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Matrix Metalloproteinases as an Inflammatory Mediator in the Neurovascular Unit

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Immunological Mechanisms and Therapies in Brain Injuries and Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR,volume 6))

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Abstract

Matrix metalloproteinases (MMPs) represent a critical set of mediators in the neurovascular unit after stroke. Responses in MMPs underlie both acute injury as well as delayed remodeling as tissue transitions from damage into repair. This chapter briefly reviews how MMPs may contribute to acute infarction, stroke recovery, gray versus white matter responses, and how cell–cell signaling in neuronal, glial, and vascular compartments can be interpreted in the overall context of inflammation within the perturbed neurovascular unit. Dissection of these underlying MMP pathways may eventually lead us to novel therapeutic approaches for target neuroprotection as well as new ways to search for biomarkers for mapping stroke recovery.

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References

  1. del Zoppo GJ (2009) Relationship of neurovascular elements to neuron injury during ischemia. Cerebrovasc Dis 27(Suppl 1):65–76

    Article  PubMed  Google Scholar 

  2. Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–60

    Article  PubMed  CAS  Google Scholar 

  3. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415

    Article  PubMed  CAS  Google Scholar 

  4. Lok J, Gupta P, Guo S et al (2007) Cell–cell signaling in the neurovascular unit. Neurochem Res 32:2032–45

    Article  PubMed  CAS  Google Scholar 

  5. Besancon E, Guo S, Lok J, Tymianski M, Lo EH (2008) Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 29:268–75

    Article  PubMed  CAS  Google Scholar 

  6. Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  PubMed  CAS  Google Scholar 

  7. Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17:439–47

    Article  PubMed  CAS  Google Scholar 

  8. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808

    Article  PubMed  CAS  Google Scholar 

  9. Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6:931–44

    Article  PubMed  CAS  Google Scholar 

  10. Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke; A Journal of Cerebral Circulation 29:1020–30

    Article  PubMed  CAS  Google Scholar 

  11. Gasche Y, Fujimura M, Morita-Fujimura Y et al (1999) Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood–brain barrier dysfunction. J Cereb Blood Flow Metab: official Journal of the International Society of Cerebral Blood Flow and Metabolism 19:1020–8

    Article  CAS  Google Scholar 

  12. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ (1999) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 19:624–33

    Article  CAS  Google Scholar 

  13. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 20:1681–9

    Article  CAS  Google Scholar 

  14. Wang X, Jung J, Asahi M et al (2000) Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci: The Official Journal of the Society for Neuroscience 20:7037–42

    CAS  Google Scholar 

  15. Asahi M, Wang X, Mori T et al (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci: The Official Journal of the Society for Neuroscience 21:7724–32

    CAS  Google Scholar 

  16. Lee SR, Tsuji K, Lee SR, Lo EH (2004) Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci: The Official Journal of the Society for Neuroscience 24:671–8

    Article  CAS  Google Scholar 

  17. Tejima E, Guo S, Murata Y et al (2009) Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma 26:1935–41

    Article  PubMed  Google Scholar 

  18. Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–39

    Article  PubMed  Google Scholar 

  19. Rosenberg LJ, Lucas JH (1997) The effects of ciliary neurotrophic factor on murine spinal cord neurons subjected to dendrite transection injury. Brain Res 775:209–13

    Article  PubMed  CAS  Google Scholar 

  20. Gu Z, Kaul M, Yan B et al (2002) S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297:1186–90

    Article  PubMed  CAS  Google Scholar 

  21. Lee SR, Lo EH (2004) Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. J Cereb Blood Flow Metab: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 24:720–7

    Article  CAS  Google Scholar 

  22. Gu Z, Cui J, Brown S et al (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci: The Official Journal of the Society for Neuroscience 25:6401–8

    Article  CAS  Google Scholar 

  23. Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston LL Jr, del Zoppo GJ (2004) Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke; A Journal of Cerebral Circulation 35:998–1004

    Article  PubMed  CAS  Google Scholar 

  24. Sakai T, Johnson KJ, Murozono M et al (2001) Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat Med 7:324–30

    Article  PubMed  CAS  Google Scholar 

  25. Zhao BQ, Tejima E, Lo EH (2007) Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke; A Journal of Cerebral Circulation 38:748–52

    Article  PubMed  CAS  Google Scholar 

  26. Rosell A, Lo EH (2008) Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 8:82–9

    Article  PubMed  CAS  Google Scholar 

  27. Canete Soler R, Gui YH, Linask KK, Muschel RJ (1995) MMP-9 (gelatinase B) mRNA is expressed during mouse neurogenesis and may be associated with vascularization. Brain Res Dev Brain Res 88:37–52

    Article  PubMed  CAS  Google Scholar 

  28. Bergers G, Brekken R, McMahon G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–44

    Article  PubMed  CAS  Google Scholar 

  29. Meighan SE, Meighan PC, Choudhury P et al (2006) Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem 96:1227–41

    Article  PubMed  CAS  Google Scholar 

  30. Nagy V, Bozdagi O, Matynia A et al (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci: The Official Journal of the Society for Neuroscience 26:1923–34

    Article  CAS  Google Scholar 

  31. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–70

    Article  PubMed  CAS  Google Scholar 

  32. Lee SR, Kim HY, Rogowska J et al (2006) Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci: The Official Journal of the Society for Neuroscience 26:3491–5

    Article  CAS  Google Scholar 

  33. Zhao BQ, Wang S, Kim HY et al (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12:441–5

    Article  PubMed  CAS  Google Scholar 

  34. Sood RR, Taheri S, Candelario-Jalil E, Estrada EY, Rosenberg GA (2008) Early beneficial effect of matrix metalloproteinase inhibition on blood–brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. J Cereb Blood Flow Metab: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 28:431–8

    Article  CAS  Google Scholar 

  35. Goussev S, Hsu JY, Lin Y et al (2003) Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J Neurosurg 99:188–97

    Article  PubMed  CAS  Google Scholar 

  36. Hsu JY, McKeon R, Goussev S et al (2006) Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J Neurosci: The Official Journal of the Society for Neuroscience 26:9841–50

    Article  CAS  Google Scholar 

  37. Arai K, Lo EH (2009) Experimental models for analysis of oligodendrocyte pathophysiology in stroke. Exp Transl Stroke Med 1:6

    Article  PubMed  Google Scholar 

  38. Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468:244–52

    Article  PubMed  CAS  Google Scholar 

  39. Arai K, Lo EH (2009) An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J Neurosci 29:4351–5

    Article  PubMed  CAS  Google Scholar 

  40. Arai K, Lo EH (2010) Astrocytes protect oligodendrocyte precursor cells via MEK/ERK and PI3K/Akt signaling. J Neurosci Res 88:758–63

    PubMed  CAS  Google Scholar 

  41. Proost P, Van Damme J, Opdenakker G (1993) Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein. Biochem Biophys Res Commun 192:1175–81

    Article  PubMed  CAS  Google Scholar 

  42. Gijbels K, Proost P, Masure S, Carton H, Billiau A, Opdenakker G (1993) Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. J Neurosci Res 36:432–40

    Article  PubMed  CAS  Google Scholar 

  43. Wang X, Jung J, Asahi M et al (2000) Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 20:7037–42

    PubMed  CAS  Google Scholar 

  44. Lander AD, Fujii DK, Reichardt LF (1985) Laminin is associated with the “neurite outgrowth-promoting factors” found in conditioned media. Proc Natl Acad Sci USA 82:2183–7

    Article  PubMed  CAS  Google Scholar 

  45. Costa S, Planchenault T, Charriere-Bertrand C et al (2002) Astroglial permissivity for neuritic outgrowth in neuron-astrocyte cocultures depends on regulation of laminin bioavailability. Glia 37:105–13

    Article  PubMed  Google Scholar 

  46. Seo JH, Miyamoto N, Hayakawa K et al (2013) Oligodendrocyte precursors induce early blood–brain barrier opening after white matter injury. J Clin Invest 123:782–6

    PubMed  CAS  Google Scholar 

  47. Montaner J, Alvarez-Sabin J, Molina C et al (2001) Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke; A Journal of Cerebral Circulation 32:1759–66

    Article  PubMed  CAS  Google Scholar 

  48. Montaner J, Alvarez-Sabin J, Molina CA et al (2001) Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke; A Journal of Cerebral Circulation 32:2762–7

    Article  PubMed  CAS  Google Scholar 

  49. Sumii T, Lo EH (2002) Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke; A Journal of Cerebral Circulation 33:831–6

    Article  PubMed  CAS  Google Scholar 

  50. Montaner J, Molina CA, Monasterio J et al (2003) Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107:598–603

    Article  PubMed  CAS  Google Scholar 

  51. Ning M, Furie KL, Koroshetz WJ et al (2006) Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 66:1550–5

    Article  PubMed  CAS  Google Scholar 

  52. Tang Y, Xu H, Du X et al (2006) Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 26:1089–102

    Article  CAS  Google Scholar 

  53. Barr TL, Conley Y, Ding J et al (2010) Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling. Neurology 75:1009–14

    Article  PubMed  CAS  Google Scholar 

  54. Tejima E, Zhao BQ, Tsuji K et al (2007) Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 27:460–8

    Article  CAS  Google Scholar 

  55. Gidday JM, Gasche YG, Copin JC et al (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood–brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289:H558–68

    Article  PubMed  CAS  Google Scholar 

  56. Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J (2008) MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke; A Journal of Cerebral Circulation 39:1121–6

    Article  PubMed  CAS  Google Scholar 

  57. Wang X, Lee SR, Arai K et al (2003) Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9:1313–7

    Article  PubMed  CAS  Google Scholar 

  58. Fagan SC, Cronic LE, Hess DC (2011) Minocycline development for acute ischemic stroke. Transl Stroke Res 2:202–8

    Article  PubMed  CAS  Google Scholar 

  59. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke; A Journal of Cerebral Circulation 39:3372–7

    Article  PubMed  CAS  Google Scholar 

  60. Fagan SC, Waller JL, Nichols FT et al (2010) Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke; A Journal of Cerebral Circulation 41:2283–7

    Article  PubMed  CAS  Google Scholar 

  61. Switzer JA, Hess DC, Ergul A et al (2011) Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke; A Journal of Cerebral Circulation 42:2633–5

    Article  PubMed  CAS  Google Scholar 

  62. Gordon PH, Moore DH, Miller RG et al (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6:1045–53

    Article  PubMed  CAS  Google Scholar 

  63. Chou SH, Feske SK, Simmons SL et al (2011) Elevated peripheral neutrophils and matrix metalloproteinase 9 as biomarkers of functional outcome following subarachnoid hemorrhage. Transl Stroke Res 2:600–7

    Article  PubMed  CAS  Google Scholar 

  64. Chou SH, Lee PS, Konigsberg RG et al (2011) Plasma-type gelsolin is decreased in human blood and cerebrospinal fluid after subarachnoid hemorrhage. Stroke; A Journal of Cerebral Circulation 42:3624–7

    Article  PubMed  CAS  Google Scholar 

  65. Guo ZD, Zhang XD, Wu HT, Lin B, Sun XC, Zhang JH (2011) Matrix metalloproteinase 9 inhibition reduces early brain injury in cortex after subarachnoid hemorrhage. Acta Neurochir Suppl 110:81–4

    PubMed  Google Scholar 

  66. Adair JC, Charlie J, Dencoff JE et al (2004) Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke 35:e159–62

    Article  PubMed  CAS  Google Scholar 

  67. Bjerke M, Zetterberg H, Edman A, Blennow K, Wallin A, Andreasson U (2011) Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer’s disease. J Alzheimers Dis 27:665–76

    PubMed  CAS  Google Scholar 

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Acknowledgments

Supported in part by grants from the American Heart Association, NIH, and the Rappaport Foundation. Based in part on ideas previously discussed in Seo et al. (Curr Pharm Des 2012), Xing et al. (Neurol Res 2012), and Rosell et al. (Curr Opin Pharmacol 2008).

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Authors and Affiliations

  1. Massachusetts General Hospital, Harvard University, Charlestown, MA, USA

    Changhong Xing, Ji Hae Seo, Ken Arai & Eng H. Lo

  2. Department of Neurology, Kyoto University, Kyoto, Japan

    Takakuni Maki

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  1. Changhong Xing
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  2. Takakuni Maki
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  3. Ji Hae Seo
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  4. Ken Arai
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  5. Eng H. Lo
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Correspondence to Eng H. Lo .

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Editors and Affiliations

  1. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Jun Chen

  2. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Xiaoming Hu

  3. Molecular Microbiology & Immunology, Oregon Health & Sciences University, Portland, Oregon, USA

    Mary Stenzel-Poore

  4. Loma Linda University, Loma Linda, California, USA

    John H. Zhang

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Xing, C., Maki, T., Seo, J.H., Arai, K., Lo, E.H. (2014). Matrix Metalloproteinases as an Inflammatory Mediator in the Neurovascular Unit. In: Chen, J., Hu, X., Stenzel-Poore, M., Zhang, J. (eds) Immunological Mechanisms and Therapies in Brain Injuries and Stroke. Springer Series in Translational Stroke Research, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8915-3_6

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  • DOI: https://doi.org/10.1007/978-1-4614-8915-3_6

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