Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation (bulk RNA-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: Bulk RNA-seq analysis of FACS isolated CD45loCD11b+ microglia and CD45hiCD11b+ infiltrating monocytes/macrophages from EAE (onset of disease) spinal cord tissue. Microglia and macrophage subpopulations were classified into four populations based on the expression of MHC II and ROS (MHC II+ ROS+, MHC II– ROS– (baseline), MHC II– ROS+ and MHC II+ROS–). Detailed methods of sample extraction and data analysis are provided.