Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses

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.