CFIm25-Dependent Alternative Polyadenylation in AKT2 mRNA Programs Macrophage Polarization
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Macrophage polarization is essential for immune responses, tissue homeostasis, and progression of many diseases. It is a tightly regulated process involving an intricate network of signaling pathways and control mechanisms at the level of transcription, alternative mRNA splicing, translation and mRNA stability. However, regulation through alternative mRNA polyadenylation (APA), remains poorly understood. This study explores the function of CFIm25, a key APA regulator, in macrophage polarization. Our findings show that CFIm25 overexpression drives M1 polarization, as evident from increased nitric oxide synthase activity, CD80 expression, and pro-inflammatory cytokine secretion, but dampens the M2 phenotype. Conversely, CFIm25 knockdown suppresses M1 traits and promotes M2 characteristics. Functionally, CFIm25 enhances phagocytosis, migration, and cancer cell inhibition. Mechanistically, CFIm25 favors proximal polyadenylation site usage of AKT2 mRNA, increasing Akt2 protein levels to support M1 polarization. Blocking this site with an antisense oligonucleotide reduces Akt2 expression and M1 traits. These findings establish CFIm25 as a crucial regulator of macrophage identity, offering insights into RNA-based immune regulation and potential therapeutic targets.
In brief
CFIm25 drives macrophage polarization toward the M1 phenotype through specific regulatory pathways. The presence of CFIm25 profoundly shifts surface marker expression, enhancing M1 markers while suppressing M2 signatures. This extends to biochemical properties, where CFIm25 boosts nitric oxide and pro-inflammatory cytokine production while reducing anti-inflammatory mediators. Functionally, CFIm25 enhances phagocytosis, inflammatory migration, and cancer cell killing. Mechanistically, this orchestration of the M1 polarization program involves CFIm25’s regulation of AKT2 mRNA alternative polyadenylation which increases Akt2 protein expression and amplifies NF-κB pathway activation, a central driver of M1 polarization.
Highlights
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CFIm25 overexpression enhances M1 surface markers and biochemical properties including nitric oxide production and pro-inflammatory cytokine secretion.
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CFIm25 promotes M1 functional activities including phagocytosis, migration, and cancer-cytotoxic effects.
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Blocking the AKT2 proximal polyadenylation site usage causes a decrease in Akt2 protein, suppressing M1 polarization phenotypes including NOS activity and cytokine profiles.
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The CFIm25-Akt2-NF-κB axis represents a novel target for macrophage polarization reprogramming.
