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

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Macrophages are key immune cells that can adopt pro-inflammatory or anti-inflammatory phenotypes.
• Persistent pro-inflammatory macrophage states contribute to chronic inflammatory diseases.
• Arginase 2 (Arg2) is a mitochondrial enzyme that resolves inflammation and is regulated by miR-155.

Purpose of the Study:

• To develop and evaluate a target site blocker (TSB) to inhibit miR-155 binding to Arg2 mRNA.
• To investigate the therapeutic potential of modulating macrophage phenotype via Arg2 upregulation.

Main Methods:

• Design and synthesis of an Arg2 TSB.
• Transfection of bone marrow-derived macrophages with Arg2 TSB.
• Assessment of macrophage polarization markers, metabolic activity, and cytokine secretion.
• Evaluation of Arg2 TSB efficacy in an LPS-induced acute inflammation mouse model.

Main Results:

• Arg2 TSB transfection increased Arg2 expression and activity in macrophages.
• Macrophages treated with Arg2 TSB exhibited a shift towards an anti-inflammatory phenotype, evidenced by altered surface markers (CD80, CD71), enhanced mitochondrial respiration, and reduced pro-inflammatory cytokine secretion (IL-1β, IL-6, TNF).
• In vivo administration of Arg2 TSB decreased systemic pro-inflammatory cytokine levels during acute inflammation.

Conclusions:

• The developed Arg2 TSB is a viable proof-of-concept strategy for reprogramming pro-inflammatory macrophages to an anti-inflammatory state.
• This approach holds promise for the therapeutic modulation of macrophage phenotype in inflammatory conditions.