NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair?

Abstract

Microglia are the resident immune cells of the brain and play major roles in central nervous system development, maintenance, and disease. Brain insults cause microglia to proliferate, migrate, and transform into one or more activated states. Classical M1 activation triggers the production of proinflammatory factors such as tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO), and reactive oxygen species which, in excess, can exacerbate brain injury. The mechanisms underlying microglial activation are not fully understood, yet reactive oxygen species are increasingly implicated as mediators of microglial activation. In this review, we highlight studies linking reactive oxygen species, in particular hydrogen peroxide derived from NADPH oxidase-generated superoxide, to the classical activation of microglia. In addition, we critically evaluate controversial evidence suggesting a specific role for mitochondrial reactive oxygen species in the activation of the NLRP3 inflammasome, a multiprotein complex that mediates the production of IL-1β and IL-18. Finally, the limitations of common techniques used to implicate mitochondrial ROS in microglial and inflammasome activation, such as the use of the mitochondrially-targeted ROS indicator MitoSOX and the mitochondrially-targeted antioxidant MitoTEMPO, are also discussed.

Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells

“…In fact, one study suggested that p38-Omi/HtrA2 stressresponse pathway is actively engaged in protecting mitochondria from stress, and p38 may mediate the regulation of the Omi/HtrA2 catalytic activity [48]. Inflammatory stimulus provides an indirect effect on mitochondrial functions [49]. The mechanism in which IL-1β exerts its effect on Omi/HtrA2 release is not clear.…”

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

“…1 Metabolic pathway of leucine catabolism with 3-hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency found in vivo (Halliwell and Gutteridge 2007a). Superoxide can also be released upon activation of resident macrophages of the nervous system (Kim and Joh 2006;Bordt and Polster 2014) or can be originated by the reaction of other autoxidizable compounds, such as catecholamines (Pattison et al 2002). Apart from SOD, hydrogen peroxide can also be generated by other enzymes, such as monoamine oxidase, glycolate oxidase and xanthine oxidase.…”

A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats

“…Microglia activation induced by the brain insults results with a range of responses which could be neurotoxic or neuroprotective (Bordt and Polster, 2014;Prinz et al, 2011;Ransohoff and Cardona, 2010), and their neuroinflammatory role in the production and releases of different pro-inflammatory factors such as cytokines and free radicals in the pathophysiology of several CNS diseases and injuries, including TBI, has been recognized (Frank-Cannon et al, 2009;Loane and Byrnes, 2010;Yrjänheikki et al, 1998).…”