Mechanistic Insight into PPARγ and Tregs in Atherosclerotic Immune Inflammation

Abstract

Atherosclerosis (AS) is the main pathological cause of acute cardiovascular and cerebrovascular diseases, such as acute myocardial infarction and cerebral apoplexy. As an immune-mediated inflammatory disease, the pathogenesis of AS involves endothelial cell dysfunction, lipid accumulation, foam cell formation, vascular smooth muscle cell (VSMC) migration, and inflammatory factor infiltration. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in lipid metabolism, inflammation, and apoptosis by antagonizing the Wnt/β-catenin pathway and regulating cholesterol efflux and inflammatory factors. Importantly, PPARγ-dependant fatty acid uptake is critical for metabolic programming. Activated PPARγ can exert an anti-atherosclerotic effect by inhibiting the expression of various inflammatory factors, improving endothelial cell function, and restraining the proliferation and migration of VSMCs. Regulatory T cells (Tregs) are the only subset of T lymphocytes that have a completely negative regulatory effect on the autoimmune response. They play a critical role in suppressing excessive immune responses and inflammatory reactions and widely affect AS-associated foam cell formation, plaque rupture, and other processes. Recent studies have shown that PPARγ activation promotes the recruitment of Tregs to reduce inflammation, thereby exerting its anti-atherosclerotic effect. In this review, we provide an overview of the anti-AS roles of PPARγ and Tregs by discussing their pathological mechanisms from the perspective of AS and immune-mediated inflammation, with a focus on basic research and clinical trials of their efficacies alone or in combination in inhibiting atherosclerotic inflammation. Additionally, we explore new ideas for AS treatment and plaque stabilization and establish a foundation for the development of natural PPARγ agonists with Treg recruitment capability.

Keywords: atherosclerosis; immunoregulation; inflammation; peroxisome proliferator-activated receptor gamma; tregs.

FIGURE 1

The anti-atherosclerosis pathways of PPARγ. The activation of PPARγ can recruit Tregs to improve endothelial function, inhibit the release of TNF-α, IL-6, and other inflammatory cytokines, reduce the production of MCP-1, suppress the differentiation of monocytes to macrophages and foam cells. In contrast, PPARγ activation can directly inhibit NF-KB phosphorylation or can indirectly inhibit the activation of NF-KB by competitively binding p65 to reduce the production of pro-inflammatory cytokines and restrain AS.

FIGURE 2

The multiple anti-AS mechanisms of Tregs. Tregs can kill effector T cells via direct contact with T cells, and inhibit the secretion of pro-inflammatory cytokines and the production of immunosuppressive enzymes by secreting TGF-β and IL-10. Tregs can also 1) inhibit the secretion of IL-1 and IL-2 to influence the proliferation of effector T cells by secreting TGF-β and IL-10; 2)suppress the secretion of IFN-γ, TNF-α and IL-4 by Th1 and Th2 cells; and 3) reduce the expression of MHC II on DC and macrophages membrane, and affect the stimulation of CD28/B7 pathway on T cells, and consequently play an important role in inhibiting, slowing down the process of AS and increasing the stability of plaques.

FIGURE 3

Mechanism of the combined action of PPARγ and Tregs against AS. Tregs expressing PPARγ in VAT exert inhibitory effects on immune cells activity and prevents the occurrence and development of inflammation. Foxp3 is a specific molecule of Tregs. The ectopical co-expression of Foxp3 and PPARγ can induce an increase in Treg levels and the release of cytokines such as TGF-β and IL-10 to inhibit inflammation and exert anti-AS effects. In addition, PPARγ indirectly induces the expression of Tregs by promoting the transformation of macrophages to the anti-inflammatory M2 type and induces the secretion of cytokines such as TGF-β and IL-10 by M2 type macrophages. PPARγ also inhibits the inflammatory response and plays a role in the anti-AS by activating the TGF-β/Smad signalling pathway and inhibiting the Th1, Th2, Th17/Tregs ratio.