Brown 2010 Abstract MiP2010
|The mitochondrion in flames: mitochondria in inflammatory neurodegeneration.|
Brown GC (2010)
Inflammatory neurodegeneration is neuronal degeneration due to inflammation, and is thought to contribute to neuronal loss in infectious, ischemic, traumatic and neurodegenerative brain pathologies. We have identified three mechanisms by which inflamed glia kill neurons: iNOS, PHOX and phagocytosis.
A variety of inflammatory mediators induce the expression in microglia and astrocytes of inducible nitric oxide synthase (iNOS), which produces high levels of NO. NO acutely and potently inhibits mitochondrial respiration at cytochrome oxidase in competition with oxygen, while NO derivatives peroxynitrite and S-nitrosothiols inactivate mitochondrial Complex I, resulting in a stimulation of oxidant production by mitochondria. We find that a high level of glial iNOS expression induces neuronal death in synergy with hypoxia, basically by NO inhibition of neuronal respiration resulting in glutamate release and excitotoxicity. This suggests that the inflamed brain may be more sensitive to hypoxic damage. NO from nNOS can also synergise with hypoxia to induce neuronal death via inhibition of mitochondrial respiration (if glycolysis is blocked).
The phagocyte NADPH oxidase (PHOX) is constitutively expressed primarily on the plasma membrane of microglia. Acute activation of PHOX (by e.g. PMA, ATP or Aβ) produces superoxide and hydrogen peroxide. This stimulates microglial production of TNF-α and IL-1β and microglial proliferation, which is blocked by inhibiting PHOX or by removing H2O2 with catalase, and is replicated by adding H2O2. Thus PHOX appears to regulate microglial proliferation and activation through H2O2 production, but has no apparent direct effect on neuronal death. However, if we activated PHOX in glia where iNOS had previously been induced there was considerable synergy in inducing apoptosis of co-cultured neurons. And this apoptosis was prevented either by inhibiting iNOS or PHOX, or scavenging peroxynitrite (the neurotoxic product of NO reacting with superoxide).
However, we find that apoptosis, as measured by phosphatidyserine (PS) exposure, can be reversible in neurons. Temporary exposure of neurons to low levels of H2O2, glutamate or peroxynitrite results in reversible PS exposure on neurons. And such neurons go on to survive, if their phagocytosis by inflamed microglia is prevented at the time of PS exposure. Inflammatory activation of neuronal-glial co-cultures with LPS, LTA or β-amyloid (in the absence of pro-inflammatory cytokines) results in progressive loss of neurons (without any apparent cell death) which is accompanied by microglial phagocytosis of neurons, and is prevented by blocking phagocytosis, in culture and in vivo.
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2. Jekabsone A, Nehrer J, Borutaite V, Brown GC (2007) NO from neuronal nitric oxide synthase sensitises neurons to hypoxia-induced death via competitive inhibition of cytochrome oxidase. J. Neurochem. 103: 346-356.
3. Brown GC, Neher JJ (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol. Neurobiol. Mar 2.
Stress:Oxidative stress;RONS, Mitochondrial disease
Tissue;cell: Nervous system