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Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia

The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (IT...

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Autores principales: Du, Sheng-hong, Xiang, Yu-jiao, Liu, Lu, Nie, Mu, Hou, Yu, Wang, Ling, Li, Ban-ban, Xu, Miao, Teng, Qing-liang, Peng, Jun, Hou, Ming, Shi, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855704/
https://www.ncbi.nlm.nih.gov/pubmed/33552061
http://dx.doi.org/10.3389/fimmu.2020.603278
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author Du, Sheng-hong
Xiang, Yu-jiao
Liu, Lu
Nie, Mu
Hou, Yu
Wang, Ling
Li, Ban-ban
Xu, Miao
Teng, Qing-liang
Peng, Jun
Hou, Ming
Shi, Yan
author_facet Du, Sheng-hong
Xiang, Yu-jiao
Liu, Lu
Nie, Mu
Hou, Yu
Wang, Ling
Li, Ban-ban
Xu, Miao
Teng, Qing-liang
Peng, Jun
Hou, Ming
Shi, Yan
author_sort Du, Sheng-hong
collection PubMed
description The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. We found that the expression of the immunoproteasome catalytic subunit, large multifunctional protease 2 (LMP2), was significantly upregulated in peripheral blood mononuclear cells of active ITP patients compared to those of healthy controls. No significant differences in LMP7 expression were observed between patients and controls. ML604440, an specific LMP2 inhibitor, had no significant impact on the platelet count of ITP mice, while ONX-0914 (an inhibitor of both LMP2 and LMP7) increased the number of platelets. In vitro assays revealed that ONX-0914 decreased the expression of FcγRI in ITP mice and decreased that of FcγRIII in ITP patients, inhibited the activation of CD4(+) T cells, and affected the differentiation of Th1 cells in patients with ITP. These results suggest that the inhibition of immunoproteasome is a potential therapeutic approach for ITP patients.
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spelling pubmed-78557042021-02-04 Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia Du, Sheng-hong Xiang, Yu-jiao Liu, Lu Nie, Mu Hou, Yu Wang, Ling Li, Ban-ban Xu, Miao Teng, Qing-liang Peng, Jun Hou, Ming Shi, Yan Front Immunol Immunology The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. We found that the expression of the immunoproteasome catalytic subunit, large multifunctional protease 2 (LMP2), was significantly upregulated in peripheral blood mononuclear cells of active ITP patients compared to those of healthy controls. No significant differences in LMP7 expression were observed between patients and controls. ML604440, an specific LMP2 inhibitor, had no significant impact on the platelet count of ITP mice, while ONX-0914 (an inhibitor of both LMP2 and LMP7) increased the number of platelets. In vitro assays revealed that ONX-0914 decreased the expression of FcγRI in ITP mice and decreased that of FcγRIII in ITP patients, inhibited the activation of CD4(+) T cells, and affected the differentiation of Th1 cells in patients with ITP. These results suggest that the inhibition of immunoproteasome is a potential therapeutic approach for ITP patients. Frontiers Media S.A. 2021-01-20 /pmc/articles/PMC7855704/ /pubmed/33552061 http://dx.doi.org/10.3389/fimmu.2020.603278 Text en Copyright © 2021 Du, Xiang, Liu, Nie, Hou, Wang, Li, Xu, Teng, Peng, Hou and Shi http://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
Du, Sheng-hong
Xiang, Yu-jiao
Liu, Lu
Nie, Mu
Hou, Yu
Wang, Ling
Li, Ban-ban
Xu, Miao
Teng, Qing-liang
Peng, Jun
Hou, Ming
Shi, Yan
Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia
title Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia
title_full Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia
title_fullStr Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia
title_full_unstemmed Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia
title_short Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia
title_sort co-inhibition of the immunoproteasome subunits lmp2 and lmp7 ameliorates immune thrombocytopenia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855704/
https://www.ncbi.nlm.nih.gov/pubmed/33552061
http://dx.doi.org/10.3389/fimmu.2020.603278
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