Science immunology · 2026
Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.
СтатьяНазвание и аннотация: Перевод в очереди
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Villar-Vesga Juan, De Feo Donatella, Clément Pauline, Bugada Viola, Meuffels Elèni, Van Hove Hannah, Bijnen Mitchell, King James, Grundschober Sophie, Ulutekin Can, Pena-Francesch Maria, Costa-Pereira Sara, Oberbichler Laura, Gogoleva Violetta, Kim Jeanne, Schmidt Katarina Wendy, Bhat Musadiq A, Greis Deborah, Seehusen Frauke, Prisco Francesco, Dalvi Urvashi, Benke Dietmar, Schreiner Bettina, Patriarchi Tommaso, Ingelfinger Florian, Arnold Isabelle C, Münz Christian, Greter Melanie, Saab Aiman S, Becher Burkhard, Mundt Sarah
Аннотация
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.