Inhibition of Pro-inflammatory Signaling in Human Primary Macrophages by Enhancing Arginase-2 Via Target Site Blockers

Overview

Journal Mol Ther Nucleic Acids

Publisher Cell Press

Date 2023 Sep 13

PMID 37701067

Authors

Stephen Fitzsimons

Maria Munoz-San Martin

Frances Nally

Eugene Dillon

Ifeolutembi A Fashina

Moritz J Strowitzki

Lluis Ramio-Torrenta

Jennifer K Dowling

Chiara de Santi

Claire E McCoy

Affiliations

Soon will be listed here.

Abstract

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 3' UTR mRNA. TSBs targeting miR-155 (TSB-155) and miR-3202 (TSB-3202) MREs increased 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. 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.

Citing Articles

Arginine metabolism in myeloid cells in health and disease.

Karadima E, Chavakis T, Alexaki V Semin Immunopathol. 2025; 47(1):11.

PMID: 39863828 PMC: 11762783. DOI: 10.1007/s00281-025-01038-9.

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