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Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype

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posted on 2023-10-11, 15:43 authored by Chiara De SantiChiara De Santi, Frances Nally, Remsha Afzal, Conor P Duffy, Stephen Fitzsimons, Stephanie AnnettStephanie Annett, Tracy RobsonTracy Robson, Jennifer DowlingJennifer Dowling, Sally-Ann CryanSally-Ann Cryan, Claire McCoy

Macrophages are plastic cells playing a crucial role in innate immunity. While fundamental in responding to infections, when persistently maintained in a pro-inflammatory state they can initiate and sustain inflammatory diseases. Therefore, a strategy that reprograms pro-inflammatory macrophages toward an anti-inflammatory phenotype could hold therapeutic potential in that context. We have recently shown that arginase 2 (Arg2), a mitochondrial enzyme involved in arginine metabolism, promotes the resolution of inflammation in macrophages and it is targeted by miR-155. Here, we designed and tested a target site blocker (TSB) that specifically interferes and blocks the interaction between miR-155 and Arg2 mRNA, leading to Arg2 increased expression and activity. In bone marrow-derived macrophages transfected with Arg2 TSB (in the presence or absence of the pro-inflammatory stimulus LPS), we observed an overall shift of the polarization status of macrophages toward an anti-inflammatory phenotype, as shown by significant changes in surface markers (CD80 and CD71), metabolic parameters (mitochondrial oxidative phosphorylation) and cytokines secretion (IL-1β, IL-6, and TNF). Moreover, in an in vivo model of LPS-induced acute inflammation, intraperitoneal administration of Arg2 TSB led to an overall decrease in systemic levels of pro-inflammatory cytokines. Overall, this proof-of-concept strategy represent a promising approach to modulating macrophage phenotype. 

Funding

Science Foundation Ireland (SFI16/FRL/3855)

Irish Research Council (GOIPD/2018/575 and GOIPG/2018/2648)

Enterprise Ireland and Knowledge Transfer Ireland (SI 2020 3049)

FutureNeuro (seed fund 2020)

Psoriasis Foundation

National Children's Research Centre (C/18/9)

SFI Strategic Partnership Programme - Precision Oncology Ireland (18/SPP/3522)

SFI-FFP program (20/FFP-A/8361)

SFI IvP (13/IA/1840)

History

Comments

The original article is available at https://www.sciencedirect.com/

Published Citation

De Santi C, et al. Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype. Mol Ther Nucleic Acids. 2022;29:643-655.

Publication Date

4 August 2022

PubMed ID

36090747

Department/Unit

  • School of Pharmacy and Biomolecular Sciences
  • FutureNeuro Centre
  • Tissue Engineering Research Group (TERG)
  • Amber (Advanced Material & Bioengineering Research) Centre
  • CURAM Centre for Research in Medical Devices
  • Anatomy and Regenerative Medicine

Publisher

Elsevier B.V.,

Version

  • Published Version (Version of Record)

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