Targeting the PI3K/Akt/NF-κB axis: Cluster of differentiation 5-like-mediated immunometabolic regulation of macrophage polarization in abdominal aortic aneurysm

  • J Cell Commun Signal. 2025 Oct 1;19(4):e70048. doi: 10.1002/ccs3.70048.
Hemoren Yi  1 ,  Nan Liu  2 ,  Zhengyang Wu  3  4 ,  Lei Li  1 ,  Tingting Li  5 ,  Qixiang Liu  1 ,  Man Duan  6 ,  Taihu Wan  7
Affiliations
  • 1. Department of Vascular Surgery Qian Wei Hospital of Jilin Province Changchun China.
  • 2. Department of General Surgery Qian Wei Hospital of Jilin Province Changchun China.
  • 3. Department of Anesthesiology The First Hospital of Jilin University Changchun Jilin China.
  • 4. College of Clinical Medicine Changchun University of Chinese Medicine Changchun Jilin China.
  • 5. Department of Ultrasound Qian Wei Hospital of Jilin Province Changchun Jilin China.
  • 6. Department of Vascular Surgery China-Japan Union Hospital of Jilin University Changchun Jilin China.
  • 7. Department of Interventional Oncology China-Japan Union Hospital of Jilin University Changchun Jilin China.
PMID: 41040887 DOI: 10.1002/ccs3.70048
Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder lacking effective pharmacological interventions. We identified CD5 molecule-like (CD5L) as a regulator of macrophage polarization in AAA via the phosphoinositide 3-kinase/protein kinase B/nuclear factor kappa B (PI3K/Akt/NF-κB) pathway. Transcriptomic analyses (GSE47472 and GSE57691) and angiotensin II (AngII)-infused Apolipoprotein E-deficient (apoE-/-) mice showed CD5L upregulation, inversely correlated with M1 macrophage infiltration. In vitro CD5L overexpression reduced, whereas knockdown increased M1 polarization and pro-inflammatory cytokines in RAW264.7 cells and human monocyte-derived macrophages. In vivo, CD5L knockdown aggravated aortic dilation, vascular disruption, and inflammatory mediator expression. Pharmacological modulation confirmed PI3K/Akt as essential for CD5L's anti-inflammatory action: LY294002 amplified, whereas PI3K Activator 740Y-P mitigated CD5L deficiency effects. RNA Sequencing confirmed PI3K/Akt activation downstream of CD5L. These results define CD5L as an immunometabolic checkpoint that suppresses NF-κB-mediated inflammation, suggesting a therapeutic target for AAA.

Keywords
CD5L; NF‐κB; PI3K/Akt signaling pathway; RNA sequencing; abdominal aortic aneurysm; macrophage polarization.
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