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Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers

The modulation of macrophage phenotype from a pro-inflammatory to an anti-inflammatory state holds therapeutic potential in the treatment of inflammatory disease. We have previously shown that arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response....

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Autores principales: Fitzsimons, Stephen, Muñoz-San Martín, María, Nally, Frances, Dillon, Eugene, Fashina, Ifeolutembi A., Strowitzki, Moritz J., Ramió-Torrentà, Lluís, Dowling, Jennifer K., De Santi, Chiara, McCoy, Claire E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10494319/
https://www.ncbi.nlm.nih.gov/pubmed/37701067
http://dx.doi.org/10.1016/j.omtn.2023.08.023
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author Fitzsimons, Stephen
Muñoz-San Martín, María
Nally, Frances
Dillon, Eugene
Fashina, Ifeolutembi A.
Strowitzki, Moritz J.
Ramió-Torrentà, Lluís
Dowling, Jennifer K.
De Santi, Chiara
McCoy, Claire E.
author_facet Fitzsimons, Stephen
Muñoz-San Martín, María
Nally, Frances
Dillon, Eugene
Fashina, Ifeolutembi A.
Strowitzki, Moritz J.
Ramió-Torrentà, Lluís
Dowling, Jennifer K.
De Santi, Chiara
McCoy, Claire E.
author_sort Fitzsimons, Stephen
collection PubMed
description The modulation of macrophage phenotype from a pro-inflammatory to an anti-inflammatory state holds therapeutic potential in the treatment of inflammatory disease. We have previously shown that arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response. Here, we investigate the therapeutic potential of Arg2 enhancement via target site blockers (TSBs) in human macrophages. TSBs are locked nucleic acid antisense oligonucleotides that were specifically designed to protect specific microRNA recognition elements (MREs) in human ARG2 3′ UTR mRNA. TSBs targeting miR-155 (TSB-155) and miR-3202 (TSB-3202) MREs increased ARG2 expression in human monocyte-derived macrophages. This resulted in decreased gene expression and cytokine production of TNF-α and CCL2 and, for TSB-3202, in an increase in the anti-inflammatory macrophage marker, CD206. Proteomic analysis demonstrated that a network of pro-inflammatory responsive proteins was modulated by TSBs. In silico bioinformatic analysis predicted that TSB-3202 suppressed upstream pro-inflammatory regulators including STAT-1 while enhancing anti-inflammatory associated proteins. Proteomic data were validated by confirming increased levels of sequestosome-1 and decreased levels of phosphorylated STAT-1 and STAT-1 upon TSB treatment. In conclusion, upregulation of Arg2 by TSBs inhibits pro-inflammatory signaling and is a promising novel therapeutic strategy to modulate inflammatory signaling in human macrophages.
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spelling pubmed-104943192023-09-12 Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers Fitzsimons, Stephen Muñoz-San Martín, María Nally, Frances Dillon, Eugene Fashina, Ifeolutembi A. Strowitzki, Moritz J. Ramió-Torrentà, Lluís Dowling, Jennifer K. De Santi, Chiara McCoy, Claire E. Mol Ther Nucleic Acids Original Article The modulation of macrophage phenotype from a pro-inflammatory to an anti-inflammatory state holds therapeutic potential in the treatment of inflammatory disease. We have previously shown that arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response. Here, we investigate the therapeutic potential of Arg2 enhancement via target site blockers (TSBs) in human macrophages. TSBs are locked nucleic acid antisense oligonucleotides that were specifically designed to protect specific microRNA recognition elements (MREs) in human ARG2 3′ UTR mRNA. TSBs targeting miR-155 (TSB-155) and miR-3202 (TSB-3202) MREs increased ARG2 expression in human monocyte-derived macrophages. This resulted in decreased gene expression and cytokine production of TNF-α and CCL2 and, for TSB-3202, in an increase in the anti-inflammatory macrophage marker, CD206. Proteomic analysis demonstrated that a network of pro-inflammatory responsive proteins was modulated by TSBs. In silico bioinformatic analysis predicted that TSB-3202 suppressed upstream pro-inflammatory regulators including STAT-1 while enhancing anti-inflammatory associated proteins. Proteomic data were validated by confirming increased levels of sequestosome-1 and decreased levels of phosphorylated STAT-1 and STAT-1 upon TSB treatment. In conclusion, upregulation of Arg2 by TSBs inhibits pro-inflammatory signaling and is a promising novel therapeutic strategy to modulate inflammatory signaling in human macrophages. American Society of Gene & Cell Therapy 2023-08-22 /pmc/articles/PMC10494319/ /pubmed/37701067 http://dx.doi.org/10.1016/j.omtn.2023.08.023 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Fitzsimons, Stephen
Muñoz-San Martín, María
Nally, Frances
Dillon, Eugene
Fashina, Ifeolutembi A.
Strowitzki, Moritz J.
Ramió-Torrentà, Lluís
Dowling, Jennifer K.
De Santi, Chiara
McCoy, Claire E.
Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
title Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
title_full Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
title_fullStr Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
title_full_unstemmed Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
title_short Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
title_sort inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10494319/
https://www.ncbi.nlm.nih.gov/pubmed/37701067
http://dx.doi.org/10.1016/j.omtn.2023.08.023
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