Abstract
BackgroundNeurodegenerative diseases are characterized by both mitochondrial dysfunction and activation of microglia, the macrophages of the brain. Here, we investigate the effects of mitochondrial dysfunction on the activation profile of microglial cells.MethodsWe incubated primary mouse microglia with the mitochondrial toxins 3-nitropropionic acid (3-NP) or rotenone. These mitochondrial toxins are known to induce neurodegeneration in humans and in experimental animals. We characterized lipopolysaccharide- (LPS-) induced microglial activation and the alternative, interleukin-4- (IL-4-) induced microglial activation in these mitochondrial toxin-treated microglial cells.ResultsWe found that, while mitochondrial toxins did not affect LPS-induced activation, as measured by release of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), they did inhibit part of the IL-4-induced alternative activation, as measured by arginase activity and expression, induction of insulin-like growth factor 1 (IGF-1) and the counteraction of the LPS induced cytokine release.ConclusionsMitochondrial dysfunction in microglial cells inhibits part of the IL-4-induced alternative response. Because this alternative activation is considered to be associated with wound healing and an attenuation of inflammation, mitochondrial dysfunction in microglial cells might contribute to the detrimental effects of neuroinflammation seen in neurodegenerative diseases.
Highlights
Neurodegenerative diseases are characterized by both mitochondrial dysfunction and activation of microglia, the macrophages of the brain
We investigated whether the mitochondrial toxins 3-nitropropionic acid (3-NP) and rotenone, both of which affect the mitochondrial electron transport chain, have an effect on this LPS-induced inflammatory activation of microglial cells
In this study we show that mitochondrial dysfunction in mouse microglial cells inhibits specific responses of alternative activation, whereas classic activation remained unchanged
Summary
Neurodegenerative diseases are characterized by both mitochondrial dysfunction and activation of microglia, the macrophages of the brain. We investigate the effects of mitochondrial dysfunction on the activation profile of microglial cells. Activated microglia release a combination of bioactive agents including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa), and insulin-like growth factor 1 (IGF-1). These bioactive agents have both protective and detrimental consequences for the surrounding brain tissue [2,3]. Levels of proinflammatory cytokines such as TNFa increase, suggesting that a pro-inflammatory activation of microglia, as seen with lipopolysaccharide (LPS) stimulation, outweighs the protective effects of microglia in these diseases. Microglial cells constitutively express SOD1 and other proteins that harbor neurodegeneration-causing mutations, e.g huntingtin and alphasynuclein, and this might modulate microglial activation [6,7,8,9,10,11]
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