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).