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.
Authors
- James L. Cairns (ORCID: https://orcid.org/0000-0003-4986-1015)
- Laura Oberbichler (ORCID: https://orcid.org/0009-0002-9925-6710)
- Kristaps Klavins (ORCID: https://orcid.org/0000-0001-9577-9990)
- Martina Kerndl (ORCID: https://orcid.org/0000-0001-5060-8944)
- Tobias Bausbacher (ORCID: https://orcid.org/0000-0003-4384-5612)
- Simon Hametner (ORCID: https://orcid.org/0000-0002-5160-5208)
- Laszlo Musiejovsky (ORCID: https://orcid.org/0009-0002-9238-4752)
- Ryan D. Sheldon (ORCID: https://orcid.org/0000-0002-1573-9719)
- Omar Sharif (ORCID: https://orcid.org/0000-0003-0496-2904)
- Thomas Rattei (ORCID: https://orcid.org/0000-0002-0592-7791)
- Markus Kieler (ORCID: https://orcid.org/0000-0002-4082-5731)
- Lucia Quemada Garrido
- Carsten Hopf (ORCID: https://orcid.org/0000-0003-0802-6451)
- Melanie Hofmann (ORCID: https://orcid.org/0000-0002-0835-4183)
- Julia S. Brunner (ORCID: https://orcid.org/0000-0002-3195-147X)
- Christian J. Riedl (ORCID: https://orcid.org/0000-0002-3641-768X)
- Andrea Vogel (ORCID: https://orcid.org/0000-0002-2613-140X)
- Andrea Komljenović (ORCID: https://orcid.org/0000-0002-8739-748X)
- Kerstin Kitt
- Anja Dobrijević
- Lara Veronika Perko Budja
- Hon Shing Lam
- Stephan Blüml (ORCID: https://orcid.org/0000-0002-2758-4400)
- Roko Sango
- Christine Isaguirre
- Gernot Schabbauer (ORCID: https://orcid.org/0000-0002-7490-8009)
- Paul Cheng
- Thomas Köcher
- Lenka Matejovicova
Institutions
- Technische Hochschule Mannheim (DE)
- University of Vienna (AT)
- Van Andel Institute (US)
- Boehringer Ingelheim (Germany) (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Riga Technical University (LV)
- University of Zurich (CH)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Bioforschung Austria (AT)
- Christian Doppler Laboratory for Thermoelectricity (AT)
- International Network for Cancer Treatment and Research (BE)
- Bernstein Center for Computational Neuroscience Heidelberg-Mannheim (DE)
- Vienna Biocenter (AT)
- Vienna BioCenter Core Facilities (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1038/s41590-026-02516-4
- Primary Topic
- Cancer Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Österreichischen Akademie der Wissenschaften
- Bundesministerium für Bildung und Forschung
- Austrian Science Fund
- Christian Doppler Forschungsgesellschaft