Quercetin Reprograms Immunometabolism of Macrophages via the SIRT1/PGC-1α Signaling Pathway to Ameliorate Lipopolysaccharide-Induced Oxidative Damage

Abstract

The redox system is closely related to changes in cellular metabolism. Regulating immune cell metabolism and preventing abnormal activation by adding antioxidants may become an effective treatment for oxidative stress and inflammation-related diseases. Quercetin is a naturally sourced flavonoid with anti-inflammatory and antioxidant activities. However, whether quercetin can inhibit LPS-induced oxidative stress in inflammatory macrophages by affecting immunometabolism has been rarely reported. Therefore, the present study combined cell biology and molecular biology methods to investigate the antioxidant effect and mechanism of quercetin in LPS-induced inflammatory macrophages at the RNA and protein levels. Firstly, quercetin was found to attenuate the effect of LPS on macrophage proliferation and reduce LPS-induced cell proliferation and pseudopodia formation by inhibiting cell differentiation, as measured by cell activity and proliferation. Subsequently, through the detection of intracellular reactive oxygen species (ROS) levels, mRNA expression of pro-inflammatory factors and antioxidant enzyme activity, it was found that quercetin can improve the antioxidant enzyme activity of inflammatory macrophages and inhibit their ROS production and overexpression of inflammatory factors. In addition, the results of mitochondrial morphology and mitochondrial function assays showed that quercetin could upregulate the mitochondrial membrane potential, ATP production and ATP synthase content decrease induced by LPS, and reverse the mitochondrial morphology damage to a certain extent. Finally, Western blotting analysis demonstrated that quercetin significantly upregulated the protein expressions of SIRT1 and PGC-1α, that were inhibited by LPS. And the inhibitory effects of quercetin on LPS-induced ROS production in macrophages and the protective effects on mitochondrial morphology and membrane potential were significantly decreased by the addition of SIRT1 inhibitors. These results suggested that quercetin reprograms the mitochondria metabolism of macrophages through the SIRT1/PGC-1α signaling pathway, thereby exerting its effect of alleviating LPS-induced oxidative stress damage.

Piceatannol Upregulates SIRT1 Expression in Skeletal Muscle Cells and in Human Whole Blood: In Vitro Assay and a Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Trial

“…Thus, PIC may be a more potent polyphenol than RES for activating SIRT1. Some polyphenols, such as cocoa polyphenol extract or quercetin, were reported to induce SIRT1 expression [57,58]. Further studies on the differences in SIRT1 induction effects between PIC and other polyphenols will clarify the characteristics of PIC effects.…”

Effects of Quercetin on Codeine-Induced Reproductive Hormone Disorder

“…Lipid peroxidation (55). In addition, quercetin plays a role in the respiratory chain, producing ATP and an essential source of cellular energy (56). As a result, quercetin, an antioxidant that increases these hormones, caused higher blood levels of testosterone and luteinizing hormone in rabbits exposed to cadmium (57).…”

Polyphenols: immunonutrients tipping the balance of immunometabolism in chronic diseases

“…Notably, quercetin upregulates Sirt1/PGC1a signaling and improves mitochondrial function and morphology (e.g. mtROS, mitochondrial membrane potential, ATP production) in LPSinduced inflammatory macrophages (103).…”