HDLR-SR-BI Expression and Cholesterol Uptake are Regulated via Indoleamine-2,3-dioxygenase 1 in Macrophages under Inflammation

Macrophages play crucial roles in inflammation, and their dysfunction is a contributing factor to various human diseases. Maintaining the balance of cholesterol and lipid metabolism is central to macrophage function, and any disruption in this balance increases the risk of conditions such as cardiovascular disease, atherosclerosis, and others. HDLR-SR-BI (SR-BI) is pivotal for reverse cholesterol transport and cholesterol homeostasis. Our studies demonstrate that the expression of SR-BI is reduced along with a decrease in cholesterol uptake in macrophages, both of which are regulated by the activation of NF-κB. Furthermore, we have discovered that indoleamine-2,3-dioxygenase 1 (IDO1), which is a critical player in tryptophan (Trp) catabolism, is crucial to the regulation of SR-BI expression. Inflammation leads to elevated levels of IDO1 and the associated Trp catabolite kynurenine (KYN) in macrophages. Interestingly, knockdown or inhibition of IDO1 results in the downregulation of LPS-induced inflammation, decreased KYN levels, and the restoration of SR-BI expression as well as cholesterol uptake in macrophages. Beyond LPS, stimulation with pro-inflammatory cytokine IFNγ exhibits similar trends in inflammatory response, IDO1 regulation, and cholesterol uptake in macrophages. These observations suggest that IDO1 plays a critical role in SR-BI expression and cholesterol uptake in macrophages under inflammation.