Choline uptake is vital for IL-1β-driven inflammation

Abstract

Sp ri ng er N at ur e Li m it ed inhibition of choline uptake and phosphorylation prevents production of iL-1β and iL-18 by activated macrophages, according to the results of a study published in Cell Metabolism. Choline is an essential human nutrient; its uptake is mediated by choline transporters, including CtL1. Previous background work has shown that CtL1 expression is strongly induced during macrophage activation but the effect of choline uptake on macrophage biology was unknown. “Our experimental approach [was] based on standard CtL1 knockdown experiments that we complemented by the use of choline-free medium and choline kinase inhibitors,” says Michael Karin, corresponding author. In a series of in vitro experiments, the researchers demonstrated that impaired choline uptake alters the mitochondrial lipid profile by reducing levels of mitochondrial phosphatidylcholine and increasing levels of mitochondrial sphingomyelin. importantly, inhibiting choline uptake reduces synthesis of mitochondrial atP and stimulates aMPK activation. aMPK stimulates mitophagy, leading to the removal of damaged mitochondria and the NLrP3 activating ligand ox-mtDNa (oxidized mitochondrial DNa). thus, inhibition of choline uptake prevents NLrP3 inflammasome activation and iL-1β and iL-18 production. In vivo experiments confirmed the preliminary findings. a choline kinase inhibitor attenuated inflammation in two acute experimental models of iL-1β-dependent inflammation (lipopolysaccharide-induced septic shock and air-pouch gouty arthritis). Notably, treatment with a choline kinase inhibitor also ameliorated pathogenesis in a mouse model of Muckle–wells syndrome (a cryopyrin-associated periodic syndrome that arises from NLrP3 gene mutations causing inflammasome activation). “these results provide a direct demonstration that induction of mitophagy can be used to prevent and reverse inflammation in vivo,” explains Karin. “we are planning to test the efficacy of choline kinase inhibitors in a number of iL-1β and iL-18-dependent diseases, especially lupus nephritis, osteoarthritis and alzheimer disease.” Isobel Leake i n F l a M M at i O n