3 T cells
To prevent autoimmunity and chronic inflammation, Tregs can dampen overactive immune responses(Tabas and Lichtman, 2017; Baardman and Lutgens, 2020). Treg deficiency or dysfunction is linked to the pathogenesis of atherosclerosis(Newton et al., 2016; Pacella and Piconese, 2019; Saigusa et al., 2020). More and more data suggest that the intracellular metabolism of Tregs is a critical regulator of their proliferation, inhibitory activity, and stability(Buck et al., 2015; Georgiev et al., 2019; Sakaguchi et al., 2020). Foxp3 inhibits glycolysis (NAD+ consumption pathway) and promotes monophosphate (NAD+ production) to compensate for the drop in NAD+ levels and enable Treg to tolerate a low-glucose, high-lactate environment(Tomas et al., 2018; Ketelhuth et al., 2019). Oxidative stress and other factors downregulate the expression of Foxp3 and disrupt this metabolic advantage, resulting in decreased Treg function and disease development(Marsch et al., 2013; Hsu and Lai, 2018).
In the peculiar milieu of atherosclerotic plaques, ROS causes oxLDL synthesis, and intracellular accumulation following oxLDL uptake inhibits the mevalonate pathway(Wang et al., 2016; Mailer et al., 2017), downregulates Foxp3 expression, and reduces the atheroprotective capacity of Tregs(De Rosa et al., 2015; Becker et al., 2017; Kälin et al., 2017). On the other hand, the hypoxic environment of atherosclerotic plaques regulates HIF-1 via oxidative stress, promotes the shunting of pyruvate to lactate, upregulates glycolysis(Cole et al., 2015; Polyzos et al., 2015; Forteza et al., 2018), and causes Foxp3 ubiquitination and proteasomal degradation, which affects Treg function. While HIF-1 increases suppressive activity in Tregs, it decreases their migratory capacity, indicating that glycolysis is essential for Treg migration and that oxidative stress leads to atherosclerosis(Chang et al., 2013; Gerriets et al., 2016). The precise effect of HIF-1 on Tregs in sclerotic plaques requires further investigation(Gerriets et al., 2015). The downregulation of Foxp3 and the increase in glycolysis are essential to this pathological response(Gaddis et al., 2018).