Extracellular proteases are crucial regulators of cell function. The family of matrix metalloproteinases (MMPs) has classically been described in the context of extracellular matrix (ECM) remodelling, which occurs throughout life in diverse processes that range from tissue morphogenesis to wound healing. Recent evidence has implicated MMPs in the regulation of other functions, including survival, angiogenesis, inflammation and signalling. There are at least 25 members of the MMP family and, collectively, these proteases can degrade all constituents of the ECM. As a result of their potent proteolytic activity, abnormal MMP function can also lead to pathological conditions. The most widely studied disease that involves MMPs is cancer metastasis. In this case, the tumour cell is thought to use MMPs to overcome multiple structural barriers and establish a new focus of growth at a distant site from the primary tumour mass. In the nervous system, MMPs have also been associated with pathogenesis, particularly in multiple sclerosis (MS) and malignant gliomas 1 . A growing literature has linked MMPs to stroke, to Alzheimer's disease and to viral infections of the central nervous system (CNS). The goal of this review is to acquaint the reader with the biology of MMPs, particularly the functions of MMPs that are not associated with matrix turnover. We will highlight the roles of MMPs in pathology of the nervous system, and emphasize the fact that MMPs can also have physiological functions during CNS repair and ontogeny. Last, we will discuss the function of another group of metalloproteinases -ADAMs (a DISINTEGRIN and metalloproteinase) -in CNS pathophysiology, as these proteins might be responsible for many of the activities previously ascribed to MMPs. Metalloproteinases -the cast DISINTEGRINSPeptides found in the venoms of various snakes that inhibit the function of integrins of the β1 and β3 classes. 502 | JULY 2001 | VOLUME 2 www.nature.com/reviews/neuro R E V I E W S © 2001 Macmillan Magazines Ltd sion, sperm-egg fusion (for example, ADAM1 and -2), myoblast fusion (ADAM12) and the ectodomain shedding of cell-surface proteins (for example, ADAM9, -10 and -17). Most ADAMs have a prodomain, a metalloprotease region, a disintegrin domain for adhesion, a cysteine-rich region, epidermal-growth-factor (EGF) repeats, a transmembrane module and a cytoplasmic tail (FIG. 1). So, ADAMs are unique among cell-surface proteins in having both adhesive and proteolytic activities. The cysteine-rich region and EGF repeats are thought to mediate cell fusion or the interaction of ADAMs with other molecules such as chaperone proteins. The cytoplasmic tails of ADAM9 and -12 interact with protein kinase C and with src, respectively, implicating some ADAM family members as signalling molecules 5,6 . Although most ADAMs are transmembrane proteins, some members (for example, ADAM11, -12, -17 and -28) also have alternatively spliced forms that diverge before the transmembrane module to generate a soluble, secreted protein. It is important to not...

Microglia and macrophages in the CNS contain multimolecular complexes termed inflammasomes. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals that are associated with neurological diseases, including meningitis, stroke and Alzheimer's disease. Assembly of an inflammasome activates caspase 1 and, subsequently, the proteolysis and release of the cytokines interleukin-1β and interleukin-18, as well as pyroptotic cell death. Since the discovery of inflammasomes in 2002, there has been burgeoning recognition of their complexities and functions. Here, we review the current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases.

Chemokines provide directional cues for leukocyte migration and activation that are essential for normal leukocytic trafficking and for host responses during processes such as inflammation, infection, and cancer. Recently we reported that matrix metalloproteinases (MMPs) modulate the activity of the CC chemokine monocyte chemoattractant protein-3 by selective proteolysis to release the N-terminal tetrapeptide. Here we report the N-terminal processing, also at position 4-5, of the CXC chemokines stromal cell-derived factor (SDF)-1alpha and beta by MMP-2 (gelatinase A). Robustness of the MMP family for chemokine cleavage was revealed from identical cleavage site specificity of MMPs 1, 3, 9, 13, and 14 (MT1-MMP) toward SDF-1; selectivity was indicated by absence of cleavage by MMPs 7 and 8. Efficient cleavage of SDF-1alpha by MMP-2 is the result of a strong interaction with the MMP hemopexin C domain at an exosite that overlaps the monocyte chemoattractant protein-3 binding site. The association of SDF-1alpha with different glycosaminoglycans did not inhibit cleavage. MMP cleavage of SDF-1alpha resulted in loss of binding to its cognate receptor CXCR-4. This was reflected in a loss of chemoattractant activity for CD34(+) hematopoietic progenitor stem cells and pre-B cells, and unlike full-length SDF-1alpha, the MMP-cleaved chemokine was unable to block CXCR-4-dependent human immunodeficiency virus-1 infection of CD4(+) cells. These data suggest that MMPs may be important regulatory proteases in attenuating SDF-1 function and point to a deep convergence of two important networks, chemokines and MMPs, to regulate leukocytic activity in vivo.

Activated monocytes release a number of substances, including inf lammatory cytokines and eicosanoids, that are highly toxic to cells of the central nervous system. Because monocytic infiltration of the central nervous system closely correlates with HIV-1-associated dementia, it has been suggested that monocyte-derived toxins mediate nervous system damage. In the present study, we show that the HIV-1 transactivator protein Tat significantly increases astrocytic expression and release of monocyte chemoattractant protein-1 (MCP-1). Astrocytic release of ␤-chemokines, which are relatively less selective for monocytes, including RANTES, macrophage inf lammatory protein-1␣, and macrophage inf lammatory protein-1␤, was not observed. We also show that MCP-1 is expressed in the brains of patients with HIV-1-associated dementia and that, of the ␤-chemokines tested, only MCP-1 could be detected in the cerebrospinal f luid of patients with this condition. Together, these data provide a potential link between the presence of HIV-1 in the brain and the monocytic infiltration that may substantially contribute to dementia.