NF-kappa B activation in astrocytes drives a stage-specific beneficial neuroimmunological response in ALS

作者：Ouali Alami Najwa; Schurr Christine; Olde Heuvel Florian; Tang Linyun; Li Qian; Tasdogan Alpaslan; Kimbara Atsushi; Nettekoven Matthias; Ottaviani Giorgio; Raposo Catarina; Roever Stephan; Rogers Evans Mark; Rothenhaeusler Benno; Ullmer Christoph; Fingerle Juergen; Grether Uwe; Knuesel Irene; Boeckers Tobias M; Ludolph Albert; Wirth Thomas^*; Roselli Francesco^*; Baumann Bernd^*

来源：The EMBO Journal, 2018, 37(16): UNSP e98697.

DOI：10.15252/embj.201798697

• amyotrophic lateral sclerosis
• astrocytes
• CB2 receptor agonist
• NF-kappa B
• Wnt

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-kappa B 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-kappa B activation. While NF-kappa B activation in astrocytes induced a Wnt-dependent microglial proliferation in the presymptomatic phase with neuroprotective effects on motoneurons, in later stage, astrocyte NF-kappa B-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.

• 出版日期2018-8-15