Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation.

Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. Although tissue-specific Mdc reprogramming is well established, how Mdc infiltration alters tissue metabolism remains unclear. Here, using a mouse neuroinflammation model coupled with genetic fate mapping, metabolomics and metabolite imaging, we identify that central nervous system (CNS) Mdc infiltration is associated with substantial metabolic changes and assign disease-linked metabolites therein. In particular, we found that increased arginine catabolism driven by lesion-associated arginase 1 (Arg1)-expressing Mdcs promoted oxidative damage, lipid accumulation and Mdc dysfunction. Genetic ARG1 deficiency within Mdcs during neuroinflammation increased extracellular arginine and was associated with rewiring of the CNS metabolic landscape, including attenuated disease-linked metabolites. This was accompanied by enhanced Mdc-driven anti-inflammation, regulatory T cell expansion and improved disease outcome. Opposing effects were observed following dietary arginine deficiency. Together, our work highlights key roles for Mdcs in CNS metabolism and reveals the pleiotropic beneficial effects of arginine in neuroinflammation.