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. 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 microglia, ameliorated disease severity in acute neuroinflammation.
While core phagocyte functions were unaltered in mCAT-expressing MdMs, our
results establish a direct neurotoxic role of mtROS. Together, we identify
MdMs as the primary driver of ROS-mediated oxidative neurological tissue
damage.