Microglia antioxidant systems and redox signalling

Abstract

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...

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior

“…In addition to RSV’s potent anti-inflammatory effects, it has also been suggested to inhibit nuclear factor kappa B through histone deacetylation by SIRT-1 (Bagul et al, 2015; Borra et al, 2005), a factor which has been linked to the development of depressive-like states (Haslund-Vinding et al, 2016; Patki et al, 2013b; Vilhardt et al, 2016). In the present study there were no differences in SIRT-1 protein levels between stress or treatment groups.…”

Redox‐based therapeutics in neurodegenerative disease

“…It is well established that NO release from activated glial cells has the capacity to cause extensive neurodegeneration, for example, via inhibition of mitochondrial cytochrome oxidase (Brown and Cooper, ) or release of glutamate causing hyperactivation of NMDA receptors (Bal‐Price and Brown, ). The mechanisms of microglial cell activation are the subject of recent reviews and will not be discussed here (Rojo et al ., ; Vilhardt et al ., ). However, the oxidative effects of increased NO production are pertinent to this discussion and are viewed as a potential target for redox‐based therapeutics.…”

Nitroxidative Signaling Mechanisms in Pathological Pain

“…Another transcription factor, forkhead box, class O (FoxO), is also responsible for the production of SOD2 and catalase [141]. Many of these antioxidants are ubiquitously expressed, and their catabolic function is summarized in Figure 1 [142]. …”