Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity

Abstract

Trained monocytes and macrophages produce reactive oxygen species (ROS), which trigger antioxidative glutathione (GSH) response to buffer the rising ROS. However, whether and how the trained immunity is shaped by GSH synthesis remains unknown. Here, we report that β-glucan-trained macrophages from mice harboring a myeloid-specific deletion of the catalytic subunit of glutamate-cysteine ligase ( Gclc) showed impaired GSH synthesis and decreased proinflammatory cytokine production in response to lipopolysaccharide challenge. Gclc deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of c-Myc transcription factors, abrogating the energy utilization and the metabolic reprogramming that allows β-glucan-trained macrophages to switch to glycolysis and glutaminolysis. Furthermore, Gclc deletion repressed effective H3K27me3 demethylation in the promoters of immunometabolic genes, such as Gls , Hk2, and Glut1, in β-glucan-trained macrophages by promoting the methyltransferase enhancer of zeste homolog 2 (EZH2). In vivo , myeloid-specific ablation of Gclc decreased the secretion of proinflammatory cytokines upon rechallenge with Candida albicans and these animals were less protected against the infection, compared with control littermates. Moreover, pharmacological inhibition of EZH2 enhanced the trained immunity response against Candida infection in Gclc-deficient mouse and human peripheral blood mononuclear cells treated with GCLC inhibitor buthionine sulfoximine (BSO). Thus, antioxidative GSH synthesis supports an environment conducive to β-glucan-induced metabolic and epigenetic reprogramming in trained immunity, allowing exploration of its functional consequences in autoimmune or inflammatory disease.

Trained immunity: A Yin‐Yang balance

“…Metabolic profiles indicating glycolysis upregulation were also observed in oxLDL‐trained innate immune cells 45,46 . More recently, it was found that impaired glutathione generation compromised mTOR activation, and suppressed β‐glucan‐induced proinflammatory cytokine production and protection against heterologous second challenge 52 . During this process of glycolysis activation, rapamycin might inhibit the mTOR pathway in a dose‐dependent manner to suppress the training effect 50 .…”

“… 45 , 46 More recently, it was found that impaired glutathione generation compromised mTOR activation, and suppressed β‐glucan‐induced proinflammatory cytokine production and protection against heterologous second challenge. 52 During this process of glycolysis activation, rapamycin might inhibit the mTOR pathway in a dose‐dependent manner to suppress the training effect. 50 In addition, SHIP‐1‐deficient macrophages exhibited increased phosphorylation of Akt, and this correlated with augmented glycolytic metabolism; inhibition of SHIP‐1 could enhance trained immunity.…”

“… 65 In addition, the impaired glutathione synthesis in β‐glucan‐trained macrophages decreased the H3K27me3 demethylation in the promoters of immunometabolic genes by raising the level of the methyltransferase enhancer of zeste homolog 2; inhibition of zeste homolog 2 amplified trained immunity‐mediated heterologous immune protection. 52 The metabolic rewiring and epigenomic reprogramming of innate immune cells and their progenitors that underlies trained immunity are summarized in Figure 3 .…”

Noncoding RNAs in the Glycolysis of Ovarian Cancer

“…Oncogenes regulate GLUT1 to intervene the glucose intake and tumor cell metabolism. The c-myc induces GLUT1 overexpression leading to increased glucose uptake ( Leen et al, 2013 ; Huang L et al, 2021 ; Su et al, 2021 ). P53 can inhibit GLUT1 expression in cells, resulting in decreased glucose uptake and thus inhibiting tumor development ( Feng et al, 2018 ).…”

“…C-myc can regulate the transcriptional process of various glycolytic genes ( Gu et al, 2017 ). C-myc can bind to the regulatory region of hexokinase 2 (HK2) and thus play an essential role in tumor aerobic glycolysis ( Huang WL et al, 2021 ; Su et al, 2021 ). PK catalyzes the final step of glycolysis, PKM2, which is only found in self-renewable groups such as stem cells and tumors ( Li et al, 2017 ; van Niekerk and Engelbrecht 2018 ).…”