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Microglial functions and proteases

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Abstract

There is accumulating evidence that intracellular and extracellular proteases of microglia contribute to various events in the central nervous system (CNS) through both nonspecific and limited proteolysis. Cathepsin E and cathepsin S, endosomal/lysosomal proteases, 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 associated with MHC class II molecules, respectively. Some members of cathepsins are also involved in neuronal death after secreted from microglia and clearance of phagocytosed amyloid-β peptides. Tissue-type plasminogen activator, a serine protease, secreted from microglia participates in neuronal death, enhancement of N-methyl-d-aspartate receptor-mediated neuronal responses, and activation of microglia via either proteolytic or nonproteolytic activity. Calpain, a calcium-dependent cysteine protease, has been shown to play a pivotal role in the pathogenesis of multiple sclerosis by degrading myelin proteins extracellulary. Furthermore, matrix metalloproteases secreted from microglia also receive great attention as mediators of inflammation and tissue degradation through processing of pro-inflammatory cytokines and damage to the blood-brain barrier. The growing knowledge about proteolytic events mediated by microglial proteases will not only contribute to better understanding of microglial functions in the CNS but also may aid in the development of protease inhibitors as novel neuroprotective agents.

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References

  • Baranes D., Lederfein D., Huang Y. -Y., Chen M., Bailey C. H., and Kandel E. R. (1998) Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy pathway. Neuron 21, 813–825.

    Article  PubMed  CAS  Google Scholar 

  • Bennett K., Levine T., Ellis J. S., Peanasky R. J., Samloff I. M., Kay J., et al. (1992) Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E. Eur. J. Immunol. 22, 1519–1524.

    Article  PubMed  CAS  Google Scholar 

  • Centonze D., Saulle E., Pisani A., Bousi P., Tropepi D., Bernardi G., et al. (2002) Tissue plasminogen activator is required for striatal post-ischemic synaptic potentiation. Neuroreport 13, 115–118.

    Article  PubMed  CAS  Google Scholar 

  • Chauvet N., Palin K., Verrier D., Poole S., Dantzer R., and Lestage J. (2001) Rat microglial cells secrete predominantly the precursor of interleukin-1β in response to lipopolysaccharide. Eur. J. Neurosci. 14, 609–617.

    Article  PubMed  CAS  Google Scholar 

  • Colton C. A., Krei J. E., Chen W.-T., and Monsky W. L. (1993) Protease production by cultured microglia: substrate gel analysis and immobilized matrix degradation. J. Neurosci. Res. 35, 297–304.

    Article  PubMed  CAS  Google Scholar 

  • Deussing J., Roth W., Saftig P., Peters C., Ploegh H. L., and Villadangos J. A. (1998) Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation. Proc. Natl. Acad. Sci. USA 95, 4516–4521.

    Article  PubMed  CAS  Google Scholar 

  • Diment S. (1990) Different roles for thiol and aspartyl proteases in antigen presentation of ovalbumin. J. Immunol. 145, 417–422.

    PubMed  CAS  Google Scholar 

  • Flavin M. P. amd Zhao G. (2001) Tissue plasminogen activator protects hippocampal neurons from oxygen-glucose deprivation injury. J. Neurosci. Res. 63, 388–394.

    Article  PubMed  CAS  Google Scholar 

  • Flavin M. P., Zhao G., and Ho L. T. (2000) Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro. Glia 29, 347–354.

    Article  PubMed  CAS  Google Scholar 

  • Gingrich M. B., Junge C. E., Lyuboslavsky P., and Traynelis S. F. (2000) Potentiation of NMDA receptor function by serine protease thrombin. J. Neurosci. 20, 4582–4595.

    PubMed  CAS  Google Scholar 

  • Giulian D., Vaca K., and Corpus M. (1993) Brain glia release factors with opposing actions upon neuronal survival. J. Neurosci. 13, 29–37.

    PubMed  CAS  Google Scholar 

  • Gresser O., Weber E., Hellwing A., Riese S., and Regnier-Vigouroux A. (2001) Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsin L and cathepsin S. Eur. J. Immunol. 31, 1813–1824.

    Article  PubMed  CAS  Google Scholar 

  • Guicciardi M. E., Deussing J., Miyoshi H., Bronk S. F., Svingen P. S., Peters C., et al. (2000) Cathepsin B contributes to TNF-α-mediated hapatocyte apoptosis by promoting mitochondria release of cytochrom c. J. Clin. Invest. 106, 1127–1137.

    PubMed  CAS  Google Scholar 

  • Hamazaki H. (1996) Cathepsin D is involved in the clearance of Alzheimer’s β-amyloid protein. FEBS Lett. 396, 139–142.

    Article  PubMed  CAS  Google Scholar 

  • Huang Y.-Y., Bach M. E., Lipp H. -P., Zhuo M., Wolfer D. P., Hawkins R. D., et al. (1996) Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways. Proc. Natl. Acad. Sci. USA 93, 8699–8704.

    Article  PubMed  CAS  Google Scholar 

  • Husemann J., Loike J. D., Kodama T., and Silverstein S. C. (2001) Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar β-amyloid. J. Neuroimmunol. 114, 142–150.

    Article  PubMed  CAS  Google Scholar 

  • Inoue K., Koizumi S., Nakajima K., Hamanoue M., and Kohsaka S. (1994) Modulatory effect of plasminogen on NMDA-induced increase in intracellular free calcium concentration in rat cultured hippocampal neurons. Neurosci. Lett. 179, 87–90.

    Article  PubMed  CAS  Google Scholar 

  • Kakimura J., Kitamura Y., Takata K., Umeki M., Suzuki S., Shibagaki K., et al. (2002) microglial activation and amyloid-β clearance induced by exogenous heat-shock proteins. FASEB J. 16, 601–603.

    PubMed  CAS  Google Scholar 

  • Kingham P. J. and Pocock J. M. (2000) Microglial apoptosis induced by chromogranin A is mediated by mithochondrial depolarization and the permeability transition but not by cytochrome c release. J. Neurochem. 74, 1452–1452.

    Article  PubMed  CAS  Google Scholar 

  • Kingham P. J. and Pocock J. M. (2001) Microglial secreted cathepsin B induces neuronal apoptosis. J. Neurochem. 76, 1475–1484.

    Article  PubMed  CAS  Google Scholar 

  • Koike M., Nakanishi H., Saftig P., Ezaki J., Isahara K., Ohsawa Y., et al. (2000) Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J. Neurosci. 20, 6869–6906.

    Google Scholar 

  • Kolson D. L., Lavi E., and Gonzalez-Scarano F. (1998) The effects of human immunodeficiency virus in the central nervous system. Adv. Virus Res. 50, 1–47.

    Article  PubMed  CAS  Google Scholar 

  • Lee J., Hurt J., Lee P., Kim J. Y., Cho N., Kim S. Y., et al. (2001) Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells. J. Biol. Chem. 276, 32,956–32,965.

    CAS  Google Scholar 

  • Liu B., Wang K., Gao H. -M., Mandavilli B., Wang J. -Y., and Hong J. -S. (2001) Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. J. Neurochem. 77, 182–189.

    Article  PubMed  CAS  Google Scholar 

  • Madani R., Hulo S., Toni N., Madani H., Steimer T., Muller D., et al. (1999) Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J. 18, 3007–3012.

    Article  PubMed  CAS  Google Scholar 

  • Maric M. A., Taylor M. D., and Blum J. S. (1994) Endosomal aspartic proteinases are required for invariant-chain processing. Proc. Natl. Acad. Sci. USA 91, 2171–2175.

    Article  PubMed  CAS  Google Scholar 

  • McDermott J. R. and Gibson A. M. (1996) Degradation of Alzheimer’s β-amyloid protein by human cathepsin D. Neuroreport 7, 2163–2166.

    Article  PubMed  CAS  Google Scholar 

  • Mittmann T., Luhmann H. J., Schmidt-Kastner R., Eysel U. T., Weigel H., and Heinemann U. (1994) Lesion-induced transient suppression of inhibitory function in rat neocortex in vitro. Neuroscience 60, 891–906.

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki S., Katayama Y., Furuichi M., Kano T., Yoshino A., and Tsubokawa T. (1994) N-methyl-d-asspartate receptor mediated, prolonged after-discharges of CA1 pyramidal cells following transient cerebral ischemia in the rat hippocampus. Brain Res. 657, 325–329.

    Article  PubMed  CAS  Google Scholar 

  • Nakagami Y., Abe K., Nishiyama N., and Matsuki N. (2000) Laminin degradation by plasmin regulates long-term potentiation. J. Neurosci. 20, 2002–2010.

    Google Scholar 

  • Nakajima K., Tsuzaki N., Shimojo M., Hamanoue M., and Kohsaka S. (1992) Microglia isolated from rat brain secrete a urokinase-type plasminogen activator. Brain Res. 577, 258–292.

    Article  Google Scholar 

  • Nakanishi H., Zhang J., Koike M., Nishioku T., Okamoto Y., Kominami E., et al. (2001) Involvement of nitric oxide released from microgliamacrophages in pathological changes of cathepsin D-deficient mice. J. Neurosci. 21, 7526–7533.

    PubMed  CAS  Google Scholar 

  • Nicole O., Docagne F., Ali C., Margailli I., Carmeliet P., MacKenzie E. T., et al. (2001) The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nature Med. 7, 59–64.

    Article  PubMed  CAS  Google Scholar 

  • Nishioku T., Takai N., Miyamaoto K. -I., Murao K., Hara C., Yamamoto K., et al. (2000) Involvement of caspase 3-like protease in methylmercury-induced apoptosis of primary cultured rat cerebral microglia. Brain Res. 871, 160–164.

    Article  PubMed  CAS  Google Scholar 

  • Nishioku T., Hashimoto K., Yamashita K., Liou S. -Y., Kagamiishi Y., Maegawa H., et al. (2002) Involvement of cathepsin E in exogenous antigen processing in primary cultured murine microglia. J. Biol. Chem. 277, 4821–4822.

    Article  CAS  Google Scholar 

  • Paresce D. M., Chung H., and Maxfield F. R. (1997) Slow degradation of aggregates of the Alzheimer’s disease amyloid β-protein by microglial cells. J. Biol. Chem. 46, 29,390–29,397.

    Google Scholar 

  • Paresce D. M., Ghosh R. N., and Maxfield F. R. (1996) Microglial cells internalize aggregates of the Altzheimer’s disease amyloid β-protein via scavenger receptor. Neuron 17, 553–565.

    Article  PubMed  CAS  Google Scholar 

  • Petanceska S., Canoll P., and Devi L. A. L. (1996) Expression of rat cathepsin S in phagocytic cells. J. Biol. Chem. 271, 4403–4409.

    Article  PubMed  CAS  Google Scholar 

  • Piani D. and Fontana A. (1994) Involvement of the cystine transport system Xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J. Immunol. 152, 3578–3585.

    PubMed  CAS  Google Scholar 

  • Qiu W. Q., Walsh D. M. W., Ye Z., Vekrellis K., Zhang J., Podlisny M. B., et al. (1998) Insulin-degrading enzyme regulates extracellar levels of amyloid β-protein by degradation. J. Biol. Chem. 273, 32,730–32,738.

    CAS  Google Scholar 

  • Qiu W. Q., Ye Z., Kholodenko D., Seubert P., and Selkoe D. J. (1997) Degradation of amyloid β-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J. Biol. Chem. 272, 6641–6646.

    Article  PubMed  CAS  Google Scholar 

  • Riese R. J. and Chapman H. A. (2000) Cathepsins and compartmentalization in antigen presentation. Curr. Opin. Immunol. 12, 107–113.

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez G. M. and Diment S. (1992) Role of cathepsin D in antigen presentation of ovalbumin. J. Immunol. 19, 2894–2898.

    Google Scholar 

  • Rogove A., Saio C. -J., Keyt B., Strickland S., and Tsirka S. E. (1999) Activation of microglia reveals a non-proteolytyc cytokine function tissue plasminogen activator in the central nervous system. J. Cell Sci. 112, 4007–4016.

    PubMed  CAS  Google Scholar 

  • Ryan R. E., Sloane B. F., Sameni M., and Wood P. L. (1995) Microglial cathepsin B: an immunological examination of cellular and secreted species. J. Neurochem. 65, 1035–1045.

    Article  PubMed  CAS  Google Scholar 

  • Ryu J., Ryo H., Jou I., and Joe E. (2000) Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-κB. J. Biol. Chem. 275, 29,955–29,959.

    CAS  Google Scholar 

  • Santambrogio L., Belyanskaya S. L., Fisher F. R., Cipriani B., Brosnan C. F., Ricciardi-Castagnoli P., et al. (2001) Developmental plasticity of CNS microglia. Proc. Natl. Acad. Sci. USA 98, 6295–6300.

    Article  PubMed  CAS  Google Scholar 

  • Sastradipura D. F., Nakanishi H., Tsukuba T., Nishishita K., Sakai H., Kato Y., et al. (1998) Identification of cellular compartment involved in processing of cathepsin E in primary cultures of rat microglia. J. Neurochem. 70, 2045–2056.

    Article  PubMed  CAS  Google Scholar 

  • Schenk D., Barbour R., Dunn W., Gordon G., Grajeda H., Guido T., et al. (1999) Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177.

    Article  PubMed  CAS  Google Scholar 

  • Schotte P., Van Criekinge W., Van der Craen M., Van Loo G., Desmedt M., Grooten J., et al. (1998) Cathepsin B-mediated activation of the proinflammatory caspase-11. Biochem. Biophys. Res. Commun. 251, 379–387.

    Article  PubMed  CAS  Google Scholar 

  • Sealy L., Mota F., Rayment N., Tatnell P., Kay J., and Chain B. (1996) Regulation of cathepsin E expression during human B cell differentiation in vitro. Eur. J. Immunol. 26, 1838–1843.

    Article  PubMed  CAS  Google Scholar 

  • Shields D. C., Schaecher K. E., Saido T. C., and Banil N. L. (1999) A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. Proc. Natl. Acad. Sci. USA 96, 11,486–11,491.

    Article  CAS  Google Scholar 

  • Shields D. C., Tyor W. R., Deibler G. E., Hogan E. L., and Banik N. L. (1998) Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis. Proc. Natl. Acad. Sci. USA 95, 5768–5772.

    Article  PubMed  CAS  Google Scholar 

  • Siao C.-J. and Tsirka S. E. (2002) Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II. J. Neurosci. 22, 3352–3358.

    PubMed  CAS  Google Scholar 

  • Stohwasser R., Giesebrecht J., Kraft R., Müller E.-C., Häusler K. G., Kettenmann H., et al. (2000) Biochemical analysis of proteasomes from mouse microglia: Induction of immunoproteasomes by interferon-γ and lipopolysaccharide. Glia 29, 355–365.

    Article  PubMed  CAS  Google Scholar 

  • Stoka V., Turk B., Schendel S. L., Kim T.-H., Cirman T., Snipas S. J., et al. (2001) Lysosomal protease pathway to apoptosis. Cleavage of Bid, not procaspases, is the most likely route. J. Bio. Chem. 276, 3149–3157.

    Article  CAS  Google Scholar 

  • Suo Z., Wu M., Ameenuddin S., Anderson H. E., Zoloty J. E., Citron B. A., et al. (2002) Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J. Neurochem. 80, 655–666.

    Article  PubMed  CAS  Google Scholar 

  • Takai N., Nakanishi H., Tanabe K., Nishioku T., Sugiyama T., Fujiwara M., et al. (1998) Involvement of caspase-like proteases in apoptosis of neuronal PC12 cells and primary cultured microglia induced by 6-hydroxydopamine. J. Neurosci Res. 54, 214–222.

    Article  PubMed  CAS  Google Scholar 

  • Tsirka S. E., Gualandrils A., Amaral D. G., and Strickland S. (1995) Excitation-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377, 340–344.

    Article  PubMed  CAS  Google Scholar 

  • Vancompernolle K., Van Herreweghe F., Pynaert G., Van der Craen M., De Vos K., Totty N., et al. (1998) Atracyloside-induced release of cathepisn B, a protease with caspase-processing ctivity. FEBS Lett. 438, 150–158.

    Article  PubMed  CAS  Google Scholar 

  • van Noort J. M. and Jacobs M. J. (1994) Cathepsin D, but not cathepsin B, releases T cell stimulatory fragments from lysozyme that are functional in the context of multiple murine class II MHC molecules. Eur. J. Immunol. 24, 2175–2180.

    Article  PubMed  Google Scholar 

  • Villadangos J. A., Bryan R. A. R., Deussing J., Driessen C., Lennon-Dumenil A., Riese R. J., et al. (1999) Proteases involved in MHC class II antigen presentation. Immun. Rev. 172, 109–120.

    Article  PubMed  CAS  Google Scholar 

  • Villadangos J. A., Riese R. J., Peters C., Chapman H. A., and Ploegh H. L. (1997) Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism. J. Exp. Med. 186, 549–560.

    Article  PubMed  CAS  Google Scholar 

  • Zhang T., Maekawa Y., Yasutomo K., Ishikawa H., Nashed B. F., Dainichi T., et al. (2000) Pepstatin A-sensitive aspartic proteases in lysosome are involved in degradation of invariant chain and antigen-processing in antigen presenting cells of mice infected with Leishmania major. Biochem. Biophys. Res. Commun. 276, 693–701.

    Article  PubMed  CAS  Google Scholar 

  • Zhuo M., Holtzman D. M., Li Y., Osaka H., DeMaro J., Jacquin M., et al. (2000) Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J. Neurosci. 20, 542–549.

    PubMed  CAS  Google Scholar 

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Nakanishi, H. Microglial functions and proteases. Mol Neurobiol 27, 163–176 (2003). https://doi.org/10.1385/MN:27:2:163

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