Adiponectin attenuates atherosclerosis via macrophage polarization-mediated T Cell exhaustion by modulating the NF-κB p65/PI3K/Akt signaling pathway

Objective

This study aimed to investigate the role of adiponectin (AD) in attenuating atherosclerosis (AS) by modulating macrophage polarization and inducing T cell exhaustion.

Methods

Male Apolipoprotein E deficient (ApoE^−/−) mice were fed a high-fat diet (HFD) to establish AS models. Mice were randomized into four groups (n = 10): Model, AD, anti-PD-1, and AD+PD-1 combination therapy. Plasma lipid profiles were quantified via ELISA. Atherosclerotic plaques were assessed by HE and Oil Red O staining. Splenic T cell subsets were analyzed using immunofluorescence, while protein expression of inhibitory receptors and NF-κB p65/PI3K/Akt pathway components was evaluated by Western blot.

Results

AD administration significantly improved systemic lipid metabolism, reducing serum triglycerides and low-density lipoprotein levels while elevating high-density lipoprotein. AD induced macrophage polarization toward an anti-inflammatory M2 phenotype, characterized by upregulated CD206 and CD163 expression and suppressed CD64 and CD80 levels. This shift correlated with diminished cytokines including IFN-γ, IL-4 and IL-10 production in atherosclerotic plaques. AD also induced T cell exhaustion, marked by increased the expression of inhibitory receptors (PD-1, LAG3, TIM3, CTLA-4), expansion of regulatory T cells (CD4 +Foxp3 +, CD4 +IL-4 +), and suppression of CD4 +IFN-γ+ , CD4 +IL-9 + and CD8 +IL-9 + subsets. Mechanistically, AD inhibited NF-κB p65 nuclear translocation and PI3K/Akt signaling.

Conclusion

AD ameliorates AS through a dual mechanism of immunometabolic regulation, which involves the stabilization of plaques via macrophage M2 polarization and the induction of T cell exhaustion. This process limits tissue damage resulting from excessive immune activation, mediated by the NF-κB/PI3K/Akt signaling pathway.