Microglial responses after ischemic stroke and intracerebral hemorrhage

Roslyn A Taylor, Lauren H Sansing, Roslyn A Taylor, Lauren H Sansing

Abstract

Stroke is a leading cause of death worldwide. Ischemic stroke is caused by blockage of blood vessels in the brain leading to tissue death, while intracerebral hemorrhage (ICH) occurs when a blood vessel ruptures, exposing the brain to blood components. Both are associated with glial toxicity and neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), continually sample the environment for signs of injury and infection. Under homeostatic conditions, they have a ramified morphology and phagocytose debris. After stroke, microglia become activated, obtain an amoeboid morphology, and release inflammatory cytokines (the M1 phenotype). However, microglia can also be alternatively activated, performing crucial roles in limiting inflammation and phagocytosing tissue debris (the M2 phenotype). In rodent models, microglial activation occurs very early after stroke and ICH; however, their specific roles in injury and repair remain unclear. This review summarizes the literature on microglial responses after ischemic stroke and ICH, highlighting the mediators of microglial activation and potential therapeutic targets for each condition.

Figures

Figure 1
Figure 1
Microglia polarization is characterized by distinct phenotypes.

References

    1. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–845.
    1. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FMV. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neuroscience. 2007;10(12):1538–1543.
    1. Eyo U, Dailey M. Microglia: key elements in neural development, plasticity, and pathology. Journal of Neuroimmune Pharmacology. 2013;8(3):494–509.
    1. Suzuki Y, Sa Q, Gehman M, Ochiai E. Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain. Expert reviews in molecular medicine. 2011;13:p. e31.
    1. Puntener U, Booth SG, Perry VH, Teeling JL. Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. Journal of Neuroinflammation. 2012;9:p. 146.
    1. Browne TC, McQuillan K, McManus RM, 'Reilly JAO, Mills KH, Lynch MA. IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. The Journal of Immunology. 2013;190(5):2241–2251.
    1. Imamoto N, Momosaki S, Fujita M, et al. [11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats. Neuroimage. 2013;79:121–128.
    1. Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Progress in Neurobiology. 2010;92(4):463–477.
    1. Campanella M, Sciorati C, Tarozzo G, Beltramo M. Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke. 2002;33(2):586–592.
    1. Starossom S, Mascanfroni I, Imitola J, et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012;37(2):249–263.
    1. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. Journal of Clinical Investigation. 2012;122(4):1164–1171.
    1. Kawanokuchi J, Shimizu K, Nitta A, et al. Production and functions of IL-17 in microglia. Journal of Neuroimmunology. 2008;194(1-2):54–61.
    1. Zhou M, Wang C, Yang WL, Wang P. Microglial CD14 activated by iNOS contributes to neuroinflammation in cerebral ischemia. Brain Research. 2013;1506:105–114.
    1. Onwuekwe I, Ezeala-Adikaibe B. Ischemic stroke and neuroprotection. Annals of Medical and Health Sciences Research. 2012;2(2):186–190.
    1. Towfighi A, Saver JL. Stroke declines from third to fourth leading cause of death in the United States: historical perspective and challenges ahead. Stroke. 2011;42(8):2351–2355.
    1. Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nature Medicine. 2011;17(7):796–808.
    1. Savitz S, Mattle H. Advances in stroke: emerging therapies. Stroke. 2013;44(2):314–315.
    1. Urra X, Chamorro A. Emerging issues in acute ischemic stroke. Journal of Neurology. 2013;260(6):1687–1692.
    1. Gregersen R, Lambertsen K, Finsen B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. Journal of Cerebral Blood Flow and Metabolism. 2000;20(1):53–65.
    1. Parada E, Egea J, Buendia I, et al. The Microglial alpha7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxidants & Redox Signaling. 2013;19(11):1135–1148.
    1. Lehrmann E, Kiefer R, Christensen T, et al. Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. Glia. 1998;24(4):437–448.
    1. De Bilbao F, Arsenijevic D, Moll T, et al. In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. Journal of Neurochemistry. 2009;110(1):12–22.
    1. Lalancette-Hébert M, Swarup V, Beaulieu J, et al. Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. The Journal of Neuroscience. 2012;32(30):10383–10395.
    1. Morrison HW, Filosa JA. A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. Journal of Neuroinflammation. 2013;10:p. 4.
    1. Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke. 2001;32(5):1208–1215.
    1. Perego C, Fumagalli S, De Simoni M-G. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. Journal of Neuroinflammation. 2011;8, article 174
    1. Hu X, Li P, Guo Y, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43(11):3063–3070.
    1. Schroeter M, Jander S, Witte OW, Stoll G. Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex. Neuroscience. 1999;89(4):1367–1377.
    1. Schroeter M, Dennin MA, Walberer M, et al. Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study. Journal of Cerebral Blood Flow and Metabolism. 2009;29(6):1216–1225.
    1. Wiart M, Davoust N, Pialat J-B, et al. MRI monitoring of neuroinflammation in mouse focal ischemia. Stroke. 2007;38(1):131–137.
    1. Denes A, Vidyasagar R, Feng J, et al. Proliferating resident microglia after focal cerebral ischaemia in mice. Journal of Cerebral Blood Flow and Metabolism. 2007;27(12):1941–1953.
    1. Walberer M, Rueger MA, Simard M-L, et al. Dynamics of neuroinflammation in the macrosphere model of arterio-arterial embolic focal ischemia: an approximation to human stroke patterns. Experimental and Translational Stroke Medicine. 2010;2(1, article 22)
    1. Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Experimental Neurology. 2003;183(1):25–33.
    1. Schilling M, Besselmann M, Müller M, Strecker JK, Ringelstein EB, Kiefer R. Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Experimental Neurology. 2005;196(2):290–297.
    1. Getts DR, Terry RL, Getts MT, et al. Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. Journal of Experimental Medicine. 2008;205(10):2319–2337.
    1. Schielke GP, Yang G-Y, Shivers BD, Betz AL. Reduced ischemic brain injury in interleukin-1β converting enzyme-deficient mice. Journal of Cerebral Blood Flow and Metabolism. 1998;18(2):180–185.
    1. Ceulemans A-G, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y. The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. Journal of Neuroinflammation. 2010;7, article 74
    1. Loddick SA, Turnbull AV, Rothwell NJ. Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. Journal of Cerebral Blood Flow and Metabolism. 1998;18(2):176–179.
    1. Wang X, Feuerstein GZ, Xu L, et al. Inhibition of tumor necrosis factor-α-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. Molecular Pharmacology. 2004;65(4):890–896.
    1. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. Journal of Neuroinflammation. 2008;5, article 45
    1. Heldmann U, Thored P, Claasen J-H, Arvidsson A, Kokaia Z, Lindvall O. TNF-α antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain. Experimental Neurology. 2005;196(1):204–208.
    1. Lambertsen KL, Clausen BH, Babcock AA, et al. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. Journal of Neuroscience. 2009;29(5):1319–1330.
    1. Wesley U, Vemuganti R, Ayvaci E, Dempsey R. Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling. Brain Research. 2013;1496:1–9.
    1. Wei Z, Chigurupati S, Arumugam TV, Jo D-G, Li H, Chan SL. Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia. Stroke. 2011;42(9):2589–2594.
    1. Lloyd-Burton SM, York EM, Anwar MA, Vincent AJ, Roskams AJ. SPARC regulates microgliosis and functional recovery following cortical ischemia. The Journal of Neuroscience. 2013;33(10):4468–4481.
    1. Kim J-B, Joon SC, Yu Y-M, et al. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. Journal of Neuroscience. 2006;26(24):6413–6421.
    1. Faraco G, Fossati S, Bianchi ME, et al. High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo . Journal of Neurochemistry. 2007;103(2):590–603.
    1. Muhammad S, Barakat W, Stoyanov S, et al. The HMGB1 receptor RAGE mediates ischemic brain damage. Journal of Neuroscience. 2008;28(46):12023–12031.
    1. Chapman GA, Moores K, Harrison D, Campbell CA, Stewart BR, Strijbos PJ. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. Journal of Neuroscience. 2000;20(15):p. RC87.
    1. Tarozzo G, Campanella M, Ghiani M, Bulfone A, Beltramo M. Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia-reperfusion brain injury in the rat. European Journal of Neuroscience. 2002;15(10):1663–1668.
    1. Soriano SG, Amaravadi LS, Wang YF, et al. Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. Journal of Neuroimmunology. 2002;125(1-2):59–65.
    1. Fumagalli S, Perego C, Ortolano F, De Simoni MG. CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. Glia. 2013;61(6):827–842.
    1. Dénes Á, Ferenczi S, Halász J, Környei Z, Kovács KJ. Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. Journal of Cerebral Blood Flow and Metabolism. 2008;28(10):1707–1721.
    1. Cipriani R, Villa P, Chece G, et al. CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. Journal of Neuroscience. 2011;31(45):16327–16335.
    1. Donovan F, Pike C, Cotman C, Cunningham DD. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. Journal of Neuroscience. 1997;17(14):5316–5326.
    1. Fujimoto S, Katsuki H, Ohnishi M, Takagi M, Kume T, Akaike A. Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo. Neuroscience. 2007;144(2):694–701.
    1. Ohnishi M, Katsuki H, Fujimoto S, Takagi M, Kume T, Akaike A. Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury. Experimental Neurology. 2007;206(1):43–52.
    1. Ohnishi M, Katsuki H, Izumi Y, Kume T, Takada-Takatori Y, Akaike A. Mitogen-activated protein kinases support survival of activated microglia that mediate thrombin-induced striatal injury in organotypic slice culture. Journal of Neuroscience Research. 2010;88(10):2155–2164.
    1. Wu J, Yang S, Xi G, et al. Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochirurgica, Supplementum. 2008;(105):59–65.
    1. Xue M, Hollenberg MD, Yong VW. Combination of thrombin and matrix metalloproteinase-9 exacerbates neurotoxicity in cell culture and intracerebral hemorrhage in mice. Journal of Neuroscience. 2006;26(40):10281–10291.
    1. Koeppen AH, Dickson AC, Smith J. Heme oxygenase in experimental intracerebral hemorrhage: the benefit of tin-mesoporphyrin. Journal of Neuropathology and Experimental Neurology. 2004;63(6):587–597.
    1. Wang J, Doré S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain. 2007;130(6):1643–1652.
    1. Lin S, Yin Q, Zhong Q, et al. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. Journal of Neuroinflammation. 2012;9, article 46
    1. Harrison JK, Jiang Y, Chen S, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(18):10896–10901.
    1. Cardona AE, Pioro EP, Sasse ME, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nature Neuroscience. 2006;9(7):917–924.
    1. Zhu J, Zhou Z, Liu Y, Zheng J. Fractalkine and CX3CR1 are involved in the migration of intravenously grafted human bone marrow stromal cells toward ischemic brain lesion in rats. Brain Research. 2009;1287:173–183.
    1. Donohue MM, Cain K, Zierath D, Shibata D, Tanzi PM, Becker KJ. Higher plasma fractalkine is associated with better 6-month outcome from ischemic stroke. Stroke. 2012;43(9):2300–2306.
    1. Kobayashi K, Imagama S, Ohgomori T, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death and Disease. 2013;4:p. e525.
    1. Weng YC, Kriz J. Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Experimental Neurology. 2007;204(1):433–442.
    1. Liu Z, Fan Y, Won SJ, et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007;38(1):146–152.
    1. Brenneman M, Sharma S, Harting M, et al. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. Journal of Cerebral Blood Flow and Metabolism. 2010;30(1):140–149.
    1. Keimpema E, Fokkens MR, Nagy Z, et al. Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathology and Applied Neurobiology. 2009;35(1):89–102.
    1. de Vasconcelos dos Santos A, da Costa Reis J, Diaz Paredes B, et al. Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats. Brain Research. 2010;1306:149–158.
    1. Sharma S, Yang B, Strong R, et al. Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke. Journal of Neuroscience Research. 2010;88(13):2869–2876.
    1. Cardoso M, Franco E, de Souza C, da Silva M, Gouveia A, Gomes-Leal W. Minocycline treatment and bone marrow mononuclear cell transplantation after endothelin-1 induced striatal ischemia. Inflammation. 2013;36(1):197–205.
    1. Franco ECS, Cardoso MM, Gouvêia A, Pereira A, Gomes-Leal W. Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia. Neuroscience Research. 2012;73(2):122–132.
    1. Matsukawa N, Yasuhara T, Hara K, et al. Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. BMC Neuroscience. 2009;10, article 1471:p. 126.
    1. Narantuya D, Nagai A, Abdullah M, et al. Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement. PLoS ONE. 2010;5(7)e11746
    1. Manno E. Update on intracerebral hemorrhage. Continuum. 2012;18(3):598–610.
    1. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. The Lancet. 2009;373(9675):1632–1644.
    1. Morgenstern LB, Hemphill JC, III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41(9):2108–2129.
    1. Keep R, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurology. 2012;11(8):720–731.
    1. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunological Reviews. 2006;213(1):48–65.
    1. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42(6):1781–1786.
    1. Wang J, Doré S. Inflammation after intracerebral hemorrhage. Journal of Cerebral Blood Flow and Metabolism. 2007;27(5):894–908.
    1. Kurland DB, Gerzanich V, Simard JM. 191 Heme induces microglial CXCL2 release-a mechanism of neutrophil-mediated injury after intracerebral hemorrhage. Neurosurgery. 2013;60(supplement 1):p. 183.
    1. Xue M, Del Bigio MR. Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neuroscience Letters. 2000;283(3):230–232.
    1. Wasserman JK, Zhu X, Schlichter LC. Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment. Brain Research. 2007;1180(1):140–154.
    1. Hammond MD, Ai Y, Sansing LH. Gr1+ macrophages and dendritic cells dominate the inflammatory infiltrate 12 h after experimental intracerebral hemorrhage. Translational Stroke Research. 2012;3(1):125–131.
    1. Yabluchanskiy A, Sawle P, Homer-Vanniasinkam S, Green CJ, Motterlini R. Relationship between leukocyte kinetics and behavioral tests changes in the inflammatory process of hemorrhagic stroke recovery. International Journal of Neuroscience. 2010;120(12):765–773.
    1. Sansing LH, Harris TH, Welsh FA, Kasner SE, Hunter CA, Kariko K. Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Annals of Neurology. 2011;70(4):646–656.
    1. Moxon-Emre I, Schlichter LC. Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. Journal of Neuropathology and Experimental Neurology. 2011;70(3):218–235.
    1. Sansing LH, Harris TH, Kasner SE, Hunter CA, Kariko K. Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage. Acta Neurochirurgica, Supplementum. 2011;(111):173–178.
    1. Wu H, Wu T, Xu X, Wang J, Wang J. Iron toxicity in mice with collagenase-induced intracerebral hemorrhage. Journal of Cerebral Blood Flow and Metabolism. 2011;31(5):1243–1250.
    1. Loftspring MC, Hansen C, Clark JF. A novel brain injury mechanism after intracerebral hemorrhage: the interaction between heme products and the immune system. Medical Hypotheses. 2010;74(1):63–66.
    1. Loftspring MC, Johnson HL, Feng R, Johnson AJ, Clark JF. Unconjugated bilirubin contributes to early inflammation and edema after intracerebral hemorrhage. Journal of Cerebral Blood Flow and Metabolism. 2011;31(4):1133–1142.
    1. Fang H, Wang PF, Zhou Y, Wang YC, Yang QW. Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. Journal of Neuroinflammation. 2013;10:p. 27.
    1. Zhou Y, Xiong K-L, Lin S, et al. Elevation of high-mobility group protein box-1 in serum correlates with severity of acute intracerebral hemorrhage. Mediators of Inflammation. 2010;2010:6 pages.142458
    1. Lei C, Lin S, Zhang C, et al. High-mobility group box1 protein promotes neuroinflammation after intracerebral hemorrhage in rats. Neuroscience. 2013;228:190–199.
    1. Szymanska A, Biernaskie J, Laidley D, Granter-Button S, Corbett D. Minocycline and intracerebral hemorrhage: influence of injury severity and delay to treatment. Experimental Neurology. 2006;197(1):189–196.
    1. Wasserman JK, Schlichter LC. Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat. Experimental Neurology. 2007;207(2):227–237.
    1. Wu J, Yang S, Xi G, Fu G, Keep RF, Hua Y. Minocycline reduces intracerebral hemorrhage-induced brain injury. Neurological Research. 2009;31(2):183–188.
    1. Zhao X, Sun G, Zhang J, et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor γ in microglia/macrophages. Annals of Neurology. 2007;61(4):352–362.
    1. Zhao X, Grotta J, Gonzales N, Aronowski J. Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke. 2009;40(3):S92–S94.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever