Abstract:
:Immunoproteasome (IP) inhibition holds potential as a novel treatment option for various immune-mediated pathologies. The IP inhibitor ONX 0914 reduced T cell cytokine secretion and Th17 polarization and showed pre-clinical efficacy in a range of autoimmune disorders, transplant-allograft rejection, virus-mediated tissue damage, and colon cancer progression. However, the molecular basis of these effects has remained largely elusive. Here, we have analyzed the effects of ONX 0914 in primary human and mouse lymphocytes. ONX 0914-treatment impaired primary T cell activation in vitro and in vivo. IP inhibition reduced ERK-phosphorylation sustainment, while leaving NF-κB and other signaling pathways unaffected. Naïve T and B cells expressed nearly exclusively immuno- or mixed proteasomes but no standard proteasomes and IP inhibition but not IP-deficiency induced mild proteostasis stress, reduced DUSP5 expression and enhanced DUSP6 protein levels due to impaired degradation. However, accumulation of DUSP6 did not cause the reduced ERK-phosphorylation in a non-redundant manner. We show that broad-spectrum proteasome inhibition and immunoproteasome inhibition have distinct effects on T cell activation at the molecular level. Notably, ONX 0914-treated T cells recovered from proteostasis stress without apoptosis induction, apparently via Nrf1-mediated up-regulation of standard proteasomes. In contrast, B cells were more susceptible to apoptosis after ONX 0914-treatment. Our data thus provide mechanistic insights how IP inhibition functionally impedes T and B cells likely accounting for its therapeutic benefits.
journal_name
Front Immunoljournal_title
Frontiers in immunologyauthors
Schmidt C,Berger T,Groettrup M,Basler Mdoi
10.3389/fimmu.2018.02386subject
Has Abstractpub_date
2018-10-26 00:00:00pages
2386issn
1664-3224journal_volume
9pub_type
杂志文章abstract::Neisseria gonorrhoeae is a significant health problem worldwide due to multi-drug resistance issues and absence of an effective vaccine. Patients infected with N. gonorrhoeae have not shown a better immune response in successive infections. This might be explained by the fact that N. gonorrhoeae possesses several mech...
journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
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journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
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abstract::The immune system contributes to neurodegenerative pathologies. However, the roles of γδ T cells in Alzheimer's disease (AD) are poorly understood. Here, we evaluated somatic variability of T-cell receptor γ genes (TRGs) in patients with AD. We performed deep sequencing of the CDR3 region of TRGs in patients with AD a...
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2019.03123
更新日期:2020-01-24 00:00:00
abstract:BACKGROUND:Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy o...
journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2017.00546
更新日期:2017-05-12 00:00:00
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pub_type: 杂志文章,评审
doi:10.3389/fimmu.2018.02765
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pub_type: 杂志文章
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更新日期:2014-08-14 00:00:00
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pub_type: 杂志文章
doi:10.3389/fimmu.2020.01677
更新日期:2020-08-13 00:00:00
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journal_title:Frontiers in immunology
pub_type: 临床试验,杂志文章
doi:10.3389/fimmu.2018.02123
更新日期:2018-09-21 00:00:00
abstract::H7N9 viruses pose a threat to human health and they are no less harmful to the poultry industry than the H5N1 avian influenza viruses. However, the pathogenesis, transmissibility, and the host immune response of the H7N9 virus in chickens and mice remain unclear. In this study, we found that H7N9 viruses replicated in...
journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2018.00789
更新日期:2018-04-13 00:00:00
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journal_title:Frontiers in immunology
pub_type: 杂志文章
doi:10.3389/fimmu.2017.01476
更新日期:2017-11-06 00:00:00
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doi:10.3389/fimmu.2020.581713
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pub_type: 杂志文章
doi:10.3389/fimmu.2019.00459
更新日期:2019-03-14 00:00:00
abstract::Migraine is a common, little understood, and debilitating disease. It is much more prominent in women than in men (~2/3 are women) but the reasons for female preponderance are not clear. Migraineurs frequently experience severe comorbidities, such as allergies, depression, irritable bowel syndrome, and others; many of...
journal_title:Frontiers in immunology
pub_type: 杂志文章,评审
doi:10.3389/fimmu.2016.00140
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journal_title:Frontiers in immunology
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pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
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journal_title:Frontiers in immunology
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