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 ϩ/ϩ mice, in contrast to MMP8 Ϫ/Ϫ 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.

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…The production of cytokines, free radicals (such as reactive oxygen species), and matrix metalloproteinases by inflammatory cells within the CSF spaces can subsequently result in degradation of the glia limitans, BBB/BCSFB dysfunction, and cellular death (93)(94)(95). In bacterial meningitis, neuronal injury also occurs due to the direct effects of bacterial toxins and virulence factors (96)(97)(98).…”

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

“…Matrix metalloproteinases (MMPs) are important mediators during the process of inflammation and are consequently involved in several pathological processes, such as cancer (Decock et al, 2011;Overall & Lopez-Otin, 2002), sepsis (Vandenbroucke et al, 2011a(Vandenbroucke et al, , 2012Vanlaere & Libert, 2009), lung diseases (Vandenbroucke et al, 2011b), ischaemia/ reperfusion and arthritis (Burrage et al, 2006). They constitute a group of structurally and functionally related zinc-dependent endopeptidases responsible for cleaving and rebuilding connective tissue components such as collagen, elastin, gelatin and casein (Zitka et al, 2010).…”

Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralis Infection

“…The prevalence of increased acute-phase protein concentrations during episodes of inflammation is used as a supporting prognostic and diag-nostic tool for inflammatory gastrointestinal diseases (4). Matrix metalloproteinases (MMPs) and their endogenous inhibitor, tissue inhibitor of metalloproteinases 4 (TIMP-4), also play an important role in the process of tissue remodeling and destruction and can be detected in the sera of individuals with a variety of inflammatory disorders (5,6). Heme oxygenase 1 (HO-1), a cytoprotective enzyme with anti-inflammatory and antioxidant properties, has been shown to play a fundamental role in the control of systemic inflammation (7).…”