The PI3K-Akt-CCND2 axis couples metabolic reprogramming with macrophage M1 polarization

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Macrophage polarization, particularly M1, is central to inflammatory disorders.
• The interplay between metabolic shifts and cell-cycle regulators like Ccnd2 in macrophage polarization is not well understood.

Purpose of the Study:

• To investigate the role of the PI3K-Akt-Ccnd2 signaling axis in lipopolysaccharide (LPS)-induced macrophage inflammation.
• To evaluate the therapeutic efficacy of targeting this axis in a mouse model of sepsis-associated acute kidney injury (SA-AKI).

Main Methods:

• In vitro studies utilized RAW264.7 macrophages with various treatments (LPS, PI3K inhibitor, M-CSF, Ccnd2 inhibitor, Akt activator).
• In vivo studies employed a cecal ligation and puncture (CLP)-induced SA-AKI mouse model with M-CSF intervention.
• Techniques included transcriptomic/metabolomic profiling, Western blotting, qRT-PCR, flow cytometry, and histopathological analysis.

Main Results:

• LPS induced inflammatory pathways and downregulated Ccnd2; M-CSF restored Ccnd2 via PI3K-Akt signaling.
• Metabolomic analysis revealed significant changes in purine, glycerophospholipid, and amino acid metabolism following LPS stimulation.
• M-CSF and PI3K inhibition suppressed LPS-induced M1 polarization. In CLP mice, M-CSF treatment improved renal function and reduced inflammation, effects reversed by PI3K inhibition.

Conclusions:

• The PI3K-Akt-Ccnd2 axis links metabolic reprogramming and cell-cycle progression to macrophage M1 polarization.
• Targeting the PI3K-Akt-Ccnd2 pathway demonstrates therapeutic potential for mitigating inflammation in SA-AKI and other inflammatory conditions.