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NF‐κB activation in astrocytes drives a stage‐specific beneficial neuroimmunological response in ALS
Authors:Florian Olde Heuvel  Linyun Tang  Qian Li  Alpaslan Tasdogan  Atsushi Kimbara  Matthias Nettekoven  Giorgio Ottaviani  Catarina Raposo  Stephan Röver  Mark Rogers‐Evans  Benno Rothenhäusler  Christoph Ullmer  Jürgen Fingerle  Uwe Grether  Irene Knuesel  Tobias M Boeckers  Albert Ludolph  Thomas Wirth  Francesco Roselli  Bernd Baumann
Affiliation:1. Department of Neurology, Ulm University, Ulm, Germany;2. Institute of Immunology, Ulm University, Ulm, Germany;3. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann‐La Roche Ltd., Basel, Switzerland;4. Natural and Medical Sciences Institute, Tübingen University, Reutlingen, Germany;5. Department of Anatomy and Cell Biology, Ulm University, Ulm, Germany;6. Institute of Physiological Chemistry, Ulm University, Ulm, GermanyThese authors contributed equally to this work as senior authors;7. Department of Anatomy and Cell Biology, Ulm University, Ulm, GermanyThese authors contributed equally to this work as senior authors
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:amyotrophic lateral sclerosis  astrocytes  CB2 receptor agonist  NF‐κ  B  Wnt
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