Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Nat Immunol. 2020 May;21(5):513-524. doi: 10.1038/s41590-020-0654-0. Epub 2020 Apr 13.


Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of 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 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 and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / therapeutic use
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Female
  • Gene Expression Profiling / methods*
  • Gene Regulatory Networks
  • High-Throughput Screening Assays
  • Humans
  • Immunity, Innate
  • Isoxazoles / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microglia / physiology*
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / genetics*
  • Neurogenic Inflammation / drug therapy
  • Neurogenic Inflammation / genetics*
  • Oxidative Stress
  • Sequence Analysis, RNA
  • Single-Cell Analysis


  • Antioxidants
  • Isoxazoles
  • acivicin