Oleoylethanolamide Enhances Regulatory T Cell Function to Accelerate Plaque Regression in Atherosclerosis via PPARα Activation

Abstract Regulatory T cells (Tregs) are essential for maintaining immune balance and limiting inflammatory damage within atherosclerotic plaques. Although the endogenous lipid mediator oleoylethanolamide (OEA) has reported anti-inflammatory and metabolic benefits, its effects on Treg differentiation and function during atherosclerosis are incompletely defined. Here, we tested OEA using in vitro naïve CD4⁺ T-cell polarization assays and in vivo atherosclerosis models. OEA increased CD25⁺Foxp3⁺ Treg differentiation in polarization cultures and shifted the Treg compartment in atherosclerotic mice toward a more functional phenotype. PPARα dependence was supported by pharmacologic inhibition with MK886 and by genetic loss of PPARα, both of which abrogated OEA-induced Treg differentiation and functional enhancement. Mechanistically, OEA engaged a PPARα–RORγt pathway consistent with suppression of RORγt-associated programs during Treg differentiation. In therapeutic studies, adoptive transfer of OEA-conditioned Tregs promoted regression of established atherosclerotic plaques. Together, these data identify OEA as a modulator of Treg differentiation and activity and support its potential as a PPARα-dependent strategy to promote plaque regression and immune homeostasis in atherosclerosis.