NF-κB Activation in Astrocytes Drives a Stage-Specific Beneficial Neuroimmunological Response in ALS

EMBO J. 2018 Aug 15;37(16):e98697. doi: 10.15252/embj.201798697. Epub 2018 Jun 6.

Abstract

Astrocytes are involved in non-cell-autonomous pathogenic cascades in amyotrophic lateral sclerosis (ALS); however, their role is still debated. We show that astrocytic NF-κB activation drives microglial proliferation and leukocyte infiltration in the SOD1 (G93A) ALS model. This response prolongs the presymptomatic phase, delaying muscle denervation and decreasing disease burden, but turns detrimental in the symptomatic phase, accelerating disease progression. The transition corresponds to a shift in the microglial phenotype showing two effects that can be dissociated by temporally controlling NF-κB activation. While NF-κB activation in astrocytes induced a Wnt-dependent microglial proliferation in the presymptomatic phase with neuroprotective effects on motoneurons, in later stage, astrocyte NF-κB-dependent microglial activation caused an accelerated disease progression. Notably, suppression of the early microglial response by CB2R agonists had acute detrimental effects. These data identify astrocytes as important regulators of microglia expansion and immune response. Therefore, stage-dependent microglia modulation may be an effective therapeutic strategy in ALS.

Keywords: CB2 receptor agonist; NF‐κB; Wnt; amyotrophic lateral sclerosis; astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / immunology*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / therapy
  • Animals
  • Astrocytes / immunology*
  • Astrocytes / pathology
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Microglia / immunology
  • Microglia / pathology
  • Motor Neurons / immunology
  • Motor Neurons / pathology
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / immunology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / immunology
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / immunology

Substances

  • NF-kappa B
  • Receptor, Cannabinoid, CB2
  • SOD1 G93A protein
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1