Reactive oxygen species up-regulate CD11b in microglia via nitric oxide: Implications for neurodegenerative diseases

Abstract

Microglial activation is considered as a hallmark of several neurodegenerative disorders. During microglial activation, the expression of CD11b, the beta-integrin marker of microglia, is increased. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood. The present study was undertaken to explore the role of reactive oxygen species (ROS) in the expression of CD11b in microglial cells. Bacterial lipopolysaccharide (LPS) stimulated the expression of CD11b in mouse BV-2 microglial cells and primary microglia, the effect that was blocked by antioxidants such as N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Furthermore, comicroinjection of either NAC or PDTC with LPS was also able to suppress LPSstimulated expression of CD11b in striatum in vivo. Similarly, other neurotoxic molecules, such as interleukin-1β (IL-1β), IL-12 p40 2 , fibrillar amyloid-β (Aβ) peptides, HIV-1 gp120, and doublestranded RNA (poly(IC)), also stimulated the expression of CD11b in microglia through the involvement of ROS. Complete inhibition of LPS-stimulated expression of CD11b by catalase, induction of CD11b expression by H 2 O 2 alone, and inhibition of superoxide-stimulated CD11b expression by catalase suggest that H 2 O 2 , but not superoxide, is in fact involved in the expression of CD11b. Interestingly, we also demonstrate that ROS stimulated the expression of CD11b after the induction of nitric oxide (NO) production and failed to stimulate CD11b when NO production was inhibited by either 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) or L-N6-(1-iminoethyl)-L-lysine (L-NIL). Taken together, these studies suggest that the upregulation of CD11b in microglia is redox sensitive and that ROS up-regulates CD11b via NO.

Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

“…Later studies demonstrated that monocytes/macrophages, including microglia, also express NOX, and it is now accepted that NOX activity is found in both phagocytic and non-phagocytic cells, such as astroglia and neurons (49, 251). Therefore, in addition to a role in pathogen defence, NOX participate in multiple cellular processes such as host defence, migration, changes in morphology of microglia, pro-inflammatory gene expression (251), up-regulation of different markers in response to inflammatory stimuli, and microglia-induced neurotoxicity (265). An excellent review on the role of NOX enzymes in the CNS has been recently published (207) and here, we will only provide a brief description of this system.…”

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

“…The factors which trigger the age-related activation of glia are not known, although a change in the balance between pro-and anti-inflammatory cytokines, as well as dysregulation of antioxidative processes, which are likely to promote activation, have been reported (Nolan et al, 2005;Roy et al, 2008). In addition, glial cell activation by infiltrating peripheral cells has been reported recently (McQuillan et al, 2010;Murphy et al, 2010).…”

Effects of LPLI on microglial phagocytosis in LPS-induced neuroinflammation model

“…38 Conversely, others indicated that ROS was a key player in microglial activation in which ROS increased microglial expression of CD11b via NO. 39 In fact, a recent study showed that activation of CD11b via inside-out signaling negatively regulated TLRtriggered proin°ammatory response. 40 Taken together, the current investigation demonstrates that LPLI can enhance microglial phagocytic activity through activation of PI3K/Akt pathway in LPS-induced neuroin°ammation model.…”