NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS

• Najwa Ouali Alami ^[1] ; Christine Schurr ^[2] ; Florian Olde Heuvel ^[1] ; Linyun Tang ^[1] ; Qian Li ^[1] ; Alpaslan Tasdogan ^[3] ; Atsushi Kimbara ^[4] ; Matthias Nettekoven ^[4] ; Giorgio Ottaviani ^[4] ; Catarina Raposo ^[4] ; Stephan Röver ^[4] ; Mark Rogers‐Evans ^[4] ; Benno Rothenhäusler ^[4] ; Christoph Ullmer ^[4] ; Jürgen Fingerle ^[5] ; Uwe Grether ^[4] ; Irene Knuesel ^[4] ; Tobias M Boeckers ^[6] ; Albert Ludolph ^[1] ; Thomas Wirth ^[2] ; Francesco Roselli ^[7] ; Bernd Baumann ^[2]
  1. [1] 1 Department of Neurology Ulm University Ulm Germany
  2. [2] 2 Institute of Physiological Chemistry Ulm University Ulm Germany
  3. [3] 3 Institute of Immunology Ulm University Ulm Germany
  4. [4] 4 Roche Pharma Research and Early Development Roche Innovation Center Basel F. Hoffmann‐La Roche Ltd. Basel Switzerland
  5. [5] 5 Natural and Medical Sciences Institute Tübingen University Reutlingen Germany
  6. [6] 6 Department of Anatomy and Cell Biology Ulm University Ulm Germany
  7. [7] 1 Department of Neurology Ulm University Ulm Germany; 6 Department of Anatomy and Cell Biology Ulm University Ulm Germany

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 16, 2018
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • 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.