Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation

Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. While tissue-specific Mdc reprogramming is well-established, how Mdc inflitration alters tissue metabolism remains unclear. Here, using a murine 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, assigning disease-linked metabolites (DLMs) therein. Particularly, we found 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 DLMs. This was accompanied by enhanced Mdc-driven anti-inflammation, regulatory T cell expansion, and improved disease outcome. Opposing effects were observed upon dietary arginine deficiency. Together, our work highlights key roles for Mdcs in CNS metabolism and reveals the pleiotropic beneficial effects of arginine in neuroinflammation.