Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.

Autor: Mendiola AS; Gladstone Institutes, San Francisco, CA, USA., Ryu JK; Gladstone Institutes, San Francisco, CA, USA.; Department of Neurology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Bardehle S; Gladstone Institutes, San Francisco, CA, USA., Meyer-Franke A; Gladstone Institutes, San Francisco, CA, USA., Ang KK; Small Molecule Discovery Center, University of California San Francisco, San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA., Wilson C; Small Molecule Discovery Center, University of California San Francisco, San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA., Baeten KM; Gladstone Institutes, San Francisco, CA, USA., Hanspers K; Gladstone Institutes, San Francisco, CA, USA., Merlini M; Gladstone Institutes, San Francisco, CA, USA., Thomas S; Gladstone Institutes, San Francisco, CA, USA., Petersen MA; Gladstone Institutes, San Francisco, CA, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Williams A; Gladstone Institutes, San Francisco, CA, USA., Thomas R; Gladstone Institutes, San Francisco, CA, USA., Rafalski VA; Gladstone Institutes, San Francisco, CA, USA., Meza-Acevedo R; Gladstone Institutes, San Francisco, CA, USA., Tognatta R; Gladstone Institutes, San Francisco, CA, USA., Yan Z; Gladstone Institutes, San Francisco, CA, USA., Pfaff SJ; Small Molecule Discovery Center, University of California San Francisco, San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA., Machado MR; Gladstone Institutes, San Francisco, CA, USA., Bedard C; Gladstone Institutes, San Francisco, CA, USA., Rios Coronado PE; Gladstone Institutes, San Francisco, CA, USA., Jiang X; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA., Wang J; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA., Pleiss MA; Gladstone Institutes, San Francisco, CA, USA., Green AJ; Department of Neurology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA., Zamvil SS; Department of Neurology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Pico AR; Gladstone Institutes, San Francisco, CA, USA., Bruneau BG; Gladstone Institutes, San Francisco, CA, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Arkin MR; Small Molecule Discovery Center, University of California San Francisco, San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA., Akassoglou K; Gladstone Institutes, San Francisco, CA, USA. kakassoglou@gladstone.ucsf.edu.; Department of Neurology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. kakassoglou@gladstone.ucsf.edu.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2020 May; Vol. 21 (5), pp. 513-524. Date of Electronic Publication: 2020 Apr 13.
DOI: 10.1038/s41590-020-0654-0
Abstrakt: 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.
Databáze: MEDLINE
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