Targeting the PI3K/Akt/NF-κB axis: Cluster of differentiation 5-like-mediated immunometabolic regulation of...

Area of Science:

• Vascular Biology
• Immunology
• Molecular Medicine

Background:

• Abdominal aortic aneurysm (AAA) is a critical vascular condition with limited pharmacological treatments.
• Macrophage polarization plays a key role in AAA pathogenesis.
• The phosphoinositide 3-kinase/protein kinase B/nuclear factor kappa B (PI3K/Akt/NF-κB) pathway is implicated in inflammatory processes.

Purpose of the Study:

• To investigate the role of CD5 molecule-like (CD5L) in regulating macrophage polarization within the context of abdominal aortic aneurysm (AAA).
• To elucidate the molecular mechanisms, specifically the PI3K/Akt/NF-κB pathway, through which CD5L influences AAA development.
• To evaluate CD5L as a potential therapeutic target for AAA.

Main Methods:

• Transcriptomic analysis of human and mouse AAA samples (GSE47472, GSE57691).
• In vitro studies using RAW264.7 cells and human monocyte-derived macrophages with CD5L manipulation (overexpression and knockdown).
• In vivo studies using angiotensin II-infused apolipoprotein E-deficient (ApoE-/-) mice with CD5L knockdown, alongside pharmacological modulation of the PI3K/Akt pathway.

Main Results:

• CD5L was upregulated in AAA and inversely correlated with M1 macrophage infiltration.
• CD5L overexpression reduced M1 polarization and pro-inflammatory cytokines, while knockdown exacerbated AAA phenotypes and inflammation.
• Pharmacological inhibition of PI3K/Akt amplified CD5L's anti-inflammatory effects, confirming PI3K/Akt activation downstream of CD5L.

Conclusions:

• CD5L acts as an immunometabolic checkpoint, suppressing NF-κB-mediated inflammation in AAA.
• CD5L's anti-inflammatory actions are dependent on the PI3K/Akt pathway.
• CD5L represents a promising novel therapeutic target for abdominal aortic aneurysm.