Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses

Abstract

Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we found that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulated glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosted glucose oxidation to fuel the production of acetyl-coA, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drove macrophage activation, prolonged exposure to LPS triggered tolerance to LPS, in which macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response was modulated by GPD2, which coordinated a shutdown of oxidative metabolism; this limited the availability of acetyl-coA for histone acetylation at genes encoding inflammatory mediators and thus contributed to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol-phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.

Metabolic Reprogramming in Mitochondria of Myeloid Cells

“…Mechanisms of the possible transient increase of OXPHOS by LPS are investigated as well. LPS-induced OXPHOS depends on glucose oxidation, which also supports the availability of acetyl-CoA for histone acetylation at the promoters of pro-inflammatory cytokines within 2 h [13], although acetyl-CoA is also reported to be reduced by LPS [11]. By global metabolite profiling, Glycerol 3-phosphate shuttle (GPS) pathway is identified as the top-upregulated pathway by LPS [13].…”

“…In addition, measurements of OCR at 0.5, 1, or 4 h after LPS treatment indicate elevated OXPHOS at these time points [12][13][14]18]. Whether LPS stimulation leads to a transient increase and/or delayed decrease of OXPHOS in the myeloid cells needs more evidence.…”

“…This pathway can shuttle electrons from cytosolic glycolytic NADH to FADH 2 for fueling the mitochondrial electron transport chain (ETC). LPS increases the activity of the GPS enzyme mitochondrial glycerol 3-phosphate dehydrogenase (GDP2) to drive mitochondrial respiration [13]. GDP2 knockout (KO) blocks the increase of OCR by LPS in BMDMs [13].…”

“…LPS increases the activity of the GPS enzyme mitochondrial glycerol 3-phosphate dehydrogenase (GDP2) to drive mitochondrial respiration [13]. GDP2 knockout (KO) blocks the increase of OCR by LPS in BMDMs [13]. In addition, mitochondrial Complex III (CIII) inhibitor suppresses ROS production in the first hour of IFNγ/LPS treatment [14].…”

“…The tolerance leads to suppressed immune response upon the subsequent stimulation by the lethal dose of LPS, thus prevents cytokine storm, tissue damage and mortality from septic shock [37]. In vitro, tolerant monocytes and macrophages have reduced gene expression related to glycolysis, OXPHOS, and cytokine production after a second LPS stimulation in comparison to stimulated non-tolerant cells [13,29,36]. The altered metabolism in tolerant myeloid cells is due to an impaired mTOR pathway [29] and GDP2-mediated reverse electron transport (RET), which is the consequence of overwhelming the electron transport chain (ETC) [13].…”