Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

I. Introduction II. Microglial Profiles and the Influence of Redox Dynamics A. Description of microglial phenotypes B. The microglial M1/M2 balance is modulated by the redox status C. Brain aging and neurodegenerative diseases alter microglial dynamics and the cross-talk between neurons and microglia III. Sources of ROS in Microglia: NOX and NOS Enzymes A. NOX system B. NOS enzymes C. Cross-talk between RNS and ROS IV. Glutathione and Microglial Redox Regulation A. Glutathione metabolism B. Cystine-glutamate exchanger (X-c(-)) and glutamate homeostasis in microglia C. Microglial phenotypes and the glutathione pool V. Oxidized Lipid By-Products and Chronic Inflammation A. Microglia can induce lipid peroxidation 1. 4-Hydroxy-2-nonenal 2. Acrolein 3. Malondialdehyde 4. Isoprostanes and neuroprostanes VI. Redox Signaling Through Protein Sulfhydryl Groups A. Protein-S-thiol modification B. Protein-thiol modification as a signaling mechanism in microglia C. Thioredoxin reductase system VII. Microglial Polarization Is Controlled by Transcriptional Regulation A. NF-kappa B transcription factor 1. Redox levels regulate regulatory kinases upstream of NF-kappa B 2. Redox state also controls NF-kappa B nuclear levels B. NRF2 transcription factor 1. ROS control the NRF2 through redox modification of Kelch-like ECH-associated protein 1 2. NRF2 regulation by signaling kinases 3. Epigenetic modulation of NRF2 4. NRF2 and its target genes modulate microglial phenotypes VIII. BBB Permeability Is Altered by ROS, Enabling Homing of Peripheral Immune Cells A. Blood-brain barrier B. Oxidative stress affects BBB permeability C. Activated microglia and BBB impairment D. Leukocyte trafficking across the BBB IX. Concluding Remarks Neurodegenerative diseases are characterized by chronic microglial over-activation and oxidative stress. It is now beginning to be recognized that reactive oxygen species (ROS) produced by either microglia or the surrounding environment not only impact neurons but also modulate microglial activity. In this review, we first analyze the hallmarks of pro-inflammatory and anti-inflammatory phenotypes of microglia and their regulation by ROS. Then, we consider the production of reactive oxygen and nitrogen species by NADPH oxidases and nitric oxide synthases and the new findings that also indicate an essential role of glutathione (gamma-glutamyl-l-cysteinylglycine) in redox homeostasis of microglia. The effect of oxidant modification of macromolecules on signaling is analyzed at the level of oxidized lipid by-products and sulfhydryl modification of microglial proteins. Redox signaling has a profound impact on two transcription factors that modulate microglial fate, nuclear factor kappa-light-chain-enhancer of activated B cells, and nuclear factor (erythroid-derived 2)-like 2, master regulators of the pro-inflammatory and antioxidant responses of microglia, respectively. The relevance of these proteins in the modulation of microglial activity and the interplay between them will be evaluated. Finally, the relevance of ROS in altering blood brain barrier permeability is discussed. Recent examples of the importance of these findings in the onset or progression of neurodegenerative diseases are also discussed. This review should provide a profound insight into the role of redox homeostasis in microglial activity and help in the identification of new promising targets to control neuroinflammation through redox control of the brain. Antioxid. Redox Signal. 21, 1766-1801.