Neuronal Mitochondria Modulation of LPS-Induced Neuroinflammation

Abstract

Neuronal mitochondria dysfunction and neuroinflammation are two prominent pathological features increasingly realized as important pathogenic mechanisms for neurodegenerative diseases. However, little attempt has been taken to investigate the likely interactions between them. Mitofusin2 (Mfn2) is a mitochondrial outer membrane protein regulating mitochondrial fusion, a dynamic process essential for mitochondrial function. To explore the significance of neuronal mitochondria in the regulation of neuroinflammation, male and female transgenic mice with forced overexpression of Mfn2 specifically in neurons were intraperitoneally injected with lipopolysaccharide (LPS), a widely used approach to model neurodegeneration-associated neuroinflammation. Remarkably, LPS-induced lethality was almost completely abrogated in neuronal Mfn2 overexpression mice. Compared with nontransgenic wild-type mice, mice with neuronal Mfn2 overexpression also exhibited alleviated bodyweight loss, behavioral sickness, and myocardial dysfunction. LPS-induced release of IL-1␤ but not TNF-␣ was further found greatly inhibited in the CNS of mice with neuronal Mfn2 overexpression, whereas peripheral inflammatory responses in the blood, heart, lung, and spleen remained unchanged. At the cellular and molecular levels, neuronal Mfn2 suppressed the activation of microglia, prevented LPS-induced mitochondrial fragmentation in neurons, and importantly, upregulated the expression of CX3CL1, a unique chemokine constitutively produced by neurons to suppress microglial activation. Together, these results reveal an unrecognized possible role of neuronal mitochondria in the regulation of microglial activation, and propose neuronal Mfn2 as a likely mechanistic linker between neuronal mitochondria dysfunction and neuroinflammation in neurodegeneration.

Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers

“…Levels of IL-1β have been shown to be elevated in AD brains [ 30 , 84 ]. Moreover, studies have suggested that neuroinflammation triggered by IL-1β impairs mitochondrial function [ 25 , 62 , 63 ]. Anakinra, a recombinant IL-1R antagonist [ 36 , 65 ], prevented AβO-induced mitochondrial dysfunction and alterations in MFN-1 and MFN-2 levels in mixed hippocampal cultures.…”

“…Our findings implicate altered mitochondrial dynamics in IL-1β-mediated synaptic and memory defects and are consistent with studies showing that blockade of IL-1R restores cognition and alleviates pathogenesis in AD mouse models [ 26 , 27 ]. While the role of neuroinflammation on neuronal mitochondrial dynamics in AD has not been completely explored, there is evidence showing that production of inflammatory mediators can impair mitochondrial function [ 63 , 85 ].…”

“…A very recent study [ 63 ] showed that overexpression of MFN-2 prevented peripheral lipopolysaccharide (LPS)-induced neuroinflammation in mice, with significant reductions in brain IL-1β levels and mitochondrial fragmentation in neurons. Collectively, these data support our hypothesis that neuroinflammation mediated by IL-1β affects mitochondrial dynamics and memory impairment in mice.…”

Propofol suppresses microglial phagocytosis through the downregulation of MFG-E8

“…A possible explanation for the variation in the effect of propofol on cell viability could be differences in cell origin, as cells derived from different sources could show variations in sensitivity to stimuli. For example, neurons are vulnerable to external insults, including LPS exposure and oxygen-glucose deprivation (OGD) [21][22][23], while microglia show a much higher tolerance to environmental changes. Another possible explanation for the variation in the effect of propofol on the viability of neurons and microglia could be the heterogeneity of GABA A receptor subunits within the brain [24].…”

Is loss of perineuronal nets a critical pathological event in Alzheimer's disease?

“…A hallmark of AD is neuroinflammatory changes within the cortex, thought to be both a result and cause of cell death. One of the main drivers of the neuroinflammatory process are microglia – the brain's resident immune cells [5] . Activation of microglia in AD occurs as a response to cell damage, as microglia dispose of neuronal debris by phagocytosis.…”