Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype
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 2022External DOI
PubMed ID
36090747Department/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)