title: Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases.
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.
authors: Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, B-9052 Ghent, Belgium.
authors: Roosmarijn E
authors: RE
authors: Vandenbroucke
authors: Eline
authors: E
authors: Dejonckheere
authors: Philippe
authors: P
authors: Van Lint
authors: Delphine
authors: D
authors: Demeestere
authors: Elien
authors: E
authors: Van Wonterghem
authors: Ineke
authors: I
authors: Vanlaere
authors: Leen
authors: L
authors: Puimège
authors: Filip
authors: F
authors: Van Hauwermeiren
authors: Riet
authors: R
authors: De Rycke
authors: Conor
authors: C
authors: Mc Guire
authors: Cristina
authors: C
authors: Campestre
authors: Carlos
authors: C
authors: López-Otin
authors: Patrick
authors: P
authors: Matthys
authors: Georges
authors: G
authors: Leclercq
authors: Claude
authors: C
authors: Libert
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D019446:Endotoxemia / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism*
chemical_list: D003094:Collagen; D020784:Matrix Metalloproteinase 8; D003345:Corticosterone