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<p>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 (<i>Arg1</i>)-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.</p>

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Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月18日

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  • Martina Kerndl,
  • Laszlo Musiejovsky,
  • Andrea Komljenovic,
  • Hon Shing Lam,
  • Andrea Vogel,
  • Tobias Bausbacher,
  • Christian J. Riedl,
  • Roko Sango,
  • Lenka Matejovicova,
  • Anja Dobrijevic,
  • Laura Oberbichler,
  • Melanie Hofmann,
  • Markus Kieler,
  • Lucia Quemada Garrido,
  • Lara Veronika Perko Budja,
  • Julia Stefanie Brunner,
  • James Lucas Cairns,
  • Paul Cheng,
  • Kerstin Kitt,
  • Christine Isaguirre,
  • Thomas Köcher,
  • Kristaps Klavins,
  • Thomas Rattei,
  • Simon Hametner,
  • Stephan Blüml,
  • Carsten Hopf,
  • Ryan D. Sheldon,
  • Omar Sharif,
  • Gernot Schabbauer

摘要

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.