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Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis
Published on: November 28, 2015
CFIm25-dependent alternative polyadenylation in AKT2 mRNA programs macrophage polarization
Srimoyee Mukherjee1, Atish Barua1, Marzieh Naseri1
1Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
Iscience
|May 11, 2026
Summary
Alternative mRNA polyadenylation (APA) regulates macrophage polarization. CFIm25 controls M1/M2 states by affecting AKT2 mRNA, offering a therapeutic target for immune modulation.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Macrophage polarization into M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes is crucial for immune function and tissue balance.
- While gene expression regulation at transcriptional and post-transcriptional levels is understood, the role of alternative mRNA polyadenylation (APA) in macrophage polarization remains unclear.
Purpose of the Study:
- To investigate the role of APA, specifically the regulator CFIm25, in controlling macrophage polarization.
- To elucidate the molecular mechanisms by which CFIm25 influences macrophage phenotypes.
Main Methods:
- Utilized human monocytic cell lines to study CFIm25 function.
- Manipulated CFIm25 expression (overexpression and knockdown) and analyzed macrophage polarization markers.
- Investigated the effect of CFIm25 on AKT2 mRNA polyadenylation and protein levels.
- Employed antisense oligonucleotides to block AKT2 proximal polyadenylation site.
Main Results:
- CFIm25 overexpression promoted M1 macrophage characteristics (e.g., nitric oxide production, CD80 expression, pro-inflammatory cytokine secretion, enhanced phagocytosis, migration, and cancer cell killing) and suppressed M2 traits.
- CFIm25 knockdown induced opposite effects, favoring M2-like phenotypes.
- CFIm25 was found to promote proximal polyadenylation of AKT2 mRNA, leading to shorter, more stable transcripts with increased translation efficiency, resulting in higher Akt2 protein levels.
- Increased Akt2 protein amplified NF-κB signaling, driving M1 polarization.
- Blocking AKT2 proximal polyadenylation site with antisense oligonucleotides reduced Akt2 expression and promoted M2-like phenotypes.
Conclusions:
- Alternative mRNA polyadenylation is a critical regulatory mechanism in macrophage polarization.
- The CFIm25-Akt2-NF-κB signaling axis is identified as a key pathway controlling macrophage polarization states.
- This axis represents a potential therapeutic target for modulating immune responses and treating related diseases.
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