Arginine metabolism supports metabolic reprogramming in trained immunity

Abstract Trained immunity, also termed innate immune memory, is supported by the metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells’ phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated the induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.