Matrix Metalloproteinases in Central Nervous System Disease

CNS injury triggers a host immune response that generates inflammatory cytokines that increase BBB permeability and mediates the recruitment of peripheral immune cells. matrix metalloproteinases (MMPs) have been implicated in many CNS diseases (Kieseier, Seifert et al. 1999; Hashimoto, Wen et al. 2003). During injury, resident CNS cells and peripheral infiltrating leukocytes can secrete cytokines and MMPs which mediate inflammation by the acute opening of the BBB, demyelination and axonal injury, and cell death (Rosenberg 1995; Kieseier, Seifert et al. 1999; Yong, Power et al. 2001). MMPs and tissue inhibitor of matrix metalloproteinases (TIMPs) have been implicated in MS and EAE and MMP genetic polymorphisms are associated with risk and clinical course of MS (Dasilva and Yong 2008; Mirowska-Guzel, Gromadzka et al. 2009; Alexander, Harris et al. 2010). MMP-12-null mice induced with MOG_35-55 peptide EAE exhibit a more severe disease course than wildtype controls (Weaver, Goncalves da Silva et al. 2005). During EAE disease onset and prior to clinical symptoms, MMP-12 is highly expressed and secreted by a subpopulation of monocytoid Iba-1-reactive cells, resident microglia and infiltrating macrophages (Dasilva and Yong 2008). MMP-12 expression and activity continues into the early phase but is lost following peak clinical disease (Dasilva and Yong 2008).

During early CNS disease, astrocytes become reactive and respond in astrogliosis, and mediate many pathogenic mechanisms. It has been shown that astrocytes increase MMP-13 expression in a time-dependant manner in various diseases (Brinckerhoff, Rutter et al. 2000; Stickens, Behonick et al. 2004; Lu, Yu et al. 2009). Furthermore, astrocyte-derived MMP-13 perturbs the continuity and mediates the destruction of the ZO-1 protein which leads to increased BBB permeability in hypoxic brain injury (Lu, Yu et al. 2009). In addition to MMP-13, reactive astrocytes also increase their expression of MMP-9 in various CNS injury models (Bauer, Burgers et al. 2010; Wang, Hsieh et al. 2010) It has been shown that MMP-9 mediates increased BBB permeability via gap formation and tight junction protein (occludin and ZO-1) discontinuity (Bauer, Burgers et al. 2010). Treatment with an MMP inhibitor reduced vascular leakage and attenuated TJ disorganization (Bauer, Burgers et al. 2010). BBB hyperpermeability allows CNS infiltration of leukocytes which secrete a variety of cytokines and factors, among them is leukocyte-derived MMP-9, which exerts its proinflammatory actions by promoting leukocyte recruitment and migration in CNS parenchyma (Gidday, Gasche et al. 2005; Zozulya, Reinke et al. 2007).

Inflammatory cytokines and signaling factors play an important role in the regulation and activity of MMPs. Tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1 β), two key factors implicated in MS and EAE, are closely associated with the disruption of the BBB (Sharief and Thompson 1992) and TNF-α, IL-1β, and platelet activating factor (PAF) are implicated in MMP production, specifically MMP-9, 12 and 13 (Birkedal-Hansen, Moore et al. 1993; Lee, Shin et al. 2003). Transforming growth factor (TGF)-ß mediates increased in vitro endothelial cell layer permeability by inducing MMP-9 expression which leads to reduced occludin levels in TJs (Behzadian, Wang et al. 2001). In many CNS injury models including EAE, BBB hyperpermeability is dependent on vascular endothelial growth factor (VEGF) which mediates changes in TJ protein expression and rearrangement (Proescholdt, Jacobson et al. 2002; Schoch, Fischer et al. 2002; Sasaki, Lankford et al. 2010). VEGF increases endothelial permeability through direct activation of MMP-9 and inhibition of VEGF not only blocks vascular leakage but also attenuates MMP-9 activity (Bauer, Burgers et al. 2010).

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