Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

• Published in: Nature immunology Vol. 21; no. 5; pp. 513 - 524
• Main Authors: Mendiola, Andrew S., Ryu, Jae Kyu, Bardehle, Sophia, Meyer-Franke, Anke, Ang, Kenny Kean-Hooi, Wilson, Chris, Baeten, Kim M., Hanspers, Kristina, Merlini, Mario, Thomas, Sean, Petersen, Mark A., Williams, Alexander, Thomas, Reuben, Rafalski, Victoria A., Meza-Acevedo, Rosa, Tognatta, Reshmi, Yan, Zhaoqi, Pfaff, Samuel J., Machado, Michael R., Bedard, Catherine, Rios Coronado, Pamela E., Jiang, Xiqian, Wang, Jin, Pleiss, Michael A., Green, Ari J., Zamvil, Scott S., Pico, Alexander R., Bruneau, Benoit G., Arkin, Michelle R., Akassoglou, Katerina
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2020; Nature Publishing Group
• Subjects: 631/250/2504/342/1952; 631/250/371; Animals; Antioxidants - therapeutic use; Biomedical and Life Sciences; Biomedicine; Care and treatment; Central nervous system; Central nervous system diseases; Coagulation; Degeneration; Development and progression; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - genetics; Female; Gene Expression Profiling - methods; Gene Regulatory Networks; Genes; Genetic aspects; Genetic transcription; Glutathione; Health aspects; High-Throughput Screening Assays; Humans; Immunity, Innate; Immunology; Infectious Diseases; Inflammation; Isoxazoles - therapeutic use; Macrophages; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microglia; Microglia - physiology; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - genetics; Nervous system; Neurodegeneration; Neurogenic Inflammation - drug therapy; Neurogenic Inflammation - genetics; Neuroprotection; Neurotoxicity; Oxidation; Oxidative Stress; Ribonucleic acid; RNA; Sequence Analysis, RNA; Single-Cell Analysis; Therapeutic targets; Transcription; Transcriptomics; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-020-0654-0

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. Oxidative stress can promote neurodegeneration. Akassoglou and colleagues describe Tox-seq, a functional single-cell RNA sequencing method to identify oxidative stress transcriptional signatures in CNS-resident cells. Tox-seq identified coagulation and glutathione-redox pathway genes that are coupled to oxidative stress and that could be targeted by the glutathione-regulating small molecule acivicin.