Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月13日

查看全文
  • Xiaoyu Liu,
  • Wei Shi,
  • Lin Chai,
  • Jianyuan Liu,
  • Yanqian Su,
  • Shuxing Wei,
  • Chunkai Jia,
  • Xiaomei Zhu,
  • Shubin Guo

摘要

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.