Tumor Necrosis Factor α Mediates Lipopolysaccharide-Induced Microglial Toxicity to Developing Oligodendrocytes When Astrocytes Are Present

Abstract

Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-␣ (TNF␣) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91 phox , the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type, iNOS Ϫ/Ϫ , and gp91 phox؊/؊ mice. TNF␣ neutralizing antibody inhibited LPS toxicity, and addition of TNF␣ induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNF␣ or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNF␣ signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death.

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

“…These findings are consistent with animal studies demonstrating that the up-regulation of cytokines is related to sickness-like behavioural symptoms of anhedonia and dysfunction in cognitive function [6,108] shown by murine studies [6,111]. However, continual exposure to these cytokines results in decreased neurogenesis, apoptosis and cognitive dysfunction [6,67,112].…”

“…It is synthesized in its pro form as a monomeric type 2 transmembrane protein (tmTNF-α) and is inserted into the cell membrane and cleaved to its soluble form (solTNF-α) by a matrix metalloprotease TNF-α-converting enzyme (TACE/ADAM17) [65]. Both forms of TNF-α are biologically active and are produced in the CNS by astrocytes, microglia as well as neurons [10,66,67].…”

“…TNF-α can further influence astrocytes and microglia to release nitrogen and oxygen reactive species that cause oxidative stress to neurons and glial cells [6,67,112,116]. Such oxidative damage is particularly noticeable in Figure 4.…”

Lipocalin 2 modulates the cellular response to amyloid beta

“…However, taking into account recent observations suggesting that LCN2 alone is not able to induce apoptosis in astrocytes, 26 we cannot discard an indirect modulation of astrocytes' survival by molecules secreted by activated microglia (o5% in astrocyte-enriched cultures), because of their ability to respond to LCN2. 28 In fact, others have shown that in response to LPS, microglia are able to influence the survival of brain cells, oligodendrocytes in particular, by secreting proinflammatory molecules like TNF, 40 and that this process is modulated, in vivo, by LCN2. 28 Of notice, neuronal apoptosis in response to Ab 1-42 is independent of their ability to produce LCN2 as the survival of Lcn2( þ / þ ) and Lcn2( À / À ) neurons significantly decreased in response to Ab .…”

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

“…Of note, peroxynitrite is also responsible for the LPS-induced degeneration of developing oligodendrocytes in coculture experiments (66). However, when astrocytes were present along with oligodendrocytes and microglia, the LPS-induced microglia-dependent toxicity to developing oligodendrocytes was mediated by a mechanism involving TNF-a signaling (67). Thus, in addition to redox-triggered signaling, microgliamediated toxicity is also dependent on a number of immunologically relevant cytokines that can activate conserved DAMPs and PAMPs.…”