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Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases

Roosmarijn Vandenbroucke UGent, Eline Dejonckheere UGent, Philippe Van Lint, Delphine Demeestere UGent, Elien Van Wonterghem UGent, Ineke Vanlaere UGent, Leen Puimège UGent, Filip Van Hauwermeiren UGent, Riet De Rycke UGent and Conor Mc Guire UGent, et al. (2012) JOURNAL OF NEUROSCIENCE. 32(29). p.9805-9816
abstract
Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain "immune sensor" involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8(+/+) mice, in contrast to MMP8(-/-) mice, show no anti-inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EPITHELIAL-CELLS, CHOROID-PLEXUS, TUMOR-NECROSIS-FACTOR, POLYMYXIN-B HEMOPERFUSION, CEREBROSPINAL FLUID BARRIER, BASEMENT-MEMBRANE, SEPTIC SHOCK, DRUG TARGETS, IN-VITRO, SEPSIS
journal title
JOURNAL OF NEUROSCIENCE
J. Neurosci.
volume
32
issue
29
pages
9805 - 9816
Web of Science type
Article
Web of Science id
000306528200005
JCR category
NEUROSCIENCES
JCR impact factor
6.908 (2012)
JCR rank
22/251 (2012)
JCR quartile
1 (2012)
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.0967-12.2012
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2972197
handle
http://hdl.handle.net/1854/LU-2972197
date created
2012-08-16 10:34:42
date last changed
2012-09-04 15:39:37
@article{2972197,
  abstract     = {Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain {\textacutedbl}immune sensor{\textacutedbl} involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8(+/+) mice, in contrast to MMP8(-/-) mice, show no anti-inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity.},
  author       = {Vandenbroucke, Roosmarijn and Dejonckheere, Eline and Van Lint, Philippe and Demeestere, Delphine and Van Wonterghem, Elien and Vanlaere, Ineke and Puim{\`e}ge, Leen and Van Hauwermeiren, Filip and De Rycke, Riet and Mc Guire, Conor and Campestre, Cristina and L{\'o}pez-Otin, Carlos and Matthys, Patrick and Leclercq, Georges and Libert, Claude},
  issn         = {0270-6474},
  journal      = {JOURNAL OF NEUROSCIENCE},
  keyword      = {EPITHELIAL-CELLS,CHOROID-PLEXUS,TUMOR-NECROSIS-FACTOR,POLYMYXIN-B HEMOPERFUSION,CEREBROSPINAL FLUID BARRIER,BASEMENT-MEMBRANE,SEPTIC SHOCK,DRUG TARGETS,IN-VITRO,SEPSIS},
  language     = {eng},
  number       = {29},
  pages        = {9805--9816},
  title        = {Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0967-12.2012},
  volume       = {32},
  year         = {2012},
}

Chicago
Vandenbroucke, Roosmarijn, Eline Dejonckheere, Philippe Van Lint, Delphine Demeestere, Elien Van Wonterghem, Ineke Vanlaere, Leen Puimège, et al. 2012. “Matrix Metalloprotease 8-dependent Extracellular Matrix Cleavage at the blood-CSF Barrier Contributes to Lethality During Systemic Inflammatory Diseases.” Journal of Neuroscience 32 (29): 9805–9816.
APA
Vandenbroucke, R., Dejonckheere, E., Van Lint, P., Demeestere, D., Van Wonterghem, E., Vanlaere, I., Puimège, L., et al. (2012). Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases. JOURNAL OF NEUROSCIENCE, 32(29), 9805–9816.
Vancouver
1.
Vandenbroucke R, Dejonckheere E, Van Lint P, Demeestere D, Van Wonterghem E, Vanlaere I, et al. Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases. JOURNAL OF NEUROSCIENCE. 2012;32(29):9805–16.
MLA
Vandenbroucke, Roosmarijn, Eline Dejonckheere, Philippe Van Lint, et al. “Matrix Metalloprotease 8-dependent Extracellular Matrix Cleavage at the blood-CSF Barrier Contributes to Lethality During Systemic Inflammatory Diseases.” JOURNAL OF NEUROSCIENCE 32.29 (2012): 9805–9816. Print.