Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis

Abstract

SUMMARY Neuroinflammation is one of the most striking hallmarks of amyotrophic lateral sclerosis (ALS). Nuclear Factor-kappa B (NF-κB), a master regulator of inflammation, is upregulated in spinal cords of ALS patients and SOD1-G93A mice. In this study, we show that selective NF-κB inhibition in ALS astrocytes is not sufficient to rescue motor neuron (MN) death. However, the localization of NF-κB activity and subsequent deletion of NF-κB signaling in microglia rescued MNs from microglial-mediated death in vitro and extended survival in ALS mice by impairing pro-inflammatory microglial activation. Conversely, constitutive activation of NF-κB selectively in wild-type microglia induced gliosis and MN death in vitro and in vivo. Taken together, these data provide a mechanism by which microglia induce MN death in ALS, and suggest a novel therapeutic target that can be modulated to slow the progression of ALS and possibly other neurodegenerative diseases by which microglial activation plays a role.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Third, the effects of Htr2b ablation on ALS progression are strikingly similar to interventions performed on mononuclear phagocytes. For instance, knocking out mutant SOD1 or NF-kappaB signaling from CD11b-positive cells improved disease progression, but had no effect El Oussini and collaborators 16 on disease onset [5,25]. Despite these parallels, our current results cannot exclude that at least part of the effects of Htr2b ablation are caused by its expression in other cell types.…”

“…in all macrophages, prolongs disease progression suggesting that mutant SOD1 exerts toxic action in these cells thereby accelerating disease [5]. Furthermore, decreased activation of the pro-inflammatory transcription factor NF-kappaB in microglial cells potently slowed down disease progression [25]. An open question is whether the toxic effect of macrophages is mediated by resident microglia and/or by infiltrating blood monocytes.…”

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Inhibition of both iNOS and IL-1β have been proposed as potential therapeutic approach to ALS, as in ALS mice upregulation of iNOS occurs in parallel with motor neuron loss [36], and treatment of presymptomatic ALS mice with IL-1 blocker anakinra increases survival without affecting the time of disease onset [37]. M1 microglia-mediated motor neuron death, driven by nuclear factor kB-dependent mechanisms, has been shown in mSOD1 G93A mice and heterozygous inhibition of nuclear factor kB specifically in the myeloid lineage of mSOD1 G93A mice significantly delayed disease progression and increased survival [4], further supporting the hypothesis that a dampened M1 response might contribute to protective action of fingolimod. Our data are also consistent with recent studies demonstrating that fingolimod is able to modulate microglial inflammatory phenotype both in vitro and in vivo [38], in an animal model of multiple sclerosis [39].…”

“…A growing body of evidence suggests that, besides many other mechanisms (e.g., excitotoxicity, oxidative stress, toxicity by protein misfolding, and mitochondrial dysfunction, see [2]), neuroinflammation and immune reaction are pivotal features both in patients with ALS and in animal models [3][4][5].…”

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

“…Dysregulation of NF‐κB has been linked to cancer and neurodegenerative diseases such as Huntington's (Ghose, Sinha, Das, Jana, & Bhattacharyya, 2011) and ALS (Frakes et al, 2014; Prell et al, 2014). Interestingly, FUS augments NF‐ĸB‐dependent gene expression induced by physiological stimuli such as TNFα (Uranishi, 2001).…”