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The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis

Cell survival and function critically relies on the fine-tuned balance of protein synthesis and degradation. In the steady state, the standard proteasome is sufficient to maintain this proteostasis. However, upon inflammation, the sharp increase in protein production requires additional mechanisms t...

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Autores principales: French, Timothy, Israel, Nicole, Düsedau, Henning Peter, Tersteegen, Anne, Steffen, Johannes, Cammann, Clemens, Topfstedt, Eylin, Dieterich, Daniela, Schüler, Thomas, Seifert, Ulrike, Dunay, Ildiko Rita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099150/
https://www.ncbi.nlm.nih.gov/pubmed/33968021
http://dx.doi.org/10.3389/fimmu.2021.619465
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author French, Timothy
Israel, Nicole
Düsedau, Henning Peter
Tersteegen, Anne
Steffen, Johannes
Cammann, Clemens
Topfstedt, Eylin
Dieterich, Daniela
Schüler, Thomas
Seifert, Ulrike
Dunay, Ildiko Rita
author_facet French, Timothy
Israel, Nicole
Düsedau, Henning Peter
Tersteegen, Anne
Steffen, Johannes
Cammann, Clemens
Topfstedt, Eylin
Dieterich, Daniela
Schüler, Thomas
Seifert, Ulrike
Dunay, Ildiko Rita
author_sort French, Timothy
collection PubMed
description Cell survival and function critically relies on the fine-tuned balance of protein synthesis and degradation. In the steady state, the standard proteasome is sufficient to maintain this proteostasis. However, upon inflammation, the sharp increase in protein production requires additional mechanisms to limit protein-associated cellular stress. Under inflammatory conditions and the release of interferons, the immunoproteasome (IP) is induced to support protein processing and recycling. In antigen-presenting cells constitutively expressing IPs, inflammation-related mechanisms contribute to the formation of MHC class I/II-peptide complexes, which are required for the induction of T cell responses. The control of Toxoplasma gondii infection relies on Interferon-γ (IFNγ)-related T cell responses. Whether and how the IP affects the course of anti-parasitic T cell responses along the infection as well as inflammation of the central nervous system is still unknown. To answer this question we used triple knockout (TKO) mice lacking the 3 catalytic subunits of the immunoproteasome (β1i/LMP2, β2i/MECL-1 and β5i/LMP7). Here we show that the numbers of dendritic cells, monocytes and CD8(+) T cells were reduced in Toxoplasma gondii-infected TKO mice. Furthermore, impaired IFNγ, TNF and iNOS production was accompanied by dysregulated chemokine expression and altered immune cell recruitment to the brain. T cell differentiation was altered, apoptosis rates of microglia and monocytes were elevated and STAT3 downstream signaling was diminished. Consequently, anti-parasitic immune responses were impaired in TKO mice leading to elevated T. gondii burden and prolonged neuroinflammation. In summary we provide evidence for a critical role of the IP subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 for the control of cerebral Toxoplasma gondii infection and subsequent neuroinflammation.
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spelling pubmed-80991502021-05-06 The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis French, Timothy Israel, Nicole Düsedau, Henning Peter Tersteegen, Anne Steffen, Johannes Cammann, Clemens Topfstedt, Eylin Dieterich, Daniela Schüler, Thomas Seifert, Ulrike Dunay, Ildiko Rita Front Immunol Immunology Cell survival and function critically relies on the fine-tuned balance of protein synthesis and degradation. In the steady state, the standard proteasome is sufficient to maintain this proteostasis. However, upon inflammation, the sharp increase in protein production requires additional mechanisms to limit protein-associated cellular stress. Under inflammatory conditions and the release of interferons, the immunoproteasome (IP) is induced to support protein processing and recycling. In antigen-presenting cells constitutively expressing IPs, inflammation-related mechanisms contribute to the formation of MHC class I/II-peptide complexes, which are required for the induction of T cell responses. The control of Toxoplasma gondii infection relies on Interferon-γ (IFNγ)-related T cell responses. Whether and how the IP affects the course of anti-parasitic T cell responses along the infection as well as inflammation of the central nervous system is still unknown. To answer this question we used triple knockout (TKO) mice lacking the 3 catalytic subunits of the immunoproteasome (β1i/LMP2, β2i/MECL-1 and β5i/LMP7). Here we show that the numbers of dendritic cells, monocytes and CD8(+) T cells were reduced in Toxoplasma gondii-infected TKO mice. Furthermore, impaired IFNγ, TNF and iNOS production was accompanied by dysregulated chemokine expression and altered immune cell recruitment to the brain. T cell differentiation was altered, apoptosis rates of microglia and monocytes were elevated and STAT3 downstream signaling was diminished. Consequently, anti-parasitic immune responses were impaired in TKO mice leading to elevated T. gondii burden and prolonged neuroinflammation. In summary we provide evidence for a critical role of the IP subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 for the control of cerebral Toxoplasma gondii infection and subsequent neuroinflammation. Frontiers Media S.A. 2021-04-21 /pmc/articles/PMC8099150/ /pubmed/33968021 http://dx.doi.org/10.3389/fimmu.2021.619465 Text en Copyright © 2021 French, Israel, Düsedau, Tersteegen, Steffen, Cammann, Topfstedt, Dieterich, Schüler, Seifert and Dunay https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
French, Timothy
Israel, Nicole
Düsedau, Henning Peter
Tersteegen, Anne
Steffen, Johannes
Cammann, Clemens
Topfstedt, Eylin
Dieterich, Daniela
Schüler, Thomas
Seifert, Ulrike
Dunay, Ildiko Rita
The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis
title The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis
title_full The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis
title_fullStr The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis
title_full_unstemmed The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis
title_short The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis
title_sort immunoproteasome subunits lmp2, lmp7 and mecl-1 are crucial along the induction of cerebral toxoplasmosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099150/
https://www.ncbi.nlm.nih.gov/pubmed/33968021
http://dx.doi.org/10.3389/fimmu.2021.619465
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