小胶质细胞在缺血性中风后作用研究
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摘要
缺血性中风是因栓塞或者血栓引起的大脑中血管阻塞。其全球病死率高,是长期致残的主要原因。缺血性中风发生后,中枢神经系统的常驻免疫细胞小胶质细胞(Microglia)的过度活化会抑制中枢神经系统的修复甚至进一步加重脑组织损伤。但也可以清除细胞碎片,在缺血性中风发生之后的神经重塑和神经发生中发挥重要作用。近年的研究发现,小胶质细胞之所以拥有神经保护和神经毒性的双重作用,主要因为其表型具有高度可塑性。在缺血性中风发生后,因其表型的改变,不同极化状态的小胶质细胞对中风的预后产生了不同的影响。文章将介绍小胶质细胞在缺血性中风后发挥的双重作用。
Ischemic stroke is an occlusion of blood vessels in the brain caused by embolism or thrombosis. It is the main cause of long-term disability with high global mortality rate. After the occurrence of ischemic stroke,excessive activation of microglia,the resident immune cell of the central nervous system,inhibits repair of the central nervous system and even further aggravates brain damage. However,it can also remove cell debris and play an important role in nerve remodeling and neurogenesis after the occurrence of ischemic stroke. Recent studies have found that microglia cells have the dual role of neuroprotection and neurotoxicity,mainly because of their highly malleable phenotype. After ischemic stroke,microglia with different polarization states have different effects on the prognosis of stroke due to changes in their phenotype. This article will introduce the dual role of microglia in ischemic stroke.
Ischemic stroke is an occlusion of blood vessels in the brain caused by embolism or thrombosis. It is the main cause of long-term disability with high global mortality rate. After the occurrence of ischemic stroke,excessive activation of microglia,the resident immune cell of the central nervous system,inhibits repair of the central nervous system and even further aggravates brain damage. However,it can also remove cell debris and play an important role in nerve remodeling and neurogenesis after the occurrence of ischemic stroke. Recent studies have found that microglia cells have the dual role of neuroprotection and neurotoxicity,mainly because of their highly malleable phenotype. After ischemic stroke,microglia with different polarization states have different effects on the prognosis of stroke due to changes in their phenotype. This article will introduce the dual role of microglia in ischemic stroke.
引文
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[8]Iadecola C,Anrather J.The immunology of stroke:from mechanisms to translation[J]. Nature Medicine,2011,17(7):796-808.
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[10]Ekdahl C T,Kokaia Z,Lindvall O. Brain inflammation and adult neurogenesis:the dual role of microglia[J]. Neuroscience,2009,158(3):1021-1029.
[11]Varnum M M,Ikezu T.The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain[J]. Arch Immunol Ther Exp,2012,60(4):251-266.
[12]Lambertsen K L,Biber K,Finsen B. Inflammatory cytokines in experimental and human stroke[J]. Journal of Cerebral Blood Flow&Metabolism Official Journal of the International Society of Cerebral Blood Flow&Metabolism,2012,32(9):1677-1698.
[13]Park K M,Yule D I,Bowers W J. Tumor Necrosis Factor-α Potentiates Intraneuronal Ca2+ Signaling via Regulation of the Inositol 1,4,5-Trisphosphate Receptor[J]. Journal of Biological Chemistry,2008,283(48):33069.
[14]Christov A,Ottman J T,Grammas P. Vascular inflammatory,oxidative and protease-based processes:implications for neuronal cell death in Alzheimer''s disease[J]. Neurological Research,2004,26(5):540.
[15]Hosomi N,Ban C R,Naya T,et al. Tumor necrosis factor-alpha neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia.[J]. Journal of Cerebral Blood Flow&Metabolism Official Journal of the International Society of Cerebral Blood Flow&Metabolism,2005,25(8):959-967.
[16]Denes A,Wilkinson F,Bigger B,et al.Central and haematopoietic interleukin-1 both contribute to ischaemic brain injury in mice[J]. Disease Models&Mechanisms,2013,6(4):1043-1048.
[17]Simi A,Tsakiri N,Wang P,et al.Interleukin-1 and inflammatory neurodegeneration[J]. Biochem Soc Trans,2007,35(5):1122-1126.
[18]Spooren A,Kolmus K,Laureys G,et al. Interleukin-6,a mental cytokine[J]. Brain Research Reviews,2011,67(1):157-183.
[19]Roughton K,Andreasson U,Blomgren K,et al.Lipopolysaccharide-induced inflammation aggravates irradiation-induced injury to the young mouse brain[J].Developmental Neuroscience,2013,35(5):406-15.
[20]Kitayama M,Ueno M,Itakura T,et al. Activated Microglia Inhibit Axonal Growth through RGMa[J]. Plos One,2011,6(9):e25234.
[21]Wang G,Zhang J,Hu X,et al.Microglia/macrophage polarization dynamics in white matter after traumatic brain injury[J]. Journal of Cerebral Blood Flow&Metabolism,2013,33(12):1864-1874.
[22]Willenborg S,Lucas T,Van L G,et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair[J]. Blood,2012,120(3):613-625.
[23]Horn K P,Busch S A,Hawthorne A L,et al. Another barrier to regeneration in the CNS:activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions[J]. Journal of Neuroscience the Official Journal of the Society for Neuroscience,2008,28(38):9330.
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[25]Frenkel D,Huang Z,Maron R,et al. Neuroprotection by IL-10-producing MOG CD4+T cells following ischemic stroke[J].Journal of the Neurological Sciences,2005,233(1):125-132.
[26]Gliem M,Mausberg A K,Lee J I,et al. Macrophages prevent hemorrhagic infarct transformation in murine stroke models[J].Annals of Neurology,2012,71(6):743-752.
[27]Redzic Z B,Rabie T,Sutherland B A,et al. Differential effects of paracrine factors on the survival of cells of the neurovascular unit during oxygen glucose deprivation[J]. International Journal of Stroke,2015,10(3):407-414.
[28]Xu G,Fan X,Zhu W,et al. Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone[J]. BMC Neuroscience,2008,9(1):117.
[29]Butovsky O,Ziv Y,Schwartz A,et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells[J].Molecular&Cellular Neuroscience,2006,31(1):149-160.
[30]Yan Y P,Lang B T,Vemuganti R,et al. Galectin-3 mediates post-ischemic tissue remodeling[J]. Brain Research,2009,1288:116.
[31]Zhao X,Wang H,Sun G,et al. Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage[J].Journal of Neuroscience the Official Journal of the Society for Neuroscience,2015,35(32):11281.
[32]Mead E L,Mosley A,Eaton S,et al. Microglial neurotransmitter receptors trigger superoxide production in microglia;consequences for microglial-neuronal interactions[J]. Journal of Neurochemistry,2012,121(2):287-301.
[33]Porta C,Rimoldi M,Raes G,et al. Tolerance and M2(alternative)macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB[J]. Proceedings of the National Academy of Sciences of the United States of America,2009,106(35):14978-14983.
[34]Egashira Y,Suzuki Y,Azuma Y,et al. The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment[J]. Journal of Neuroinflammation,2013,10(1):105.
[35]Herwig M C,Bergstrom C,Wells J R,et al. M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles[J].Experimental Eye Research,2013,107(1):52-58.
[36]Li D,Wang C,Yao Y,et al. mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type[J]. Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology,2016,30(10):3388.
[37]Ruffell D,Mourkioti F,Gambardella A,et al. A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair[J]. Proceedings of the National Academy of Sciences of the United States of America,2009,106(41):17475-17480.
[38]Sica A,Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development[J]. Journal of Clinical Investigation,2007,117(5):1155-1166.
[39]Qin H,Holdbrooks A T,Liu Y,et al. SOCS3 deficiency promotes M1 macrophage polarization and inflammation[J].Journal of Immunology,2012,189(7):3439-3448.
[40]Martineznunez R T,Louafi F,Sanchezelsner T. The interleukin13(IL-13)pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1(IL13Ralpha1)[J]. Journal of Biological Chemistry,2011,286(3):1786.
[41]KoscsóB,Csóka B,Kókai E,et al. Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages[J]. Journal of Leukocyte Biology,2013,94(6):1309-1315.
[42]Qin H,Yeh W I,Sarno P D,et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3(STAT3/SOCS3)axis in myeloid cells regulates neuroinflammation[J].Proc Natl Acad Sci U S A,2012,109(13):5004-5009.
[43]Hasegawamoriyama M,Kurimoto T,Nakama M,et al.Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages[J]. Pain,2013,154(8):1402-1412.
[44]Ponomarev E D,Veremeyko T,Weiner H L. MicroRNAs are universal regulators of differentiation,activation and polarization of microglia and macrophages in normal and diseased CNS[J].Glia,2013,61(1):91-103.
[45]Moore C S,Rao V T,Durafourt B A,et al. miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization[J]. Annals of Neurology,2013,74(5):709-720.
[46]Ponomarev E D,Veremeyko T,Barteneva N,et al.MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-?±-PU.1pathway[J]. Nature Medicine,2011,17(1):64-70.
[2]Go AS,Mozaffarian D,Roger VL,et al. Executive summary:heart disease and stroke statistics-2014 update:a report from the american heart association[J]. Circulation,2014,399-410.
[3]Liu Y C,Zou X B,Chai Y F,et al. Macrophage Polarization in Inflammatory Diseases[J]. International Journal of Biological Sciences,2014,130:520.
[4]Malyshev I,Malyshev Y. Current Concept and Update of the Macrophage Plasticity Concept:Intracellular Mechanisms of Reprogramming and M3 Macrophage“Switch”Phenotype[J].Biomed Research International,2015,2015(13):341308.
[5]David S,Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury[J].Nature Reviews Neuroscience,2011,12(7):388-99.
[6]Hu X,Liou A K F,Leak R K,et al. Neurobiology of microglial action in CNS injuries:receptor-mediated signaling mechanisms and functional roles[J]. Progress in Neurobiology,2014,119:60-84.
[7]Ginhoux F,Lim S,Hoeffel G,et al. Origin and differentiation of microglia[J]. Frontiers in Cellular Neuroscience,2013,7(2):45.
[8]Iadecola C,Anrather J.The immunology of stroke:from mechanisms to translation[J]. Nature Medicine,2011,17(7):796-808.
[9]Steffen J,Michal S. Non-Identical Twins-Microglia and Monocyte-Derived Macrophages in Acute Injury and Autoimmune Inflammation[J]. Frontiers in Immunology,2012,3(18):89.
[10]Ekdahl C T,Kokaia Z,Lindvall O. Brain inflammation and adult neurogenesis:the dual role of microglia[J]. Neuroscience,2009,158(3):1021-1029.
[11]Varnum M M,Ikezu T.The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain[J]. Arch Immunol Ther Exp,2012,60(4):251-266.
[12]Lambertsen K L,Biber K,Finsen B. Inflammatory cytokines in experimental and human stroke[J]. Journal of Cerebral Blood Flow&Metabolism Official Journal of the International Society of Cerebral Blood Flow&Metabolism,2012,32(9):1677-1698.
[13]Park K M,Yule D I,Bowers W J. Tumor Necrosis Factor-α Potentiates Intraneuronal Ca2+ Signaling via Regulation of the Inositol 1,4,5-Trisphosphate Receptor[J]. Journal of Biological Chemistry,2008,283(48):33069.
[14]Christov A,Ottman J T,Grammas P. Vascular inflammatory,oxidative and protease-based processes:implications for neuronal cell death in Alzheimer''s disease[J]. Neurological Research,2004,26(5):540.
[15]Hosomi N,Ban C R,Naya T,et al. Tumor necrosis factor-alpha neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia.[J]. Journal of Cerebral Blood Flow&Metabolism Official Journal of the International Society of Cerebral Blood Flow&Metabolism,2005,25(8):959-967.
[16]Denes A,Wilkinson F,Bigger B,et al.Central and haematopoietic interleukin-1 both contribute to ischaemic brain injury in mice[J]. Disease Models&Mechanisms,2013,6(4):1043-1048.
[17]Simi A,Tsakiri N,Wang P,et al.Interleukin-1 and inflammatory neurodegeneration[J]. Biochem Soc Trans,2007,35(5):1122-1126.
[18]Spooren A,Kolmus K,Laureys G,et al. Interleukin-6,a mental cytokine[J]. Brain Research Reviews,2011,67(1):157-183.
[19]Roughton K,Andreasson U,Blomgren K,et al.Lipopolysaccharide-induced inflammation aggravates irradiation-induced injury to the young mouse brain[J].Developmental Neuroscience,2013,35(5):406-15.
[20]Kitayama M,Ueno M,Itakura T,et al. Activated Microglia Inhibit Axonal Growth through RGMa[J]. Plos One,2011,6(9):e25234.
[21]Wang G,Zhang J,Hu X,et al.Microglia/macrophage polarization dynamics in white matter after traumatic brain injury[J]. Journal of Cerebral Blood Flow&Metabolism,2013,33(12):1864-1874.
[22]Willenborg S,Lucas T,Van L G,et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair[J]. Blood,2012,120(3):613-625.
[23]Horn K P,Busch S A,Hawthorne A L,et al. Another barrier to regeneration in the CNS:activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions[J]. Journal of Neuroscience the Official Journal of the Society for Neuroscience,2008,28(38):9330.
[24]Puig I P,MiróF,Salasperdomo A,et al. IL-10 deficiency exacerbates the brain inflammatory response to permanent ischemia without preventing resolution of the lesion[J]. Journal of Cerebral Blood Flow&Metabolism Official Journal of the International Society of Cerebral Blood Flow&Metabolism,2013,33(12):1955.
[25]Frenkel D,Huang Z,Maron R,et al. Neuroprotection by IL-10-producing MOG CD4+T cells following ischemic stroke[J].Journal of the Neurological Sciences,2005,233(1):125-132.
[26]Gliem M,Mausberg A K,Lee J I,et al. Macrophages prevent hemorrhagic infarct transformation in murine stroke models[J].Annals of Neurology,2012,71(6):743-752.
[27]Redzic Z B,Rabie T,Sutherland B A,et al. Differential effects of paracrine factors on the survival of cells of the neurovascular unit during oxygen glucose deprivation[J]. International Journal of Stroke,2015,10(3):407-414.
[28]Xu G,Fan X,Zhu W,et al. Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone[J]. BMC Neuroscience,2008,9(1):117.
[29]Butovsky O,Ziv Y,Schwartz A,et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells[J].Molecular&Cellular Neuroscience,2006,31(1):149-160.
[30]Yan Y P,Lang B T,Vemuganti R,et al. Galectin-3 mediates post-ischemic tissue remodeling[J]. Brain Research,2009,1288:116.
[31]Zhao X,Wang H,Sun G,et al. Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage[J].Journal of Neuroscience the Official Journal of the Society for Neuroscience,2015,35(32):11281.
[32]Mead E L,Mosley A,Eaton S,et al. Microglial neurotransmitter receptors trigger superoxide production in microglia;consequences for microglial-neuronal interactions[J]. Journal of Neurochemistry,2012,121(2):287-301.
[33]Porta C,Rimoldi M,Raes G,et al. Tolerance and M2(alternative)macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB[J]. Proceedings of the National Academy of Sciences of the United States of America,2009,106(35):14978-14983.
[34]Egashira Y,Suzuki Y,Azuma Y,et al. The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment[J]. Journal of Neuroinflammation,2013,10(1):105.
[35]Herwig M C,Bergstrom C,Wells J R,et al. M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles[J].Experimental Eye Research,2013,107(1):52-58.
[36]Li D,Wang C,Yao Y,et al. mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type[J]. Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology,2016,30(10):3388.
[37]Ruffell D,Mourkioti F,Gambardella A,et al. A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair[J]. Proceedings of the National Academy of Sciences of the United States of America,2009,106(41):17475-17480.
[38]Sica A,Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development[J]. Journal of Clinical Investigation,2007,117(5):1155-1166.
[39]Qin H,Holdbrooks A T,Liu Y,et al. SOCS3 deficiency promotes M1 macrophage polarization and inflammation[J].Journal of Immunology,2012,189(7):3439-3448.
[40]Martineznunez R T,Louafi F,Sanchezelsner T. The interleukin13(IL-13)pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1(IL13Ralpha1)[J]. Journal of Biological Chemistry,2011,286(3):1786.
[41]KoscsóB,Csóka B,Kókai E,et al. Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages[J]. Journal of Leukocyte Biology,2013,94(6):1309-1315.
[42]Qin H,Yeh W I,Sarno P D,et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3(STAT3/SOCS3)axis in myeloid cells regulates neuroinflammation[J].Proc Natl Acad Sci U S A,2012,109(13):5004-5009.
[43]Hasegawamoriyama M,Kurimoto T,Nakama M,et al.Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages[J]. Pain,2013,154(8):1402-1412.
[44]Ponomarev E D,Veremeyko T,Weiner H L. MicroRNAs are universal regulators of differentiation,activation and polarization of microglia and macrophages in normal and diseased CNS[J].Glia,2013,61(1):91-103.
[45]Moore C S,Rao V T,Durafourt B A,et al. miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization[J]. Annals of Neurology,2013,74(5):709-720.
[46]Ponomarev E D,Veremeyko T,Barteneva N,et al.MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-?±-PU.1pathway[J]. Nature Medicine,2011,17(1):64-70.
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