Microglial proteases

There is growing evidence that the proteolytic machinery of microglia is closely associated with their protective and cytotoxic roles in the central nervous system (CNS). Endosomal and lysosomal proteases including cathepsins E and S have been shown to play important roles in the major histocompatibility complex (MHC) class II-mediated antigen presentation of microglia by processing of exogenous antigens and degradation of the invariant chain (Ii) associated with MHC class II molecules, respectively. There is evidence that some members of cathepsins are involved in extracellular proteolysis in addition to their functions in the endosomal-lysosomal system. We have recently found, by utilizing cathepsin S-deficient mice, that cathepsin S is required for migration of microglia toward axotomized facial motoneurons. Several studies have suggested an involvement of cathepsin D in the clearance of amyloid-β (Aβ) peptides by microglia. On the other hand, attention has been also paid to deleterious effects of proteases secreted from microglia. Cathepsins S and B secreted from microglia are also involved in tissue damage and neuronal death. Moreover, tissue-type plasminogen activator (tPA), a serine protease, secreted from microglia also participates in neuronal death, enhances N-methyl-d-aspartate (NMDA) receptor-mediated neuronal responses, and activates microglia via either its proteolytic or nonproteolytic activity. Calpain, a calcium-dependent cysteine protease, has been demonstrated to play a pivotal role in the pathogenesis of multiple sclerosis (MS) by degrading myelin proteins extracellularly. Furthermore, matrix metalloproteases (MMPs) secreted from microglia also receive great attention as mediators of inflammation and tissue degradation through processing of proinflammatory cytokines and damage to the blood-brain barrier. Therefore, the accumulating knowledge about proteolytic events mediated by microglial proteases will contribute to better understanding of microglial functions in the CNS.