Cleavage of the myristoylated alanine-rich C kinase substrate (MARCKS) by cysteine cathepsins in cells and tissues of stefin B-deficient mice

2007 ◽  
Vol 388 (8) ◽  
pp. 847-852 ◽  
Author(s):  
Nataša Kopitar-Jerala ◽  
Boris Turk
Keyword(s):  
Cathepsin B ◽  
Cysteine Proteinases ◽  
Endogenous Inhibitor ◽  
Wild Type ◽  
Kinase Substrate ◽  
Cysteine Cathepsins ◽  
Kinase C ◽  
Liver And Kidney ◽  
The Brain ◽  
Deficient Mice

Abstract The myristoylated alanine-rich C kinase substrate (MARCKS) is a substrate of protein kinase C (PKC). Besides regulation at the level of gene transcription, MARCKS concentrations within the cell are also regulated by proteolytic cleavage by cathepsins and calpains, which are cysteine proteinases. Stefin B (cystatin B) is an endogenous inhibitor of lysosomal cysteine cathepsins, but not calpains. We have observed increased cleavage of MARCKS in brain and macrophages, but not in liver and kidney extracts of stefin B-deficient mice compared to wild-type mice. Processing of cathepsin B was unaltered in the brain of stefin B-deficient mice and we conclude that increased cleavage of MARCKS could be attributed to the lack of inhibitor.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

2005 ◽  
Vol 79 (21) ◽  
pp. 13509-13518 ◽  
Author(s):  
Jürgen Hausmann ◽  
Axel Pagenstecher ◽  
Karen Baur ◽  
Kirsten Richter ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Virus ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-γ) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-γ-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-γ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-γ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

scholarly journals Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

2019 ◽  
Author(s):  
Paul Dembny ◽  
Andrew G. Newman ◽  
Manvendra Singh ◽  
Michael Hinz ◽  
Michal Szczepek ◽  
...  
Keyword(s):  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Endogenous Ligand ◽  
Human Endogenous Retroviruses ◽  
Retroviral Transcripts ◽  
The Brain ◽  
Deficient Mice

AbstractAlthough human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer’s disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

scholarly journals Gamma Interferon-Induced Inhibition ofToxoplasma gondii in Astrocytes Is Mediated by IGTP

2001 ◽  
Vol 69 (9) ◽  
pp. 5573-5576 ◽  
Author(s):  
Sandra K. Halonen ◽  
Gregory A. Taylor ◽  
Louis M. Weiss
Keyword(s):  
Immunoblot Analysis ◽  
Significant Inhibition ◽  
Gamma Interferon ◽  
Wild Type ◽  
Effector Cells ◽  
Inhibition Of Growth ◽  
The Central Nervous System ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice

ABSTRACT Toxoplasma gondii is an important pathogen in the central nervous system, causing a severe and often fatal encephalitis in patients with AIDS. Gamma interferon (IFN-γ) is the main cytokine preventing reactivation of Toxoplasma encephalitis in the brain. Microglia are important IFN-γ-activated effector cells controlling the growth of T. gondii in the brain via a nitric oxide (NO)-mediated mechanism. IFN-γ can also activate astrocytes to inhibit the growth of T. gondii. Previous studies found that the mechanism in murine astrocytes is independent of NO and all other known anti-Toxoplasma mechanisms. In this study we investigated the role of IGTP, a recently identified IFN-γ-regulated gene, in IFN-γ inhibition of T. gondii in murine astrocytes. Primary astrocytes were cultivated from IGTP-deficient mice, treated with IFN-γ, and then tested for anti-Toxoplasma activity. In wild-type astrocytesT. gondii growth was significantly inhibited by IFN-γ, whereas in astrocytes from IGTP-deficient mice IFN-γ did not cause a significant inhibition of growth. Immunoblot analysis confirmed that IFN-γ induced significant levels of IGTP in wild-type murine astrocytes within 24 h. These results indicate that IGTP plays a central role in the IFN-γ-induced inhibition of T. gondii in murine astrocytes.

scholarly journals Vaccine-induced protection against Borna disease in wild-type and perforin-deficient mice

2005 ◽  
Vol 86 (2) ◽  
pp. 399-403 ◽  
Author(s):  
Jürgen Hausmann ◽  
Karen Baur ◽  
Karin R. Engelhardt ◽  
Timo Fischer ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurological Disease ◽  
Cell Epitope ◽  
Wild Type ◽  
Immune Priming ◽  
Boost Immunization ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

Borna disease virus (BDV) can persistently infect the central nervous system and induce CD8+ T-cell-mediated neurological disease in MRL mice. To determine whether specific immune priming would prevent disease, a prime–boost immunization protocol was established in which intramuscular injection of a recombinant parapoxvirus expressing BDV nucleoprotein (BDV-N) was followed by intraperitoneal infection with vaccinia virus expressing BDV-N. Immunized wild-type and perforin-deficient mice remained healthy after intracerebral infection with BDV and contained almost no virus in the brain at 5 weeks post-challenge. Immunization failed to induce resistance against BDV in mice lacking mature CD8+ T cells. Immunization of perforin-deficient mice with a poxvirus vector expressing mutant BDV-N lacking the known CD8+ T-cell epitope did not efficiently block multiplication of BDV in the brain and did not prevent neurological disease, indicating that vaccine-induced immunity to BDV in wild-type and perforin-deficient mice resulted from the action of CD8+ T cells.

scholarly journals Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice

2009 ◽  
Vol 296 (4) ◽  
pp. G899-G909 ◽  
Author(s):  
Kamyar Zahedi ◽  
Alex B. Lentsch ◽  
Tomohisa Okaya ◽  
Sharon Barone ◽  
Nozomu Sakai ◽  
...  
Keyword(s):  
Liver Damage ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Tubules ◽  
Wild Type ◽  
Important Mediator ◽  
Liver And Kidney ◽  
Rate Limiting ◽  
Deficient Mice ◽  
Ssat Activity

Expression of spermine/spermidine- N1-acetyltransferase (SSAT), the rate-limiting enzyme of polyamine backconversion cascade, increases after ischemia-reperfusion injuries (IRI). We hypothesized that SSAT plays an important role in the mediation of IRI. To test our hypothesis, wild-type (SSAT-wt) and SSAT-deficient (SSAT-ko) mice were subjected to liver or kidney IRI by ligation of hepatic or renal arteries. The liver and kidney content of putrescine (Put), a downstream by-product of SSAT activity, increased in SSAT-wt animals but not in SSAT-ko animals after IRI, indicating that polyamine backconversion is not functional in SSAT-deficient mice. When subjected to hepatic IRI, SSAT-ko mice were significantly protected against liver damage compared with SSAT-wt mice. Similarly, SSAT-ko animals subjected to renal IRI showed significantly greater protection against damage to kidney tubules than SSAT-wt mice. These studies indicate that SSAT-deficient animals are protected against IRI and suggest that SSAT is an important mediator of the tissue damage in IRI.

scholarly journals Effects of androgens on cardiovascular remodeling

2012 ◽  
Vol 214 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Yasumasa Ikeda ◽  
Ken-ichi Aihara ◽  
Sumiko Yoshida ◽  
Masashi Akaike ◽  
Toshio Matsumoto
Keyword(s):  
Cardiovascular System ◽  
Sex Hormones ◽  
Anticancer Agent ◽  
Biological Effects ◽  
Wild Type ◽  
Female Sex Hormones ◽  
Target Organs ◽  
Male Sex ◽  
The Brain ◽  
Deficient Mice

Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well-known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males.

scholarly journals Abca7 deletion does not affect adult neurogenesis in the mouse

2016 ◽  
Vol 36 (2) ◽  
Author(s):  
Hongyun Li ◽  
Tim Karl ◽  
Brett Garner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Abc Transporters ◽  
Atp Binding ◽  
Wild Type ◽  
Atp Binding Cassette Transporter ◽  
The Brain ◽  
Deficient Mice ◽  
Atp Binding Cassette

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and linked with Alzheimer's disease. Since other ABC transporters regulate adult neurogenesis, we assessed neurogenesis in wild-type (WT) and Abca7 deficient mice. Abca7 deletion did not affect adult neurogenesis in the mouse.

scholarly journals Genetic and Pharmacologic Alteration of Cathepsin Expression Influences Reovirus Pathogenesis

2009 ◽  
Vol 83 (19) ◽  
pp. 9630-9640 ◽  
Author(s):  
Elizabeth M. Johnson ◽  
Joshua D. Doyle ◽  
J. Denise Wetzel ◽  
R. Paul McClung ◽  
Nobuhiko Katunuma ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Survival Rates ◽  
Proteolytic Processing ◽  
Host Cells ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Cathepsin Activity ◽  
Outer Capsid ◽  
The Brain ◽  
Deficient Mice

ABSTRACT The cathepsin family of endosomal proteases is required for proteolytic processing of several viruses during entry into host cells. Mammalian reoviruses utilize cathepsins B (Ctsb), L (Ctsl), and S (Ctss) for disassembly of the virus outer capsid and activation of the membrane penetration machinery. To determine whether cathepsins contribute to reovirus tropism, spread, and disease outcome, we infected 3-day-old wild-type (wt), Ctsb −/−, Ctsl −/−, and Ctss −/− mice with the virulent reovirus strain T3SA+. The survival rate of Ctsb −/− mice was enhanced in comparison to that of wt mice, whereas the survival rates of Ctsl −/− and Ctss −/− mice were diminished. Peak titers at sites of secondary replication in all strains of cathepsin-deficient mice were lower than those in wt mice. Clearance of the virus was delayed in Ctsl −/− and Ctss −/− mice in comparison to the levels for wt and Ctsb −/− mice, consistent with a defect in cell-mediated immunity in mice lacking cathepsin L or S. Cathepsin expression was dispensable for establishment of viremia, but cathepsin L was required for maximal reovirus growth in the brain. Treatment of wt mice with an inhibitor of cathepsin L led to amelioration of reovirus infection. Collectively, these data indicate that cathepsins B, L, and S influence reovirus pathogenesis and suggest that pharmacologic modulation of cathepsin activity diminishes reovirus disease severity.

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