Production and secretion of plasminogen in cultured rat brain microglia

Nakajima, Kazuyuki; Tsuzaki, Naoko; Nagata, Kôichi; Takemoto, Nagisa; Kohsaka, Shinichi

doi:10.1016/0014-5793(92)81270-v

Cited by 91 publications

(48 citation statements)

References 33 publications

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“…It can be inferred from studies performed on cultured neurons that tPA is secreted in the extracellular compartment of the CNS (5,6,9,25,26). Although other molecule(s) may serve as substrate(s) for tPA in the brain, the presence of plasminogen mRNA indicates that brain tissues can synthesize this zymogen and directly provide neuronal tPA with its prefered substrate; this is in accord with recent work showing the production ofplasminogen by cultured microglial cells (27). Amongst the cohort of enzymes involved in extracellular proteolysis in essentially all tissues, PAs and plasmin are considered to be key participants (2): they can, directly or indirectly, catalyze the degradation of most protein components ofthe ECM, alter the structure of surface proteins, and activate latent growth factors (28)(29)(30).…”

Section: Discussionsupporting

confidence: 71%

Extracellular proteolysis in the adult murine brain.

Sappino¹,

Madani²,

Huarte³

et al. 1993

J. Clin. Invest.

330

268

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Plasminogen activators are important mediators of extracellular metabolism. In the nervous system, plasminogen activators are thought to be involved in the remodeling events required for cell migration during development and regeneration. We have now explored the expression of the plasminogen activator/ plasmin system in the adult murine central nervous system. Tissue-type plasminogen activator is synthesized by neurons of most brain regions, while prominent tissue-type plasminogen activator-catalyzed proteolysis is restricted to discrete areas, in particular whithin the hippocampus and hypothalamus. Our observations indicate that tissue-type plasminogen activatorcatalyzed proteolysis in neural tissues is not limited to ontogeny, but may also contribute to adult central nervous system physiology, for instance by influencing neuronal plasticity and synaptic reorganization. The identification of an extracellular proteolytic system active in the adult central nervous system may also help gain insights into the pathogeny of neurodegenerative disorders associated with extracellular protein deposition. (J. Clin. Invest. 1993. 92:679-685.)

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Section: Discussionsupporting

confidence: 71%

Extracellular proteolysis in the adult murine brain.

Sappino¹,

Madani²,

Huarte³

et al. 1993

J. Clin. Invest.

330

268

View full text Add to dashboard Cite

show abstract

“…Our results indicate that a bulky aromatic residue at the P2 position of WSN HA contributes greatly to viral neurovirulence, most likely because it allows efficient HA cleavage by plasminogen residing in brain tissue (4,29). In contrast, the proteases responsible for WSN HA cleavage in respiratory organs might have no preference for specific residues at the P2 position, as lung tissue expresses a variety of trypsin-like proteases (2,6,9) that are less likely to have a preference for specific residues at P2 position.…”

Section: Discussionmentioning

confidence: 68%

Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus

Sun

Tse

Ferguson

et al. 2010

J Virol

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A key determinant of influenza virus pathogenesis is mutation in the proteolytic cleavage site of the hemagglutinin (HA). Typically, low-pathogenicity forms of influenza virus are cleaved by trypsin-like proteases, whereas highly pathogenic forms are cleaved by different proteases (e.g., furin). Influenza virus A/WSN/33 (WSN) is a well-studied H1N1 strain that is trypsin independent in vitro and has the ability to replicate in mouse brain. Previous studies have indicated that mutations in the neuraminidase (NA) gene allow the recruitment of an alternate protease (plasminogen/plasmin) for HA activation. In this study we have identified an additional mutation in the P2 position of the WSN HA cleavage site (S328Y) that appears to control virus spread in a plasmin-dependent manner. We reconstructed recombinant WSN viruses containing tyrosine (Y), phenylalanine (F), or serine (S) in the P2 position of the cleavage site. The Y328 and F328 viruses allowed plaque formation in the absence of trypsin, whereas the S328 virus was unable to form plaques under these conditions. In mice, Y328 and F328 viruses were able to efficiently spread following intracranial inoculation; in contrast, the S328 virus showed only limited infection of mouse brain. Following intranasal inoculation, all viruses could replicate efficiently, but with Y328 and F328 viruses showing a limited growth defect. We also show that wild-type HA (Y328) was more efficiently cleaved by plasmin than S328 HA. Our studies form the foundation for a more complete understanding of the molecular determinants of influenza virus pathogenesis and the role of the plasminogen/plasmin system in activating HA.

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“…For example, microglia produce and release Pg in culture [39], and Pg from microglia in the brain could bind to granule and Purkinje cells to produce the pattern of immunolabeling we report. On the other hand, intracellular and extracellular proteases of microglia contribute to various events in the CNS through both nonspecific and limited proteolysis [40], so the contribution of micro-glial and other CNS cells to angiostatin production should be further clarified.…”

Section: Fig 2 Representative Fluorescence Micrographs Of Plasminogmentioning

confidence: 99%