Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.
Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely believed to drive tissue damage in multiple sclerosis (MS), yet the distinct roles of central nervous system (CNS)-resident versus CNS-invading MPs remain unclear. Here, we combined single-cell profiling and conditional gene targeting to map and modulate ROS production across CNS MPs in a preclinical mouse model of MS. We show that monocyte-derived macrophages (MdMs) exhibit a higher oxidative stress gene signature and produce more ROS than microglia (Mglia). Challenging previous assumptions, our findings reveal that phagocytic NADPH oxidase 2 is dispensable for neuroinflammation. In contrast, quenching mitochondrial ROS (mtROS) through mitochondria-targeted catalase (mCAT) expression in MdMs, but not in Mglia, ameliorated disease severity in acute neuroinflammation. Although core phagocyte functions were unaltered in mCAT-expressing MdMs, our results demonstrate a direct neurotoxic role of mtROS. In sum, we identify MdMs as the primary driver of ROS-mediated oxidative neurological tissue damage.
Authors
- Laura Oberbichler (ORCID: https://orcid.org/0009-0002-9925-6710)
- Juan Villar-Vesga (ORCID: https://orcid.org/0000-0002-1085-9922)
- Sarah Mundt (ORCID: https://orcid.org/0000-0003-2169-2109)
- Dietmar Benke (ORCID: https://orcid.org/0000-0003-1846-4711)
- Melanie Greter (ORCID: https://orcid.org/0000-0002-7220-5369)
- Donatella De Feo (ORCID: https://orcid.org/0000-0003-0121-5364)
- Bettina Schreiner (ORCID: https://orcid.org/0000-0002-3830-6991)
- Maria Pena-Francesch
- Hannah Van Hove (ORCID: https://orcid.org/0000-0002-0412-6474)
- Urvashi Dalvi
- Mitchell Bijnen (ORCID: https://orcid.org/0000-0003-2781-8702)
- Aiman S. Saab (ORCID: https://orcid.org/0000-0003-3886-8369)
- Jeanne Kim (ORCID: https://orcid.org/0009-0005-1582-5982)
- Can Ulutekin (ORCID: https://orcid.org/0000-0003-4406-5423)
- Florian Ingelfinger (ORCID: https://orcid.org/0000-0001-6890-9753)
- Pauline Clément
- Frauke Seehusen (ORCID: https://orcid.org/0000-0001-6701-7868)
- Sara Costa-Pereira (ORCID: https://orcid.org/0000-0002-9202-9796)
- Deborah Greis (ORCID: https://orcid.org/0009-0008-9487-0619)
- Viola Bugada (ORCID: https://orcid.org/0009-0006-4795-2326)
- Katarina Wendy Schmidt
- Elèni Meuffels
- James King (ORCID: https://orcid.org/0000-0002-5489-6610)
- Violetta Gogoleva
- Musadiq A Bhat
- Burkhard Becher
- Sophie Grundschober
- Tommaso Patriachi
- Christian Münz
- Francesco Prisco
- Isabelle C Arnold
Institutions
- University of Zurich (CH)
- University Medical Center Freiburg (DE)
- ETH Zurich (CH)
- Institute for Biomedical Engineering (CH)
- University Hospital of Zurich (CH)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- PubMed
- Published
- 2026-05-08
- DOI
- https://doi.org/10.1126/sciimmunol.adw5197
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00