Systemic Inflammation Alters the Kinetics of Cerebrovascular Tight Junction Disruption after Experimental Stroke in Mice

Systemic inflammatory events, such as infection, increase the risk of stroke and are associated with worse outcome, but the mediators of this clinically important effect are unknown. Our aim here was to elucidate mechanisms contributing to the detrimental effects of systemic inflammation on mild ischemic brain injury in mice. Systemic inflammation was induced in mice by peripheral interleukin-1β (IL-1β) challenge and focal cerebral ischemia by transient middle cerebral artery occlusion (MCAo). Systemic inflammation caused an alteration in the kinetics of blood–brain barrier (BBB) disruption through conversion of a transient to a sustained disruption of the tight junction protein, claudin-5, and also markedly exacerbated disruption to the cerebrovascular basal lamina protein, collagen-IV. These alterations were associated with a systemic inflammation-induced increase in neurovascular gelatinolytic activity that was mediated by a fivefold increase in neutrophil-derived matrix metalloproteinase-9 (MMP-9) in the brains of IL-1β-challenged mice after MCAo. Specific inhibition of MMP-9 abrogated the effects of systemic inflammation on the sustained but not the acute disruption of claudin-5, which was associated with phosphorylation of cerebrovascular myosin light chain. MMP-9 inhibition also attenuated the deleterious impact of systemic inflammation on brain damage, edema, neurological deficit, and incidence of hemorrhagic transformation. These data indicate that a transformation from transient to sustained BBB disruption caused by enhanced neutrophil-derived neurovascular MMP-9 activity is a critical mechanism underlying the exacerbation of ischemic brain injury by systemic inflammation. These mechanisms may contribute to the poor clinical outcome in stroke patients presenting with antecedent infection.

[1]  J. Montaner,et al.  Tissue plasminogen activator (t‐PA) promotes neutrophil degranulation and MMP‐9 release , 2008, Journal of leukocyte biology.

[2]  R. Kauppinen,et al.  Interleukin‐1 exacerbates focal cerebral ischemia and reduces ischemic brain temperature in the rat , 2008, Magnetic resonance in medicine.

[3]  H. Bramlett,et al.  Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats , 2008, Experimental Neurology.

[4]  S. Hopkins,et al.  Acute ischaemic stroke and infection: recent and emerging concepts , 2008, The Lancet Neurology.

[5]  B. Wiesner,et al.  Formation of tight junction: determinants of homophilic interaction between classic claudins , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  T. Meade,et al.  Recent respiratory infection and risk of cardiovascular disease: case-control study through a general practice database. , 2007, European heart journal.

[7]  B. McColl,et al.  Systemic inflammation and stroke: aetiology, pathology and targets for therapy. , 2007, Biochemical Society transactions.

[8]  J. I. Alvarez,et al.  Evidence for differential changes of junctional complex proteins in murine neurocysticercosis dependent upon CNS vasculature , 2007, Brain Research.

[9]  M. Prevost,et al.  Human Blood-Brain Barrier Disruption by Retroviral-Infected Lymphocytes: Role of Myosin Light Chain Kinase in Endothelial Tight-Junction Disorganization1 , 2007, The Journal of Immunology.

[10]  S. Malozowski,et al.  Interleukin-1-receptor antagonist in type 2 diabetes mellitus. , 2007, The New England journal of medicine.

[11]  H. Luhmann,et al.  Inhibition of the myosin light chain kinase prevents hypoxia‐induced blood–brain barrier disruption , 2007, Journal of neurochemistry.

[12]  Q. Pittman,et al.  Peripheral Inflammation Exacerbates Damage After Global Ischemia Independently of Temperature and Acute Brain Inflammation , 2007, Stroke.

[13]  B. McColl,et al.  Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms , 2007, The Journal of Neuroscience.

[14]  Jeffrey F. Thompson,et al.  Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  P. Gressens,et al.  Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice , 2007, Neurobiology of Disease.

[16]  Á. Chamorro,et al.  Infection After Acute Ischemic Stroke: A Manifestation of Brain-Induced Immunodepression , 2007, Stroke.

[17]  Colm Cunningham,et al.  Systemic infections and inflammation affect chronic neurodegeneration , 2007, Nature Reviews Immunology.

[18]  E. Lo,et al.  Neurovascular Proteases in Brain Injury, Hemorrhage and Remodeling After Stroke , 2007, Stroke.

[19]  G. D. del Zoppo,et al.  Integrin-matrix interactions in the cerebral microvasculature. , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[20]  G. Rosenberg,et al.  Blood–brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation , 2006, Neurobiology of Disease.

[21]  Ulrich Dirnagl,et al.  Stroke Research Priorities for the Next Decade – A Representative View of the European Scientific Community , 2006, Cerebrovascular Diseases.

[22]  Peter Libby,et al.  The immune response in atherosclerosis: a double-edged sword , 2006, Nature Reviews Immunology.

[23]  M. Bernardo,et al.  Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism‐based selective gelatinase inhibitor , 2006, International journal of cancer.

[24]  Thomas Pap,et al.  Mechanisms of Disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis , 2005, Nature Clinical Practice Rheumatology.

[25]  M. Xue,et al.  Immune pre-activation exacerbates hemorrhagic brain injury in immature mouse brain , 2005, Journal of Neuroimmunology.

[26]  Jiankun Cui,et al.  A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia , 2005, The Journal of Neuroscience.

[27]  W. Lechowicz,et al.  Assessment of Relations between Clinical Outcome of Ischemic Stroke and Activity of Inflammatory Processes in the Acute Phase Based on Examination of Selected Parameters , 2005, European Neurology.

[28]  G. Deuschl,et al.  Platelet–Leukocyte Interaction and Platelet Activation in Acute Stroke With and Without Preceding Infection , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[29]  Donald W. Miller,et al.  Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise. , 2005, Alcoholism, clinical and experimental research.

[30]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[31]  R. Hubbard,et al.  Risk of myocardial infarction and stroke after acute infection or vaccination. , 2004, The New England journal of medicine.

[32]  U. Dirnagl,et al.  Stroke-induced Immunodeficiency Promotes Spontaneous Bacterial Infections and Is Mediated by Sympathetic Activation Reversal by Poststroke T Helper Cell Type 1–like Immunostimulation , 2003, The Journal of experimental medicine.

[33]  Pamela L. Follett,et al.  Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  N. Rothwell,et al.  An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis , 2003, Journal of Neuroimmunology.

[35]  S. Tsukita,et al.  Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice , 2003, The Journal of cell biology.

[36]  M. Seishima,et al.  Lack of Interleukin-1&bgr; Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[37]  E. Lo,et al.  Involvement of Matrix Metalloproteinase in Thrombolysis-Associated Hemorrhagic Transformation After Embolic Focal Ischemia in Rats , 2002, Stroke.

[38]  Pauline M. Rudd,et al.  Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9) , 2002, Critical reviews in biochemistry and molecular biology.

[39]  P. E. Van den Steen,et al.  Gelatinase B: a tuner and amplifier of immune functions. , 2001, Trends in immunology.

[40]  M. Fini,et al.  Effects of Matrix Metalloproteinase-9 Gene Knock-Out on the Proteolysis of Blood–Brain Barrier and White Matter Components after Cerebral Ischemia , 2001, The Journal of Neuroscience.

[41]  M. Fini,et al.  Effects of Matrix Metalloproteinase-9 Gene Knock-Out on Morphological and Motor Outcomes after Traumatic Brain Injury , 2000, The Journal of Neuroscience.

[42]  G. Rosenberg,et al.  Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. , 1998, Stroke.

[43]  P. Gottschall,et al.  Zymographic measurement of gelatinase activity in brain tissue after detergent extraction and affinity-support purification , 1997, Journal of Neuroscience Methods.

[44]  P. Ehrlich.  Granules of the Human Neutrophilic Polymorphonuclear Leukocyte , 1997 .

[45]  R. Busto,et al.  Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats , 1996, Brain Research.

[46]  C. Dinarello.  Role of Interleukin‐l in Infectious Diseases , 1992 .

[47]  C. Dinarello.  Role of interleukin-1 in infectious diseases. , 1992, Immunological reviews.

[48]  R. Wysolmerski,et al.  Involvement of myosin light-chain kinase in endothelial cell retraction. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[49]  L. Pitts,et al.  Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. , 1986, Stroke.