PMID- 22815495
OWN - NLM
STAT- MEDLINE
DCOM- 20121024
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 32
IP  - 29
DP  - 2012 Jul 18
TI  - Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF 
      barrier contributes to lethality during systemic inflammatory diseases.
PG  - 9805-16
AB  - 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.
FAU - Vandenbroucke, Roosmarijn E
AU  - Vandenbroucke RE
AD  - Department for Molecular Biomedical Research, Flanders Institute for 
      Biotechnology, B-9052 Ghent, Belgium.
FAU - Dejonckheere, Eline
AU  - Dejonckheere E
FAU - Van Lint, Philippe
AU  - Van Lint P
FAU - Demeestere, Delphine
AU  - Demeestere D
FAU - Van Wonterghem, Elien
AU  - Van Wonterghem E
FAU - Vanlaere, Ineke
AU  - Vanlaere I
FAU - Puimege, Leen
AU  - Puimege L
FAU - Van Hauwermeiren, Filip
AU  - Van Hauwermeiren F
FAU - De Rycke, Riet
AU  - De Rycke R
FAU - Mc Guire, Conor
AU  - Mc Guire C
FAU - Campestre, Cristina
AU  - Campestre C
FAU - Lopez-Otin, Carlos
AU  - Lopez-Otin C
FAU - Matthys, Patrick
AU  - Matthys P
FAU - Leclercq, Georges
AU  - Leclercq G
FAU - Libert, Claude
AU  - Libert C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 9007-34-5 (Collagen)
RN  - EC 3.4.24.34 (Matrix Metalloproteinase 8)
RN  - W980KJ009P (Corticosterone)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/*metabolism
MH  - Brain/metabolism
MH  - Choroid Plexus/metabolism
MH  - Collagen/metabolism
MH  - Corticosterone/blood
MH  - Endotoxemia/*metabolism
MH  - Extracellular Matrix/*metabolism
MH  - Female
MH  - Male
MH  - Matrix Metalloproteinase 8/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Systemic Inflammatory Response Syndrome/*metabolism
PMC - PMC6621276
EDAT- 2012/07/21 06:00
MHDA- 2012/10/25 06:00
PMCR- 2013/01/18
CRDT- 2012/07/21 06:00
PHST- 2012/07/21 06:00 [entrez]
PHST- 2012/07/21 06:00 [pubmed]
PHST- 2012/10/25 06:00 [medline]
PHST- 2013/01/18 00:00 [pmc-release]
AID - 32/29/9805 [pii]
AID - 3786687 [pii]
AID - 10.1523/JNEUROSCI.0967-12.2012 [doi]
PST - ppublish
SO  - J Neurosci. 2012 Jul 18;32(29):9805-16. doi: 10.1523/JNEUROSCI.0967-12.2012.