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

Abstract

Dysregulated macrophage M1 polarization is a core pathological feature of inflammatory disorders. However, the crosstalk between metabolic reprogramming and cell-cycle regulator Ccnd2 during macrophage polarization remains largely unclear. This study explored the role of the PI3K-Akt-Ccnd2 axis in LPS-induced macrophage inflammation and verified its therapeutic potential in sepsis-associated acute kidney injury (SA-AKI). In vitro experiments were performed using RAW264.7 macrophages (Sham, LPS, PI3K inhibitor + LPS, M-CSF alone, M-CSF + LPS, Ccnd2 inhibitor, Ccnd2 inhibitor + Akt activator). In vivo studies were conducted using a cecal ligation and puncture (CLP)-induced SA-AKI mouse model with M-CSF intervention. Transcriptomic/metabolomic profiling, Western blotting, qRT-PCR, flow cytometry, and histopathological analysis were applied. Renal function, systemic inflammation, and signaling pathway activation were evaluated. LPS triggered transcriptional reprogramming enriched in PI3K-Akt, cell-cycle, and inflammatory pathways, and downregulated Ccnd2 expression; M-CSF restored Ccnd2 via PI3K-Akt signaling, which was abolished by PI3K inhibition. Metabolomic analysis identified marked alterations in purine, glycerophospholipid, and amino acid metabolism in LPS-stimulated macrophages. LPS enhanced M1 polarization, whereas M-CSF or PI3K inhibition suppressed this effect. In CLP mice, M-CSF significantly reduced serum Cre/BUN levels, alleviated systemic inflammation and renal histopathological damage, and activated the renal PI3K-Akt-Ccnd2 axis; these renoprotective effects were reversed by PI3K inhibition. LPS-induced metabolic reprogramming cooperates with PI3K-Akt signaling to regulate Ccnd2, thereby coupling macrophage cell-cycle progression and M1 polarization. The PI3K-Akt-Ccnd2 axis modulates macrophage inflammation in vitro and ameliorates CLP-induced SA-AKI in vivo, representing a promising therapeutic target for sepsis and related inflammatory organ injury. The PI3K-Akt-Ccnd2 axis may represent a candidate for further investigation for sepsis and other inflammatory disorders.