Microglia are the resident immune cells of the CNS and constitute a self-sustaining population of CNS-adapted tissue macrophages. As mononuclear phagocytic cells, they express high levels of superoxide-producing NADPH oxidases (NOX). The sole function of the members of the NOX family is to generate reactive oxygen species (ROS) that are believed to be important in CNS host defence and in the redox signalling circuits that shape the different activation phenotypes of microglia. NOX are also important in pathological conditions, where over-generation of ROS contributes to neuronal loss via direct oxidative tissue damage or disruption of redox signalling circuits. In this review, we assess the evidence for involvement of NOX in CNS physiopathology, with particular emphasis on the most important surface receptors that lead to generation of NOX-derived ROS. We evaluate the potential significance of the subcellular distribution of NOX isoforms for redox signalling or release of ROS to the extracellular medium. Inhibitory mechanisms that have been reported to restrain NOX activity in microglia and macrophages in vivo are also discussed. We provide a critical appraisal of frequently used and recently developed NOX inhibitors. Finally, we review the recent literature on NOX and other sources of ROS that are involved in activation of the inflammasome and discuss the potential influence of microglia-derived oxidants on neurogenesis, neural differentiation and culling of surplus progenitor cells. The degree to which excessive, badly timed or misplaced NOX activation in microglia may affect neuronal homeostasis in physiological or pathological conditions certainly merits further investigation. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations CR3, complement receptor 3; DPI, diphenylene iodonium; HMGB1, high mobility group box 1; JAK, Janus kinase; NAC, N-acetylcysteine; NLRP3, NOD-like receptor family, pyrin domain containing 3; SVZ, subventricular zone; TLR, toll-like receptor IntroductionMicroglia are the tissue-specific macrophages of the CNS, and unlike other brain cells, they derive from yolk sac haematopoietic stem cells, which populate the mouse brain around embryonic day 9 (Alliot et al., 1999;Ginhoux et al., 2010;Kierdorf et al., 2013). Once established in the brain parenchyma, the population of CNS microglia is maintained throughout life by proliferation when needed, which occurs independently of bone marrow-derived precursors (Prinz and Priller, 2014;Ajami et al., 2007;Elmore et al., 2014; Bruttger et al., 2015).Since they were first identified by Pio del Rio-Hortega in 1920, most research has concentrated on the neuropathological associations of microglia (Kettenmann and Verkhratsky, 2011). Many effector functions of microglia are potentially cytotoxic, and a substantial body of evidence links excessive activation of mi...

For many years, microglia, the resident CNS macrophages, have been considered only in the context of pathology, but microglia are also glial cells with important physiological functions. Microglia-derived oxidant production by NADPH oxidase (NOX2) is implicated in many CNS disorders. Oxidants do not stand alone, however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defence mechanism, and further, we discuss in the context of protein thiolation of target redox proteins the necessity for tightly localized, timed and confined oxidant production to work in concert with antioxidant proteins to promote redox signalling. NOX2-mediated redox signalling modulates the acquisition of the classical or alternative microglia activation phenotypes by regulating major transcriptional programs mediated through NF-κB and Nrf2, major regulators of the inflammatory and antioxidant response respectively. As both antioxidants and NOX-derived oxidants are co-secreted, in some instances redox signalling may extend to neighboring cells through modification of surface or cytosolic target proteins. We consider a role for microglia NOX-derived oxidants in paracrine modification of synaptic function through long term depression and in the communication with the adaptive immune system. There is little doubt that a continued foray into the functions of the antioxidant response in microglia will reveal antioxidant proteins as dynamic players in redox signalling, which in concert with NOX-derived oxidants fulfil important roles in the autocrine or paracrine regulation of essential enzymes or transcriptional programs. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations Aβ, amyloid-β peptide 1-42; DAMP, damage-associated molecular pattern molecules; GCL, glutamate cysteine ligase; GPx, GSH peroxidase; HNE, 4-hydroxy-2-nonenal; HO-1, haem oxygenase-1; KEAP1, Kelch-like ECH-associated protein; LTD, long-term depression; PLA 2 , phospholipase A 2 ; Prx, peroxiredoxins; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, cystine-glutamate exchanger IntroductionMicroglia, the resident immune cells of the brain, are exquisitely sensitive cells, which through a large and unique repertoire of sensing cell surface receptors (Hickman et al., 2013) responding to ligands of exogenous or endogenous nature (Kettenmann et al., 2013) continuously survey the brain parenchyma for even the smallest deviation from homeostasis. When the fine, motile processes of microglia encounter a problem, microglia assume an activation phenotype adapted to the quick resolution of damage and return to homeostasis. If instigating insults cannot be resolved, chronic microglia activation ensues. The differing nature of...