Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation (scRNA-seq dataset)

Oxidative stress is a central part of innate-immune induced neurodegeneration. However, the transcriptomic landscape of the central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease, and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells (Tox-seq) identified a core oxidative stress gene signature coupled to coagulation and glutathione pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen (HTS) and oxidative stress gene network analysis, identified the glutathione regulating compound acivicin with potent therapeutic effects decreasing oxidative stress and axonal damage in chronic and relapsing models of multiple sclerosis (MS). Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable the discovery of selective neuroprotective strategies. Overall design: To obtain ROS+ innate immune cells, all live cells isolated from spinal cord were stained for intracellular ROS ex vivo using 2',7'–dichlorofluorescein diacetate (DCFDA) and the innate immune cell fraction was collected by CD11b+ fluorescence-activated cell sorting. For Tox-seq, we analyzed the transcriptomes of 8,701 CD11b+ cells labelled for ROS production via scRNA-seq from the spinal cords of healthy mice or at the onset of disease (score 1) of MOG35-55 EAE mice, an autoimmune animal model for MS with paralysis and inflammatory demyelination.