谷氨酸能神经元数目的变化，以及用HPLC法检测下丘脑及丘脑组织中谷氨酸含量的变化。
4.注射DON及THA后第3天，用ELISA法检测血清中促肾上腺皮质激素（adrenocorticotropic hormone, ACTH），皮质醇（cortisol），促甲状腺激素（thyroidstimulating hormone, TSH），三碘甲状腺原氨酸（triiodothyronine, T3）及甲状腺素（thyroxin, T4）的水平，用HPLC法进行检测外周免疫器官脾脏及淋巴结中去甲肾上腺素（norepinephrine, NE）的含量变化。
结果：
1.顶核神经元发出的TRDA阳性纤维，在小脑上脚中走行，至小脑上脚交叉处交叉至对侧，并进入下丘脑，主要终止于LHA。在LHA注射逆行追踪剂FR，标记的阳性纤维逆行穿行于小脑上脚交叉，并可到达小脑顶核。结合免疫荧光组织化学染色发现顶核投射到LHA的神经元既有GABA能又有谷氨酸能。
2.双侧顶核注射VGB导致肠系膜淋巴结T细胞对Con A诱导的增殖反应，血清中抗SRBC IgM抗体水平及脾脏NK细胞杀伤肿瘤YAC-1靶细胞的杀伤活性均低于空白组及顶核注射生理盐水的对照组。而双侧顶核注射3-MP，可导致相反的变化。与此同时，顶核注射VGB可显著增加顶核至LHA投射中GABA能神经元的数目和下丘脑中GABA的含量，而顶核注射3-MP，顶核至LHA投射中GABA能神经元的数目和下丘脑中GABA的含量均降低。
3.双侧顶核注射DON后，外周血中CD3+T细胞，CD3+CD4+T细胞数目及CD4/CD8比值均低于空白组和顶核注射生理盐水的对照组，而CD3+CD8+T细胞数目没有显著变化；肠系膜淋巴结T细胞的活化和增殖能力降低；淋巴结T细胞致炎细胞因子IL-2，IFN-γ，IL-17，IL-22的mRNA表达及在细胞培养上清中的含量均显著低于空白组和生理盐水对照组，而抗炎细胞因子IL-4，IL-10，IL-5，TGF-β的mRNA表达和培养上清中IL-4，IL-10，TGF-β的含量没有显著变化。另外，外周血中B细胞数目及血清中抗BSA IgM和IgG水平也明显下降。外周血中NK细胞数目及脾脏NK细胞杀伤活性也明显降低。与此同时，顶核注射DON后，顶核至LHA投射中谷氨酸能神经元的数量及下丘脑中谷氨酸的含量也降低。顶核注射DON联合LHA注射THA可使上述外周血中CD3+及CD3+CD4+T细胞数目和CD4/CD8比值，淋巴结T细胞的活化和增殖，致炎细胞因子的mRNA表达和细胞培养上清中的含量都显著高于单独顶核注射DON组。此外，外周血中B细胞数目及血清中抗BSA抗体水平，外周血中NK细胞数目及脾脏NK细胞杀伤活性也均高于单纯顶核注射DON组。同时下丘脑中谷氨酸的含量也比单纯顶核注射DON组有所升高。顶核至VL也有直接的谷氨酸能神经投射，而顶核注射DON的同时VL注射THA，虽然丘脑中谷氨酸的含量较单纯顶核注射DON有所升高，但上述T，B，NK细胞的数目和功能降低没有显著改变。
4.双侧顶核注射DON可导致脾脏和淋巴结中NE含量高于空白组和生理盐水对照组，联合LHA注射THA后脾脏和淋巴结中NE含量较单纯注射DON组有所降低。动物注射DON及THA，血清中ACTH，皮质醇，TSH，T3及T4的水平没有显著变化。
结论：
1.小脑顶核发出直接的神经纤维投射至下丘脑，主要终止于LHA；这些神经投射中有GABA能和谷氨酸能纤维。
2.小脑顶核的GABA能神经元调节T、B和NK细胞的功能，此调节作用由顶核至下丘脑的GABA能神经投射所介导。
3.小脑顶核的谷氨酸能神经元调节T、B和NK细胞的数目和功能，这种调节作用由顶核投射至下丘脑而不是投射至丘脑的谷氨酸能神经所介导。
4.交感神经而非肾上腺皮质和甲状腺激素途径介导小脑顶核—下丘脑谷氨酸能神经投射的免疫调节作用。
5.综合上述结果，提示顶核GABA能/谷氨酸能神经元→下丘脑→交感神经→淋巴细胞途径参与介导了小脑顶核对免疫系统功能的调节。
Objectives:
Our previous work has shown that the cerebellar fastigial nucleus (FN) participates inthe modulation of lymphocyte functions. Since there are no direct connections in structurebetween the cerebellum and the immune system, it appears especially important to explorethe potential pathways and mechanisms underlying the cerebellar immunomodulation. Thehypothalamus is an important immunoregulatory center in the central nervous system.Herein, we on the one hand further revealed the pathways and properties of the FNprojections to the hypothalamus and on the other hand investigated the effects of FNγ-aminobutyric acid (GABA)-ergic and glutamatergic projections to the hypothalamus onlymphocyte functions so as to explore the central and peripheral pathways involved in thecerebellar FN immunomodulation and obtain more comprehension and knowledge oncerebellar functions.
Methods:
1. Texas red dextran amine (TRDA), an anterograde tracer, was injected into unilateralcerebellar FN to trace the traveling courses and ending locations of the neuronalprojections from the cerebellar FN to the hypothalamus. Further, retrograde tracing byinjection of Fluoro-Ruby (FR) into unilateral lateral hypothalamic area (LHA) combinedwith GABA or glutamate fluorescence immunohistochemistry were performed to identifythe properties of FN neurons projecting to the hypothalamus.
2. Vigabatrin (VGB), an inhibitor of GABA-transaminase (GABA-T) that degradesGABA, or3-mercaptopropionic acid (3-MP), an antagonist of glutamic acid decarboxylase (GAD) that synthesizes GABA, was microinjected into bilateral cerebellar FN. Rats withintact or saline-infused FN were used as controls. On the third day after the injections,carboxyl fluorescein succinimidyl ester (CFSE) and anti-CD3antibody double-labelingflow cytometry was used to detect concanavalin A (Con A)-induced T lymphocyteproliferation. Enzyme-linked immunosorbent assay (ELISA）was employed to measureanti-sheep red blood cell (SRBC) IgM antibody level in the serum. On day three followingthe second injection of VGB or3-MP, NK cell cytotoxicity to YAC-1target cells wasevaluated by means of CAM/EH-1double-labeling flow cytometry. Simultaneously, thenumber of GABA-immunoreactive neurons in FN-LHA projections and GABA content inthe hypothalamus were measured by FR retrograde tracing combined with GABAfluorescence immunohistochemistry and high performance liquid chromatography (HPLC),respectively.
3. Rats were immunized with bovine serum albumin (BSA). On the third day after theimmunization,6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase forglutamate synthesis, was microinjected in bilateral FN and D,L-threo-β-hydroxyasparticacid (THA), an inhibitor of glutamate transporters on plasma membrane, wasmicroinjected in both sides of LHA or ventrolateral thalamic nuclei (VL). On day threeafter the injections, flow cytometric assay with anti-CD3, CD4, CD8, CD45RA andNKR-P1A antibody labeling was employed to examine the percentage of T lymphocytesand its subsets, B lymphocytes and NK cells in the peripheral blood. CD3/CD25andCD3/CFSE double-labeling flow cytometry were used to detect Con A-induced Tlymphocyte activation and proliferation, respectively. Real-time PCR was used to measuremRNA expressions of IL-2, IFN-γ, IL-4, IL-5, IL-10, TGF-β, IL-22and IL-17in Tlymphocytes of the mesenteric lymph nodes and ELISA was used to detect theconcentration of IL-2, IFN-γ, IL-4, IL-10, TGF-β, IL-22and IL-17in the cell culturesupernatant. In addition, levels of anti-BSA IgM and IgG antibodies in the serum andsplenic NK cell cytotoxicity were measured by ELISA and flow cytometry, respectively.Similarily, when the lymphocyte functions were assayed, the number of glutamate-immunoreactive neurons in FN–LHA projections and glutamate content in thehypothalamus and thalamus were measured by FR retrograde tracing combined withglutamate fluorescence immunohistochemistry and HPLC, respectively.
4. On the third day after treatment with DON and THA, the levels ofadrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH),triiodothyronine (T3) and thyroxin (T4) in the serum and norepinephrine (NE) content inthe spleen and lymph nodes were detected by ELISA and HPLC, respectively.
Results:
1. TRDA-labeled fibers from the FN traveled through the superior cerebellar peduncle(SCP), crossed in decussation of SCP (XSCP), entered the hypothalamus, and primarilyterminated in the LHA. By injecting FR in the LHA, the FR-stained fibers retrogradelypassed through the XSCP and reached the FN. Combined with fluorescenceimmunohistochemistry, we observed that among these FR-positive neurons in the FN,there were GABA and glutamate immunoreactive cells.
2. After VGB injection into the bilateral FN, the Con A-induced T lymphocyteproliferation, the level of anti-SRBC IgM antibody in the serum and the NK cellcytotoxicity to YAC-1cells were all decreased in comparison with control rats with intactor saline-infused FN. However,3-MP injection in the bilateral FN resulted in the contrarychanges. Meanwhile, VGB treatment notably raised but3-MP remarkably reduced thenumber of GABAergic neurons in the FN-LHA projections and GABA content in thehypothalamus.
3. After DON injection into bilateral FN, the number of CD3+and CD3+CD4+Tlymphocytes as well as CD4/CD8ratio in the peripheral blood were all less than those ofthe intact and saline-treated control rats, but the number of CD3+CD8+T lymphocytes hadno significant change. The Con A-induced T lymphocyte activation and proliferationdecreased following DON treatment in comparison with the two control rats. The mRNAexpressions of proinflammatory cytokines of IL-2, IFN-γ, IL-17, IL-22in T lymphocytesand their concentration in the cell culture supernatant were all significantly reduced following DON treatment when compared with the intact and saline-infused rats, while themRNA expressions of IL-4, IL-10, IL-5, TGF-β and concentration of IL-4, IL-10, TGF-βin the cell culture supernatant had no remarkable change. In addition, DON treatment inthe FN notably attenuated B lymphocyte number in the peripheral blood and anti-BSA IgMand IgG levels in the serum. Injection of DON in the bilateral FN also diminished thenumber of NK cells in the peripheral blood and NK cell cytotoxicity in the spleen.Simultaneously, the number of glutamatergic neurons in the FN-LHA projections andglutamate content in the hypothalamus were also reduced after DON treatment in the FN.Combined treatment with DON in the FN and with THA in the LHA resulted in theenhancement in the number of CD3+, CD3+CD4+T lymphocytes and CD4/CD8ratio inthe peripheral blood, T lymphocyte activation and proliferation, and mRNA expressionsand concentration in the supernatant of proinflammatory cytokines when compared withDON injection alone. In addition, B lymphocyte number in peripheral blood and levels ofanti-BSA antibodies in the serum as well as the NK cell number in peripheral blood andNK cytotoxicity in the spleen were also raised relative to DON treatment alone. Combinedtreatment with DON and THA increased glutamate content in the hypothalamus incomparison with DON injection alone. There were direct glutamatergic projections fromthe FN to the VL. However, co-treatment with DON in the FN and with THA in the VL didnot significantly alter DON-dependent changes in the number and functions of T, B andNK cells, although the co-treatment altered DON-dependent glutamate content in thethalamus.
4. DON injection into bilateral FN increased NE content in the spleen and lymphnodes relative to the intact and saline-treated rats, co-treatment with DON in the FN andTHA in the LHA reduced the NE content compared with DON treatment alone. Afterinjection with DON and THA, the levels of ACTH, cortisol, TSH, T3and T4in the serumdid not significantly alter.
Conclusions:
1. There are direct GABAergic and glutamatergic projections from the cerebellar FNto the LHA.
2. The cerebellar FN GABAergic neurons regulate the functions of T, B and NK cells,this effect is mediated by the GABAergic neuronal projections from the cerebellar FN tothe hypothalamus.
3. The cerebellar FN glutamatergic neurons modulate the number and functions of T,B and NK cells, this effect is mediated by the FN glutamatergic projections to thehypothalamus, but not the thalamus.
4. The sympathetic nerve but not the adrenal cortical hormone or thyroid hormonepathways mediate the immunomodulatory effect of the cerebellar FN glutamatergicprojections to the hypothalamus.
5. In conclusion, the central and peripheral pathways involved in mediating thecerebellar FN immunomodulation may be the FN GABAergic and glutamatergicneurons—hypothalamus—sympathetic nerves—lymphocytes.
我们实验室以前的研究表明小脑顶核可参与调节淋巴细胞功能。由于小脑与免疫系统之间没有直接的结构上的联系，因此探讨小脑调节免疫功能的途径和机制对于更好地理解小脑的免疫调节功能具有重要的意义。下丘脑是中枢神经系统中重要的免疫调节中枢。为此，本研究一方面进一步揭示小脑顶核至下丘脑的神经投射路径及性质；另一方面，在上述研究的基础上分别研究小脑顶核至下丘脑γ-氨基丁酸（γ-aminobutyric acid, GABA）能和谷氨酸能神经投射对淋巴细胞功能的影响，以探讨小脑顶核调节免疫功能的中枢和外周途径，进一步拓宽和加深对小脑神经免疫调节的认识和理解。
方法：
1.单侧小脑顶核内微量注射葡聚糖-德克萨斯红（Texas red dextran amine,TRDA），顺行追踪顶核至下丘脑的神经投射路径及终止部位。单侧下丘脑外侧区（lateral hypothalamic area, LHA）内微量注射逆行追踪剂红色荧光金（Fluoro-Ruby,FR），结合GABA和谷氨酸免疫荧光组织化学染色，进一步确定顶核至下丘脑投射的性质。
2.双侧小脑顶核内微量注射GABA降解酶—GABA转氨酶的抑制剂氨已烯酸（vigabatrin, VGB）或GABA合成酶—谷氨酸脱羧酶的抑制剂3-巯基丙酸（3-mercaptopropionic acid,3-MP），并以未作任何处理的空白大鼠和双侧小脑顶核注射等量生理盐水的大鼠作为对照。注射后第3天，用羧基荧光素琥珀酰亚胺酯（carboxyl fluorescein succinimidyl ester, CFSE）和抗CD3抗体流式双标技术检测T淋巴细胞对刀豆蛋白A（concanavalin A, Con A）刺激的增殖反应；用酶联免疫吸附法（enzyme-linked immunosorbent assay, ELISA）检测血清中抗绵羊红细胞（sheep redblood cells, SRBC）特异性IgM抗体水平；动物于第6天加强注射药物，3天后用CAM/EH-1流式双标技术检测脾脏自然杀伤（natural killer, NK）细胞杀伤肿瘤靶细胞YAC-1的活性。在检测淋巴细胞功能的同时，用FR逆行追踪结合GABA免疫组化染色检测顶核至LHA投射中GABA能神经元数目的变化，并用高效液相色谱法（highperformance liquid chromatography, HPLC）检测下丘脑中GABA的含量变化。
3.大鼠用小牛血清白蛋白（bovine serum albumin, BSA）进行免疫。免疫后第3天，双侧小脑顶核内微量注射谷氨酸合成酶—谷氨酰胺酶的抑制剂6-重氮-5-氧代-L-正亮氨酸（6-diazo-5-oxo-L-norleucine, DON），同时双侧LHA或丘脑腹外侧核（ventrolateral thalamic nuclei, VL）内微量注射谷氨酸膜转运体抑制剂苏式-3-羟基天冬氨酸（D,L-threo-β-hydroxyaspartic acid, THA）。动物饲养3天，用抗CD3，CD4，CD8，CD45RA和NKR-P1A抗体标记流式检测外周血中T细胞及其亚群，B细胞和NK细胞的百分比变化；用CD3/CD25和CD3/CFSE流式双标技术分别检测肠系膜淋巴结T细胞对Con A刺激的活化和增殖能力；用real-time PCR法检测淋巴结T细胞中细胞因子IL-2，IFN-γ，IL-4，IL-5，IL-10，TGF-β，IL-22，IL-17mRNA的表达及用ELISA法检测细胞培养上清中细胞因子IL-2，IFN-γ，IL-4，IL-10，TGF-β，IL-22，IL-17的水平。此外，大鼠B细胞抗BSA IgM和IgG抗体生成能力及脾脏NK细胞的杀伤活性也分别用ELISA法及流式细胞术进行检测。在检测上述淋巴细胞功能的同时，同样用FR逆行追踪结合谷氨酸免疫组化染色检测顶核至LHA投射中谷氨酸能神经元数目的变化，以及用HPLC法检测下丘脑及丘脑组织中谷氨酸含量的变化。
4.注射DON及THA后第3天，用ELISA法检测血清中促肾上腺皮质激素（adrenocorticotropic hormone, ACTH），皮质醇（cortisol），促甲状腺激素（thyroidstimulating hormone, TSH），三碘甲状腺原氨酸（triiodothyronine, T3）及甲状腺素（thyroxin, T4）的水平，用HPLC法进行检测外周免疫器官脾脏及淋巴结中去甲肾上腺素（norepinephrine, NE）的含量变化。
结果：
1.顶核神经元发出的TRDA阳性纤维，在小脑上脚中走行，至小脑上脚交叉处交叉至对侧，并进入下丘脑，主要终止于LHA。在LHA注射逆行追踪剂FR，标记的阳性纤维逆行穿行于小脑上脚交叉，并可到达小脑顶核。结合免疫荧光组织化学染色发现顶核投射到LHA的神经元既有GABA能又有谷氨酸能。
2.双侧顶核注射VGB导致肠系膜淋巴结T细胞对Con A诱导的增殖反应，血清中抗SRBC IgM抗体水平及脾脏NK细胞杀伤肿瘤YAC-1靶细胞的杀伤活性均低于空白组及顶核注射生理盐水的对照组。而双侧顶核注射3-MP，可导致相反的变化。与此同时，顶核注射VGB可显著增加顶核至LHA投射中GABA能神经元的数目和下丘脑中GABA的含量，而顶核注射3-MP，顶核至LHA投射中GABA能神经元的数目和下丘脑中GABA的含量均降低。
3.双侧顶核注射DON后，外周血中CD3+T细胞，CD3+CD4+T细胞数目及CD4/CD8比值均低于空白组和顶核注射生理盐水的对照组，而CD3+CD8+T细胞数目没有显著变化；肠系膜淋巴结T细胞的活化和增殖能力降低；淋巴结T细胞致炎细胞因子IL-2，IFN-γ，IL-17，IL-22的mRNA表达及在细胞培养上清中的含量均显著低于空白组和生理盐水对照组，而抗炎细胞因子IL-4，IL-10，IL-5，TGF-β的mRNA表达和培养上清中IL-4，IL-10，TGF-β的含量没有显著变化。另外，外周血中B细胞数目及血清中抗BSA IgM和IgG水平也明显下降。外周血中NK细胞数目及脾脏NK细胞杀伤活性也明显降低。与此同时，顶核注射DON后，顶核至LHA投射中谷氨酸能神经元的数量及下丘脑中谷氨酸的含量也降低。顶核注射DON联合LHA注射THA可使上述外周血中CD3+及CD3+CD4+T细胞数目和CD4/CD8比值，淋巴结T细胞的活化和增殖，致炎细胞因子的mRNA表达和细胞培养上清中的含量都显著高于单独顶核注射DON组。此外，外周血中B细胞数目及血清中抗BSA抗体水平，外周血中NK细胞数目及脾脏NK细胞杀伤活性也均高于单纯顶核注射DON组。同时下丘脑中谷氨酸的含量也比单纯顶核注射DON组有所升高。顶核至VL也有直接的谷氨酸能神经投射，而顶核注射DON的同时VL注射THA，虽然丘脑中谷氨酸的含量较单纯顶核注射DON有所升高，但上述T，B，NK细胞的数目和功能降低没有显著改变。
4.双侧顶核注射DON可导致脾脏和淋巴结中NE含量高于空白组和生理盐水对照组，联合LHA注射THA后脾脏和淋巴结中NE含量较单纯注射DON组有所降低。动物注射DON及THA，血清中ACTH，皮质醇，TSH，T3及T4的水平没有显著变化。
结论：
1.小脑顶核发出直接的神经纤维投射至下丘脑，主要终止于LHA；这些神经投射中有GABA能和谷氨酸能纤维。
2.小脑顶核的GABA能神经元调节T、B和NK细胞的功能，此调节作用由顶核至下丘脑的GABA能神经投射所介导。
3.小脑顶核的谷氨酸能神经元调节T、B和NK细胞的数目和功能，这种调节作用由顶核投射至下丘脑而不是投射至丘脑的谷氨酸能神经所介导。
4.交感神经而非肾上腺皮质和甲状腺激素途径介导小脑顶核—下丘脑谷氨酸能神经投射的免疫调节作用。
5.综合上述结果，提示顶核GABA能/谷氨酸能神经元→下丘脑→交感神经→淋巴细胞途径参与介导了小脑顶核对免疫系统功能的调节。
Objectives:
Our previous work has shown that the cerebellar fastigial nucleus (FN) participates inthe modulation of lymphocyte functions. Since there are no direct connections in structurebetween the cerebellum and the immune system, it appears especially important to explorethe potential pathways and mechanisms underlying the cerebellar immunomodulation. Thehypothalamus is an important immunoregulatory center in the central nervous system.Herein, we on the one hand further revealed the pathways and properties of the FNprojections to the hypothalamus and on the other hand investigated the effects of FNγ-aminobutyric acid (GABA)-ergic and glutamatergic projections to the hypothalamus onlymphocyte functions so as to explore the central and peripheral pathways involved in thecerebellar FN immunomodulation and obtain more comprehension and knowledge oncerebellar functions.
Methods:
1. Texas red dextran amine (TRDA), an anterograde tracer, was injected into unilateralcerebellar FN to trace the traveling courses and ending locations of the neuronalprojections from the cerebellar FN to the hypothalamus. Further, retrograde tracing byinjection of Fluoro-Ruby (FR) into unilateral lateral hypothalamic area (LHA) combinedwith GABA or glutamate fluorescence immunohistochemistry were performed to identifythe properties of FN neurons projecting to the hypothalamus.
2. Vigabatrin (VGB), an inhibitor of GABA-transaminase (GABA-T) that degradesGABA, or3-mercaptopropionic acid (3-MP), an antagonist of glutamic acid decarboxylase (GAD) that synthesizes GABA, was microinjected into bilateral cerebellar FN. Rats withintact or saline-infused FN were used as controls. On the third day after the injections,carboxyl fluorescein succinimidyl ester (CFSE) and anti-CD3antibody double-labelingflow cytometry was used to detect concanavalin A (Con A)-induced T lymphocyteproliferation. Enzyme-linked immunosorbent assay (ELISA）was employed to measureanti-sheep red blood cell (SRBC) IgM antibody level in the serum. On day three followingthe second injection of VGB or3-MP, NK cell cytotoxicity to YAC-1target cells wasevaluated by means of CAM/EH-1double-labeling flow cytometry. Simultaneously, thenumber of GABA-immunoreactive neurons in FN-LHA projections and GABA content inthe hypothalamus were measured by FR retrograde tracing combined with GABAfluorescence immunohistochemistry and high performance liquid chromatography (HPLC),respectively.
3. Rats were immunized with bovine serum albumin (BSA). On the third day after theimmunization,6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase forglutamate synthesis, was microinjected in bilateral FN and D,L-threo-β-hydroxyasparticacid (THA), an inhibitor of glutamate transporters on plasma membrane, wasmicroinjected in both sides of LHA or ventrolateral thalamic nuclei (VL). On day threeafter the injections, flow cytometric assay with anti-CD3, CD4, CD8, CD45RA andNKR-P1A antibody labeling was employed to examine the percentage of T lymphocytesand its subsets, B lymphocytes and NK cells in the peripheral blood. CD3/CD25andCD3/CFSE double-labeling flow cytometry were used to detect Con A-induced Tlymphocyte activation and proliferation, respectively. Real-time PCR was used to measuremRNA expressions of IL-2, IFN-γ, IL-4, IL-5, IL-10, TGF-β, IL-22and IL-17in Tlymphocytes of the mesenteric lymph nodes and ELISA was used to detect theconcentration of IL-2, IFN-γ, IL-4, IL-10, TGF-β, IL-22and IL-17in the cell culturesupernatant. In addition, levels of anti-BSA IgM and IgG antibodies in the serum andsplenic NK cell cytotoxicity were measured by ELISA and flow cytometry, respectively.Similarily, when the lymphocyte functions were assayed, the number of glutamate-immunoreactive neurons in FN–LHA projections and glutamate content in thehypothalamus and thalamus were measured by FR retrograde tracing combined withglutamate fluorescence immunohistochemistry and HPLC, respectively.
4. On the third day after treatment with DON and THA, the levels ofadrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH),triiodothyronine (T3) and thyroxin (T4) in the serum and norepinephrine (NE) content inthe spleen and lymph nodes were detected by ELISA and HPLC, respectively.
Results:
1. TRDA-labeled fibers from the FN traveled through the superior cerebellar peduncle(SCP), crossed in decussation of SCP (XSCP), entered the hypothalamus, and primarilyterminated in the LHA. By injecting FR in the LHA, the FR-stained fibers retrogradelypassed through the XSCP and reached the FN. Combined with fluorescenceimmunohistochemistry, we observed that among these FR-positive neurons in the FN,there were GABA and glutamate immunoreactive cells.
2. After VGB injection into the bilateral FN, the Con A-induced T lymphocyteproliferation, the level of anti-SRBC IgM antibody in the serum and the NK cellcytotoxicity to YAC-1cells were all decreased in comparison with control rats with intactor saline-infused FN. However,3-MP injection in the bilateral FN resulted in the contrarychanges. Meanwhile, VGB treatment notably raised but3-MP remarkably reduced thenumber of GABAergic neurons in the FN-LHA projections and GABA content in thehypothalamus.
3. After DON injection into bilateral FN, the number of CD3+and CD3+CD4+Tlymphocytes as well as CD4/CD8ratio in the peripheral blood were all less than those ofthe intact and saline-treated control rats, but the number of CD3+CD8+T lymphocytes hadno significant change. The Con A-induced T lymphocyte activation and proliferationdecreased following DON treatment in comparison with the two control rats. The mRNAexpressions of proinflammatory cytokines of IL-2, IFN-γ, IL-17, IL-22in T lymphocytesand their concentration in the cell culture supernatant were all significantly reduced following DON treatment when compared with the intact and saline-infused rats, while themRNA expressions of IL-4, IL-10, IL-5, TGF-β and concentration of IL-4, IL-10, TGF-βin the cell culture supernatant had no remarkable change. In addition, DON treatment inthe FN notably attenuated B lymphocyte number in the peripheral blood and anti-BSA IgMand IgG levels in the serum. Injection of DON in the bilateral FN also diminished thenumber of NK cells in the peripheral blood and NK cell cytotoxicity in the spleen.Simultaneously, the number of glutamatergic neurons in the FN-LHA projections andglutamate content in the hypothalamus were also reduced after DON treatment in the FN.Combined treatment with DON in the FN and with THA in the LHA resulted in theenhancement in the number of CD3+, CD3+CD4+T lymphocytes and CD4/CD8ratio inthe peripheral blood, T lymphocyte activation and proliferation, and mRNA expressionsand concentration in the supernatant of proinflammatory cytokines when compared withDON injection alone. In addition, B lymphocyte number in peripheral blood and levels ofanti-BSA antibodies in the serum as well as the NK cell number in peripheral blood andNK cytotoxicity in the spleen were also raised relative to DON treatment alone. Combinedtreatment with DON and THA increased glutamate content in the hypothalamus incomparison with DON injection alone. There were direct glutamatergic projections fromthe FN to the VL. However, co-treatment with DON in the FN and with THA in the VL didnot significantly alter DON-dependent changes in the number and functions of T, B andNK cells, although the co-treatment altered DON-dependent glutamate content in thethalamus.
4. DON injection into bilateral FN increased NE content in the spleen and lymphnodes relative to the intact and saline-treated rats, co-treatment with DON in the FN andTHA in the LHA reduced the NE content compared with DON treatment alone. Afterinjection with DON and THA, the levels of ACTH, cortisol, TSH, T3and T4in the serumdid not significantly alter.
Conclusions:
1. There are direct GABAergic and glutamatergic projections from the cerebellar FNto the LHA.
2. The cerebellar FN GABAergic neurons regulate the functions of T, B and NK cells,this effect is mediated by the GABAergic neuronal projections from the cerebellar FN tothe hypothalamus.
3. The cerebellar FN glutamatergic neurons modulate the number and functions of T,B and NK cells, this effect is mediated by the FN glutamatergic projections to thehypothalamus, but not the thalamus.
4. The sympathetic nerve but not the adrenal cortical hormone or thyroid hormonepathways mediate the immunomodulatory effect of the cerebellar FN glutamatergicprojections to the hypothalamus.
5. In conclusion, the central and peripheral pathways involved in mediating thecerebellar FN immunomodulation may be the FN GABAergic and glutamatergicneurons—hypothalamus—sympathetic nerves—lymphocytes.
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