人参皂甙对小胶质细胞功能影响的研究
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摘要
本研究目的在于探讨中药人参皂甙(Ginseng Saponin,GS)对人小胶质细胞功能的调节作用,为把GS发展为中枢神经系统退行性病变、缺血和损伤治疗药物奠定基础。为此,我们进行了六个方面的研究:人小胶质细胞的分离、培养和鉴定;GS对小胶质细胞活化的调节作用;GS对小胶质细胞吞噬作用的影响;GS对小胶质细胞一氧化氮合成的调节作用;GS对小胶质细胞反应氧族生成的调节作用;GS对溶血磷脂所引发的钙离子内流的影响。
首先,我们从人工药物流产的胎儿脑组织分离并纯化小胶质细胞,并通过形态学和免疫荧光方法进行鉴定,纯度达到98%以上,并以此为细胞模型,进行下其他部分的研究。
由于小胶质细胞在执行其功能之前,必须由静息状态转变为活化状态。活化的小胶质细胞既能产生具有神经保护功能的因子,又能分泌具有神经毒性的分子,其形态学表现为胞膜边缘波动(membrane ruffling)。研究发现:ATP和GS均能引发小胶质细胞的活化。
小胶质细胞是中枢神经系统(central nerve system,CNS)主要的固有免疫细胞,吞噬作用是其重要功能。我们研究了GS对小胶质细胞吞噬作用的影响,结果发现:GS能够明显地促进小胶质细胞吞噬荧光微球。
一氧化氮(nitric oxide,NO)是小胶质细胞执行功能的又一效应分子,同时,NO还参与了小胶质细胞过度活化所造成的神经元的损害。为此,我们研究了GS对小胶质细胞NO生成的影响,结果发现:GS能够促进小胶质细胞基础水平上的NO合成,而一定的程度上能够抑制由LPS所引发的NO的合成。
反应氧族(Reactive oxygen species,ROS)的生理功能和毒性决定于其细胞內水平。低水平的ROS是小胶质细胞执行生理功能的效应分子;中等水平的ROS能够活化各种激酶和转录因子,如JNK、p38、NF-κB和API等;高水平的ROS可以引发小胶质细胞和神经元的凋亡乃至坏死。为此,我们研究了GS对小胶质细胞ROS产生的影响。结果发现:GS能够抑制ROS的生成。
生物活性的溶血磷脂(bioactive lysophosphlipids)是一组天然产生的脂质,它们能够调节细胞各种功能,包括增殖、创伤愈合等。其中的溶血磷脂胆碱(lysophosphatidylcholine,LPC)是一种免疫细胞的调节剂,又与炎症的发生密切相关,为此,我们研究了GS对LPC所引发的小胶质细胞Ca~(2+)內流的影响。结果发现:一定剂量的LPC可以使小胶质细胞产生瞬时的,其后,出现对钙离子导入剂的无反应性;而预先加入GS孵育后,再加入LPC,大多数的小胶质细胞出现了持续的、而不是瞬间的Ca~(2+)内流,而且这些细胞保留了对钙离子导入剂的反应性。
综上所述,人参皂甙在一定的剂量范围内,能增强小胶质细胞的吞噬作用;促进静止的小胶质细胞活化;促进或抑制小胶质细胞NO的合成;抑制小胶质细胞的反应氧族(ROS)的生成;保护小胶质细胞由溶血磷脂引起的细胞无反应性等作用。从而为把人参皂甙开发成为预防和治疗神经退行性病变的药物奠定基础。
The aims of this study is to investigate the modulating effects of Chinese medicine herb Ginseng water-soluble extracts(GS) on human microglial functionns and to develop GMSE to become an uesful therapeutic medicine of central nerve system(CNS) neurodegenerative disease,injury and ischemia.Therefore,our study is divided into six parts:isolation, culturation and identification of human microglia from fetal brain tissues;modulation of GS on activation of microglial cells;influence of GS on phagocytosis of microglia;regulation of GS on NO synthesis of microglia;modulation of GS on production of ROS in microglia;impact of GS on lysophosphlipids-induced calcium influx in microglia.
First,we isolated and purified human microglial cells from artificial abortive fetal brain tissue.After purification,we used morphological and immuno-fluorescence methods to identify the purity of microglia we got.We found that more than 98%of cells were microglia. On this condition,we made researches on the following parts.
When microglial cells exert functions,they must alter their state from resting to activated. The activated microglia can elaborate both neurotrophic and neurotoxic factors,while its morphological change is membrane ruffling.So our results showed:both ATP and GS could make microglia activated.
As the main innate immue cells in CNS,microglia has many important functions,like phagocytosis.Therefore,we tried to find out the effects of GS on microglial phagocytosis.GS obviously enhanced microglia engulfing fluorescent spheres.
NO is another functional molecule that microglia produces.Meanwhile,if too much NO synthesized by over-activated microglia,it can cause neurotoxin.In the thesis,we performed experiments to evaluate the impacts of GS on NO production by microglia.Our results showed:GS could increase NO basic-level synthesis;however,it could suppress NO production stimulated by LPS to some extent.
The physiological or toxic effects of ROS is depended on its intracellular level.Low-level ROS is a basic element that microglia needs to function normally;midi-level can activate multiple kinases and factors,such as JNK,p38 NF-κB and API,and so on;high-level may induce apoptosis or necrosis of microglia and neurons.So we examined the influence of GS on ROS production by microglia.We found that GS inhibited ROS synthesis.
Bioactive lysophophlipids are a group of natural lipids,they can modulate several cellular function,like proliferation and injury-healing.Lysophophatidycholine(LPC),which is the representative member of lysophophlipids,is an important modulator of immune cells.It also correlates tightly with inflammation.We explored the effects of GS on LPC-induced Ca~(2+) influx of microglia.As the results showed,LPC stimulated Ca~(2+) influx instantaneously,but later on,microglia had no response to calcium ionophore.When microglias were pre-incubated with GS,and then added LPC into supernatant,persistent but not instantaneous Ca~(2+) influx occurred;furthermore,those cells still responded to calcium ionophore efficiently.
In summary,at a series of definitive concentrations,GS enhanced microglial phagocytosis;GS stimulated microglial activation;GS promoted or suppressed NO synthesis depending on microglial states;GS prevented ROS production by over-activated microglia; GS protected microglia from anergy to calcium ionophore caused by LPC.Consequently,GS could be developed to be a useful medicine used to prevent and therapy neurodegenerative diseases.
首先,我们从人工药物流产的胎儿脑组织分离并纯化小胶质细胞,并通过形态学和免疫荧光方法进行鉴定,纯度达到98%以上,并以此为细胞模型,进行下其他部分的研究。
由于小胶质细胞在执行其功能之前,必须由静息状态转变为活化状态。活化的小胶质细胞既能产生具有神经保护功能的因子,又能分泌具有神经毒性的分子,其形态学表现为胞膜边缘波动(membrane ruffling)。研究发现:ATP和GS均能引发小胶质细胞的活化。
小胶质细胞是中枢神经系统(central nerve system,CNS)主要的固有免疫细胞,吞噬作用是其重要功能。我们研究了GS对小胶质细胞吞噬作用的影响,结果发现:GS能够明显地促进小胶质细胞吞噬荧光微球。
一氧化氮(nitric oxide,NO)是小胶质细胞执行功能的又一效应分子,同时,NO还参与了小胶质细胞过度活化所造成的神经元的损害。为此,我们研究了GS对小胶质细胞NO生成的影响,结果发现:GS能够促进小胶质细胞基础水平上的NO合成,而一定的程度上能够抑制由LPS所引发的NO的合成。
反应氧族(Reactive oxygen species,ROS)的生理功能和毒性决定于其细胞內水平。低水平的ROS是小胶质细胞执行生理功能的效应分子;中等水平的ROS能够活化各种激酶和转录因子,如JNK、p38、NF-κB和API等;高水平的ROS可以引发小胶质细胞和神经元的凋亡乃至坏死。为此,我们研究了GS对小胶质细胞ROS产生的影响。结果发现:GS能够抑制ROS的生成。
生物活性的溶血磷脂(bioactive lysophosphlipids)是一组天然产生的脂质,它们能够调节细胞各种功能,包括增殖、创伤愈合等。其中的溶血磷脂胆碱(lysophosphatidylcholine,LPC)是一种免疫细胞的调节剂,又与炎症的发生密切相关,为此,我们研究了GS对LPC所引发的小胶质细胞Ca~(2+)內流的影响。结果发现:一定剂量的LPC可以使小胶质细胞产生瞬时的,其后,出现对钙离子导入剂的无反应性;而预先加入GS孵育后,再加入LPC,大多数的小胶质细胞出现了持续的、而不是瞬间的Ca~(2+)内流,而且这些细胞保留了对钙离子导入剂的反应性。
综上所述,人参皂甙在一定的剂量范围内,能增强小胶质细胞的吞噬作用;促进静止的小胶质细胞活化;促进或抑制小胶质细胞NO的合成;抑制小胶质细胞的反应氧族(ROS)的生成;保护小胶质细胞由溶血磷脂引起的细胞无反应性等作用。从而为把人参皂甙开发成为预防和治疗神经退行性病变的药物奠定基础。
The aims of this study is to investigate the modulating effects of Chinese medicine herb Ginseng water-soluble extracts(GS) on human microglial functionns and to develop GMSE to become an uesful therapeutic medicine of central nerve system(CNS) neurodegenerative disease,injury and ischemia.Therefore,our study is divided into six parts:isolation, culturation and identification of human microglia from fetal brain tissues;modulation of GS on activation of microglial cells;influence of GS on phagocytosis of microglia;regulation of GS on NO synthesis of microglia;modulation of GS on production of ROS in microglia;impact of GS on lysophosphlipids-induced calcium influx in microglia.
First,we isolated and purified human microglial cells from artificial abortive fetal brain tissue.After purification,we used morphological and immuno-fluorescence methods to identify the purity of microglia we got.We found that more than 98%of cells were microglia. On this condition,we made researches on the following parts.
When microglial cells exert functions,they must alter their state from resting to activated. The activated microglia can elaborate both neurotrophic and neurotoxic factors,while its morphological change is membrane ruffling.So our results showed:both ATP and GS could make microglia activated.
As the main innate immue cells in CNS,microglia has many important functions,like phagocytosis.Therefore,we tried to find out the effects of GS on microglial phagocytosis.GS obviously enhanced microglia engulfing fluorescent spheres.
NO is another functional molecule that microglia produces.Meanwhile,if too much NO synthesized by over-activated microglia,it can cause neurotoxin.In the thesis,we performed experiments to evaluate the impacts of GS on NO production by microglia.Our results showed:GS could increase NO basic-level synthesis;however,it could suppress NO production stimulated by LPS to some extent.
The physiological or toxic effects of ROS is depended on its intracellular level.Low-level ROS is a basic element that microglia needs to function normally;midi-level can activate multiple kinases and factors,such as JNK,p38 NF-κB and API,and so on;high-level may induce apoptosis or necrosis of microglia and neurons.So we examined the influence of GS on ROS production by microglia.We found that GS inhibited ROS synthesis.
Bioactive lysophophlipids are a group of natural lipids,they can modulate several cellular function,like proliferation and injury-healing.Lysophophatidycholine(LPC),which is the representative member of lysophophlipids,is an important modulator of immune cells.It also correlates tightly with inflammation.We explored the effects of GS on LPC-induced Ca~(2+) influx of microglia.As the results showed,LPC stimulated Ca~(2+) influx instantaneously,but later on,microglia had no response to calcium ionophore.When microglias were pre-incubated with GS,and then added LPC into supernatant,persistent but not instantaneous Ca~(2+) influx occurred;furthermore,those cells still responded to calcium ionophore efficiently.
In summary,at a series of definitive concentrations,GS enhanced microglial phagocytosis;GS stimulated microglial activation;GS promoted or suppressed NO synthesis depending on microglial states;GS prevented ROS production by over-activated microglia; GS protected microglia from anergy to calcium ionophore caused by LPC.Consequently,GS could be developed to be a useful medicine used to prevent and therapy neurodegenerative diseases.
引文
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[1]Gehrmann J.Microglia:a sensor to threats in the nervous system[J]? Res Virol.1996,147(2-3):79-88.
[2]Dheen ST,Kaur C,Ling EA.Microglial activation and its implications in the brain diseases [J].Curt Med Chem.2007,14(11):1189-97.
[3]Minghetti L,Ajmone-Cat MA,De Berardinis MA,et al.Microglial activation in chronic neurodegenerative diseases:roles of apoptotic neurons and chronic stimulation[J].Brain Res Brain Res Rev. 2005, 48(2):251-6.
[4] Kim YS, Kim SS, Cho JJ, et al. Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia [J]. J Neurosci. 2005,25(14):3701-11.
[5] Kim YJ, Hwang SY, Oh ES, et al. IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways [J]. J Neurosci Res. 2006, 84(5): 1037-46.
[6] Lee DY, Oh YJ, Jin BK. Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways [J]. Glia. 2005,51(2):98-110.
[7] Saud K, Herrera-Molina R, Von Bernhardi R. Pro- and anti-inflammatory cytokines regulate the ERK pathway: implication of the timing for the activation of microglial cells [J]. Neurotox Res. 2005, 8(3-4):277-87.
[8] Garden GA, Moller T. Microglia Biology in Health and Disease [J]. J NeuroImmu Pha, 2006,1(2): 127-37.
[9] Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms [J]. Nat Rev Neurosci. 2007, 8(1):57-69.
[10] Town T, Nikolic V, Tan J. The microglial "activation" continuum: from innate to adaptive responses [J]. J Neuroinflammation. 2005, 2:24.
[11] Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases [J]. Curr Med Chem. 2007,14(11):1189-97.
[12] Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson's disease [J]. J Neural Transm Suppl. 2006, (70):373-81.
[13] Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease [J]. Exp Mol Med. 2006, 38(4):333-47.
[1] De Simone R, Ajmone-Cat MA, Tirassa P, et al. Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells [J]. J Neuropathol Exp Neurol. 2003, 62(2):208-16.
[2] Chan A, Magnus T, Gold R. Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system [J]. Glia. 2001, 33(1):87-95.
[3] Magnus T, Chan A, Linker RA, et al. Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system [J]. J Neuropathol Exp Neurol. 2002,61(9):760-6.
[4] Magnus T, Chan A, Grauer O, et al. Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation [J]. J Immunol. 2001, 167(9):5004-10.
[5] Chan A, Seguin R, Magnus T, et al. Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: termination of CNS autoimmune inflammation and modulation by interferon-beta [J]. Glia. 2003, 43(3):231-42.
[6] Chan A, Hummel V, Weilbach FX, et al. Phagocytosis of apoptotic inflammatory cells downregulates microglial chemoattractive function and migration of encephalitogenic T cells [J]. J Neurosci Res. 2006, 84(6): 1217-24.
[7] Garden GA, Moller T. Microglia Biology in Health and Disease [J]. J NeuroImmu Pha, 2006,1(2): 127-37.
[8] Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms [J]. Nat Rev Neurosci. 2007, 8(1):57-69.
[9] El Khoury J, Toft M, Hickman SE, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease [J]. Nat Med. 2007,13(4):432-8.
[10] Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis [J]. Nat Neurosci. 2006, 9(12):1512-9.
[11] Jack CS, Arbour N, Manusow J, Montgrain V, et al. TLR signaling tailors innate immune responses in human microglia and astrocytes [J]. J Immunol. 2005, 175(7):4320-30.
[12] Honda S, Sasaki Y, Ohsawa K, et al. Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors [J]. J Neurosci. 2001, 21(6):1975-82.
[13]Ohsawa K,Irino Y,Nakamura Y,et al.Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis[J].Glia.2007,55(6):604-16.
[14]Lauber K,Blumenthal SG,Waibel M,et al.Clearance of apoptotic cells:getting dd of the corpses[J].Mol Cell.2004,14(3):277-87.
[15]Ponomarev ED,Shdver LP,Dittel BN.CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation[J].J Immunol.2006,1;176(3):1402-10.
[16]Magnus T,Schreiner B,Korn T,et al.Microglial expression of the B7 family member B7homolog 1 confers strong immune inhibition:implications for immune responses and autoimmunity in the CNS[J].J Neurosci.2005,25(10):2537-46.
[17]D'Aversa TG,Eugenin EA,Berman JW.CD40-CD40 ligand interactions in human microglia induce CXCL8(intedeukin-8) secretion by a mechanism dependent on activation of ERK1/2and nuclear translocation of nuclear factor-kappaB(NFkappaB) and activator protein-1(AP-1)[J].J Neurosci Res.2007,Oct 5.
[1]Hanisch UK,Kettenmann H.Microglia:active sensor and versatile effector cells in the normal and pathologic brain[J].Nat Neurosci.2007,10(11):1387-1394.
[2]Garden GA,Moller T.Microglia Biology in Health and Disease[J].J Neurolmmu Pha,2006,1(2):127-37.
[3]Block ML,Zecca L,Hong JS.Microglia-mediated neurotoxicity:uncovering the molecular mechanisms[J].Nat Rev Neurosci.2007,8(1):57-69.
[4]Block ML,Hong JS.Microglia and inflammation-mediated neurodegeneration:multiple triggers with a common mechanism[J].Prog Neurobiol.2005,76(2):77-98.
[5]Gonzalez-Scarano F,Martin-Garcia J.The neuropathogenesis of AIDS[J].Nat Rev Immunol.2005,5(1):69-81.
[6]Klegeris A,McGeer EG,McGeer PL.Therapeutic approaches to inflammation in neurodegenerative disease[J].Curt Opin Neurol.2007,20(3):351-7.
[7]Wersinger C,Sidhu A.An inflammatory pathomechanism for Parkinson's disease[J]? Curr Med Chem.2006,13(5):591-602.
[8]Muller N,Schwarz MJ.The immune-mediated alteration of serotonin and glutamate:towards an integrated view of depression[J].Mol Psychiatry.2007,12(11):988-1000.
[9]Roulston CL,Lawrence AJ,Widdop RE,et al.Minocycline treatment attenuates microglia activation and non-angiotensin Ⅱ[125I]CGP42112 binding in brainstem following nodose ganglionectomy[J].Neuroscience.2005,135(4):1241-53.
[10]Glass JD,Wesselingh SL.Microglia in HIV-associated neurological diseases[J].Microsc Res Tech.2001,54(2):95-105.
[11]Gartner S,Liu Y.Insights into the role of immune activation in HIV neuropathogenesis[J].J Neurovirol.2002,8(2):69-75.
[12]Garden GA,Budd SL,Tsai E,et al.Caspase cascades in human immunodeficiency virus-associated neurodegeneration[J].J Neurosci.2002,22(10):4015-24.
[13]Nardacci R,Antinori A,Kroemer G,et al.Cell death mechanisms in HIV-associated dementia:the involvement of syncytia[J].Cell Death Differ.2005,12 Suppl 1:855-8.
[ 14] Ghafouri M, Amini S, Khalili K, et al. HIV-1 associated dementia: symptoms and causes [J]. Retrovirology. 2006,19;3:28.
[15] Li JL, Bentsman G, Potash MJ, et al. Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection [J]. BMC Neuroscience. 2007, 8:31.
[16] Trujillo JR, Rogers R, Molina RM, et al. Noninfectious entry of HIV-1 into peripheral and brain macrophages mediated by the mannose receptor [J]. Proc Natl Acad Sci U S A. 2007, 104(12):5097-102.
[ 17] Sui Z, Sniderhan LF, Schifitto G, et al. Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia [J]. J Immunol. 2007, 178(5):3226-36.
[18] Persidsky Y, Poluektova L. Immune privilege and HIV-1 persistence in the CNS [J]. Immunol Rev. 2006, 213:180-94.
[1]Ledeboer A,Breve JJ,Poole S,et al.Intedeukin-10,interleukin-4,and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells[J].Glia.2000,30(2):134-42.
[2]Garden GA,Moller T.Microglia Biology in Health and Disease[J].J Neurolmmu Pha,2006,1(2):127-37.
[3]Block ML,Zecca L,Hong JS.Microglia-mediated neurotoxicity:uncovering the molecular mechanisms[J].Nat Rev Neurosci.2007,8(1):57-69.
[4]Gonzalez-Scarano F,Martin-Garcia J.The neuropathogenesis of AIDS[J].Nat Rev Immunol.2005,5(1):69-81.
[5]Muller N,Schwarz MJ.The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression [J]. Mol Psychiatry. 2007,12(11):988-1000.
[6] Frank MG, Baratta MV, Sprunger DB, et al. Stress primes microglia to the presence of systemic inflammation: Implications for environmental influences on the brain [J]. Brain, Behavior, and Immunity. 2007, 21(1):45-6.
[7] Glass JD, Wesselingh SL. Microglia in HIV-associated neurological diseases [J]. Microsc Res Tech. 2001,54(2):95-105.
[8] Gartner S, Liu Y. Insights into the role of immune activation in HIV neuropathogenesis [J]. J Neurovirol. 2002,8(2):69-75.
[9] Garden GA, Budd SL, Tsai E, et al. Caspase cascades in human immunodeficiency virus-associated neurodegeneration [J]. J Neurosci. 2002,22(10):4015-24.
[10] Nardacci R, Antinori A, Kroemer G, et al. Cell death mechanisms in HIV-associated dementia: the involvement of syncytia [J]. Cell Death Differ. 2005,12 Suppl 1:855-8.
[ 11 ] Ghafouri M, Amini S, Khalili K, et al. HIV-1 associated dementia: symptoms and causes [J]. Retrovirology. 2006,19;3:28.
[12] Trujillo JR, Rogers R, Molina RM, et al. Noninfectious entry of HIV-1 into peripheral and brain macrophages mediated by the mannose receptor [J]. Proc Natl Acad Sci U S A. 2007, 104(12):5097-102.
[13] Sui Z, Sniderhan LF, Schifitto G, et al. Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia [J]. J Immunol. 2007, 178(5):3226-36.
[14] Persidsky Y, Poluektova L. Immune privilege and HIV-1 persistence in the CNS [J]. Immunol Rev. 2006, 213:180-94.
[1]Hanisch UK,Kettenmann H.Microglia:active sensor and versatile effector cells in the normal and pathologic brain[J].Nat Neurosci.2007,10(11):1387-1394.
[2]Garden GA,Moller T.Microglia Biology in Health and Disease[J].J NeuroImmu Pha,2006,1(2):127-37.
[3]Block ML,Zecca L,Hong JS.Microglia-mediated neurotoxicity:uncovering the molecular mechanisms[J].Nat Rev Neurosci.2007,8(1):57-69.
[4]Kettenmann H.Triggering the brain's pathology sensor[J].Nat Neurosci.2006,9(12):1463-4.
[5]Streit WJ.Microglial senescence:does the brain's immune system have an expiration date [J]? Trends Neurosci.2006,29(9):506-10.
[6]Becher B,Durell BG,Miga AV,et al.The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system[J].J Exp Med.2001,193(8):967-74.
[7]Erdmann N,Zhao J,Lopez AL,et al.Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase[J].J Neurochem.2007,102(2):539-49.
[8]Takenouchi T,Sato M,Kitani H,et al.Lysophosphatidylcholine potentiates Ca2+ influx,pore formation and p44/42 MAP kinase phosphorylation mediated by P2X7 receptor activation in mouse microglial cells[J].J Neurochem.2007,102(5):1518-32.
[2] Garden GA, Moller T. Microglia Biology in Health and Disease [J]. J Neurolmmu Pha, 2006, l(2):127-37
[3] Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms [J]. Nat Rev Neurosci. 2007, 8(1):57-69.
[4] Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism [J]. Prog Neurobiol. 2005, 76(2):77-98.
[5] Cardona AE, Huang D, Sasse ME, et al. Isolation of murine microglial cells for RNA analysis or flow cytometry [J]. Nat Protoc. 2006,1(4):1947-51.
[6] Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS [J]. Nat Rev Immunol. 2005,5(1):69-81.
[7] Kettenmann H. Triggering the brain's pathology sensor [J]. Nat Neurosci. 2006, 9(12): 1463-4.
[8] Persidsky Y, Poluektova L. Immune privilege and HIV-1 persistence in the CNS [J]. Immunol Rev. 2006, 213:180-94.
[9] Chan A, Hummel V, Weilbach FX, et al. Phagocytosis of apoptotic inflammatory cells downregulates microglial chemoattractive function and migration of encephalitogenic T cells [J]. J Neurosci Res. 2006, 84(6): 1217-24.
[10] Jack CS, Arbour N, Manusow J, Montgrain V, et al. TLR signaling tailors innate immune responses in human microglia and astrocytes [J]. J Immunol. 2005,175(7):4320-30.
[ 11 ] Chan A, Magnus T, Gold R. Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system [J]. Glia. 2001, 33(1):87-95.
[12] Kim YJ, Hwang SY, Oh ES, et al. IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways [J]. J Neurosci Res. 2006, 84(5): 1037-46.
[13] Lee DY, Oh YJ, Jin BK. Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways [J]. Glia. 2005,51(2):98-110.
[14] Saud K, Herrera-Molina R, Von Bernhardi R. Pro- and anti-inflammatory cytokines regulate the ERK pathway: implication of the timing for the activation of microglial cells [J]. Neurotox Res. 2005, 8(3-4):277-87.
[ 15] Ledeboer A, Breve JJ, Poole S, et al. Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells [J]. Glia. 2000,30(2): 134-42.
[16] Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression [J]. Mol Psychiatry. 2007,12(11):988-1000.
[17] De Simone R, Ajmone-Cat MA, Tirassa P, et al. Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells [J]. J Neuropathol Exp Neurol. 2003, 62(2):208-16.
[ 18] Chan A, Magnus T, Gold R. Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system [J]. Glia. 2001, 33(1):87-95.
[19] Magnus T, Chan A, Linker RA, et al. Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of gliaJ cells in the inflamed central nervous system [J]. J Neuropathol Exp Neurol. 2002, 61(9):760-6.
[20] Magnus T, Chan A, Grauer O, et al. Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation [J]. J Immunol. 2001, 167(9):5004-10.
[21] Chan A, Seguin R, Magnus T, et al. Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: termination of CNS autoimmune inflammation and modulation by interferon-beta [J]. Glia. 2003, 43(3):231-42.
[22] El Khoury J, Toft M, Hickman SE, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease [J]. Nat Med. 2007,13(4):432-8.
[23] Honda S, Sasaki Y, Ohsawa K, et al. Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors [J]. J Neurosci. 2001, 21(6): 1975-82.
[24] Town T, Nikolic V, Tan J. The microglial "activation" continuum: from innate to adaptive responses [J]. J Neuroinflammation. 2005, 2:24.
[25] Reynolds A, Laurie C, Mosley RL, et al. Oxidative stress and the pathogenesis of neurodegenerative disorders [J]. Int Rev Neurobiol. 2007, 82:297-325.
[26] Gehrmann J. Microglia: a sensor to threats in the nervous system [J]? Res Virol. 1996, 147(2-3):79-88.
[27] Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases [J]. Curr Med Chem. 2007,14(11): 1189-97.
[28] Minghetti L, Ajmone-Cat MA, De Berardinis MA, et al. Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation [J]. Brain Res Brain Res Rev. 2005,48(2):251-6.
[29] Weksler ME, Gouras G, Relkin NR, et al. The immune system, amyloid-beta peptide, and Alzheimer's disease [J]. Immunol Rev. 2005, 205:244-56.
[30] Wersinger C, Sidhu A. An inflammatory pathomechanism for Parkinson's disease [J]? Curr Med Chem. 2006,13(5):591-602.
[31] Streit WJ. Microglial senescence: does the brain's immune system have an expiration date [J]? Trends Neurosci. 2006, 29(9):506-10.
[32] Frank MG, Baratta MV, Sprunger DB, et al. Stress primes microglia to the presence of systemic inflammation: Implications for environmental influences on the brain [J]. Brain, Behavior, and Immunity. 2007, 21(1):45-6.
[33] Glass JD, Wesselingh SL. Microglia in HIV-associated neurological diseases [J]. Microsc Res Tech. 2001, 54(2):95-105.
[34] Nardacci R, Antinori A, Kroemer G, et al. Cell death mechanisms in HIV-associated dementia: the involvement of syncytia [J]. Cell Death Differ. 2005,12 Suppl 1:855-8.
[35] Ghafouri M, Amini S, Khalili K, et al. HIV-1 associated dementia: symptoms and causes [J]. Retrovirology. 2006,19;3:28.
[36] Li JL, Bentsman G, Potash MJ, et al. Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection [J]. BMC Neuroscience. 2007, 8:31.
[37] Ponomarev ED, Shriver LP, Maresz K, et al. Microglial cell activation and proliferation precedes the onset of CNS autoimmunity [J]. J Neurosci Res. 2005,81(3):374-89.
[38] Erdmann N, Zhao J, Lopez AL, et al. Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase [J]. J Neurochem. 2007, 102(2):539-49.
[39] Trujillo JR, Rogers R, Molina RM, et al. Noninfectious entry of HIV-1 into peripheral and brain macrophages mediated by the mannose receptor [J]. Proc Natl Acad Sci U S A. 2007, 104(12):5097-102.
[40] Raivich G Like cops on the beat: the active role of resting microglia [J]. Trends Neurosci. 2005, 28(11):571-3.
[41] Trujillo JR, Rogers R, Molina RM, et al. Noninfectious entry of HIV-1 into peripheral and brain macrophages mediated by the mannose receptor [J]. Proc Natl Acad Sci U S A. 2007, 104(12):5097-102.
[42] Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson's disease [J]. J Neural Transm Suppl. 2006, (70):373-81.
[43] Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease [J]. Exp Mol Med. 2006, 38(4):333-47.
[44] Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer's disease [J]. Nat Rev Immunol, 2006, 6(5):404-16.
[45] Roulston CL, Lawrence AJ, Widdop RE, et al. Minocycline treatment attenuates microglia activation and non-angiotensin II [1251] CGP42112 binding in brainstem following nodose ganglionectomy [J]. Neuroscience. 2005,135(4):1241-53.
[46] Ponomarev ED, Shriver LP, Dittel BN. CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation [J]. J Immunol. 2006, l;176(3):1402-10.
[47] Becher B, Durell BG, Miga AV, et al. The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system [J]. J Exp Med. 2001, 193(8):967-74.
[48] Magnus T, Schreiner B, Korn T, et al. Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS [J]. J Neurosci. 2005, 25(10):2537-46.
[49] D'Aversa TG, Eugenin EA, Berman JW. CD40-CD40 ligand interactions in human microglia induce CXCL8 (interleukin-8) secretion by a mechanism dependent on activation of ERK1/2 and nuclear translocation of nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP-1) [J]. J Neurosci Res. 2007, Oct 5.
[50] D'Aversa TG, Weidenheim KM, Berman JW. CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis [J]. Am J Pathol. 2002,160(2):559-67.
[51 ] Sui Z, Sniderhan LF, Schifitto G, et al. Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia [J]. J Immunol. 2007, 178(5):3226-36.
[52] Klegeris A, McGeer EG, McGeer PL. Therapeutic approaches to inflammation in neurodegenerative disease [J]. Curr Opin Neurol. 2007, 20(3):351-7.
[53] Ohsawa K, Irino Y, Nakamura Y, et al. Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis [J]. Glia. 2007, 55(6):604-16.
[54] Takenouchi T, Sato M, Kitani H, et al. Lysophosphatidylcholine potentiates Ca2+ influx, pore formation and p44/42 MAP kinase phosphorylation mediated by P2X7 receptor activation in mouse microglial cells [J]. J Neurochem. 2007,102(5): 1518-32.
[55] Zipp F, Aktas O. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases [J]. Trends Neurosci. 2006,29(9):518-27.
[56] Lauber K, Blumenthal SG, Waibel M, et al. Clearance of apoptotic cells: getting rid of the corpses [J]. Mol Cell. 2004,14(3):277-87.
[57] Garden GA, Budd SL, Tsai E, et al. Caspase cascades in human immunodeficiency virus-associated neurodegeneration [J]. J Neurosci. 2002, 22(10):4015-24.
[58] Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases [J]. Curr Med Chem. 2007, 14(11):1189-97.
[59] Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis [J]. Nat Neurosci. 2006, 9(12):1512-9.
[1]Hanisch UK,Kettenmann H.Microglia:active sensor and versatile effector cells in the normal and pathologic brain[J].Nat Neurosci.2007,10(11):1387-1394.
[2]Garden GA,Moller T.Microglia Biology in Health and Disease[J].J NeuroImmu Pha,2006,1(2):127-37.
[3]Block ML,Zecca L,Hong JS.Microglia-mediated neurotoxicity:uncovering the molecular mechanisms[J].Nat Rev Neurosci.2007,8(1):57-69.
[4]Cardona AE,Huang D,Sasse ME,et al.Isolation of routine microglial cells for RNA analysis or flow cytometry[J].Nat Protoc.2006,1(4):1947-51.
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[8]Giulian D,Baker TJ.Characterization of ameboid microglia isolated from developing mammalian brain[J].J Neurosci.1986,6(8):2163-78.
[9]Giulian D,Li J,Bartel S,et al.Cell surface morphology identifies microglia as a distinct class of mononuclear phagocyte[J].J Neurosci.1995,15(11):7712-26.
[1]Gehrmann J.Microglia:a sensor to threats in the nervous system[J]? Res Virol.1996,147(2-3):79-88.
[2]Dheen ST,Kaur C,Ling EA.Microglial activation and its implications in the brain diseases [J].Curt Med Chem.2007,14(11):1189-97.
[3]Minghetti L,Ajmone-Cat MA,De Berardinis MA,et al.Microglial activation in chronic neurodegenerative diseases:roles of apoptotic neurons and chronic stimulation[J].Brain Res Brain Res Rev. 2005, 48(2):251-6.
[4] Kim YS, Kim SS, Cho JJ, et al. Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia [J]. J Neurosci. 2005,25(14):3701-11.
[5] Kim YJ, Hwang SY, Oh ES, et al. IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways [J]. J Neurosci Res. 2006, 84(5): 1037-46.
[6] Lee DY, Oh YJ, Jin BK. Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways [J]. Glia. 2005,51(2):98-110.
[7] Saud K, Herrera-Molina R, Von Bernhardi R. Pro- and anti-inflammatory cytokines regulate the ERK pathway: implication of the timing for the activation of microglial cells [J]. Neurotox Res. 2005, 8(3-4):277-87.
[8] Garden GA, Moller T. Microglia Biology in Health and Disease [J]. J NeuroImmu Pha, 2006,1(2): 127-37.
[9] Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms [J]. Nat Rev Neurosci. 2007, 8(1):57-69.
[10] Town T, Nikolic V, Tan J. The microglial "activation" continuum: from innate to adaptive responses [J]. J Neuroinflammation. 2005, 2:24.
[11] Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases [J]. Curr Med Chem. 2007,14(11):1189-97.
[12] Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson's disease [J]. J Neural Transm Suppl. 2006, (70):373-81.
[13] Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease [J]. Exp Mol Med. 2006, 38(4):333-47.
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[1]Ledeboer A,Breve JJ,Poole S,et al.Intedeukin-10,interleukin-4,and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells[J].Glia.2000,30(2):134-42.
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[12] Trujillo JR, Rogers R, Molina RM, et al. Noninfectious entry of HIV-1 into peripheral and brain macrophages mediated by the mannose receptor [J]. Proc Natl Acad Sci U S A. 2007, 104(12):5097-102.
[13] Sui Z, Sniderhan LF, Schifitto G, et al. Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia [J]. J Immunol. 2007, 178(5):3226-36.
[14] Persidsky Y, Poluektova L. Immune privilege and HIV-1 persistence in the CNS [J]. Immunol Rev. 2006, 213:180-94.
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