Monocytes Reprogrammed by 4-PBA Potently Contribute to the Resolution of Inflammation and Atherosclerosis

Area of Science:

• Immunology
• Molecular Biology
• Cardiovascular Research

Background:

• Chronic inflammation driven by monocytes is central to atherosclerosis development.
• Effective therapies targeting monocyte-mediated inflammation are limited.
• 4-phenylbutyric acid (4-PBA) shows potential for anti-inflammatory effects in atherosclerosis.

Purpose of the Study:

• To characterize 4-PBA-reprogrammed monocytes and their therapeutic potential for atherosclerosis.
• To elucidate the molecular mechanisms underlying monocyte reprogramming by 4-PBA.
• To evaluate the in vivo efficacy of 4-PBA-trained monocytes in preventing atherosclerosis.

Main Methods:

• Single-cell RNA sequencing and immunologic approaches to characterize reprogrammed monocytes.
• Biochemical and genetic analyses to identify molecular mechanisms.
• In vivo studies using ApoE-/- mice fed a high-fat diet.
• Ex vivo monocyte training followed by in vivo transfusion.

Main Results:

• 4-PBA reprograms monocytes to an immune-resolving phenotype with reduced adhesion and increased CD24 expression.
• Mechanisms involve reduced peroxisome stress, attenuated SYK-mTOR signaling, and enhanced PPARγ neddylation.
• 4-PBA-trained monocytes propagate anti-inflammatory signals and reduce atherosclerosis in vivo.

Conclusions:

• A method to generate resolving monocytes using 4-PBA has been established.
• Novel mechanisms for monocyte reprogramming by 4-PBA were identified.
• This approach offers precision therapeutics for atherosclerosis via reprogrammed monocytes.