NF-κB activation in astrocytes drives a stage-specific beneficial neuroimmunological response in ALS.
NF-κB activation in astrocytes drives a stage-specific beneficial neuroimmunological response in ALS.
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DOI：
10.15252/embj.201798697
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发表时间：
2018-08-15
期刊：
影响因子：
--
通讯作者：
Baumann B
中科院分区：
文献类型：
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作者：
Ouali Alami N;Schurr C;Olde Heuvel F;Tang L;Li Q;Tasdogan A;Kimbara A;Nettekoven M;Ottaviani G;Raposo C;Röver S;Rogers-Evans M;Rothenhäusler B;Ullmer C;Fingerle J;Grether U;Knuesel I;Boeckers TM;Ludolph A;Wirth T;Roselli F;Baumann B
星形胶质细胞参与肌萎缩侧索硬化症（ALS）的非细胞自主致病级联反应;然而，它们的作用仍有争议。我们发现，星形胶质细胞NF-κB激活驱动小胶质细胞增殖和白细胞浸润的SOD 1（G93 A）ALS模型。这种反应延缓了症状前期，延迟了肌肉去神经支配并减少了疾病负担，但在症状期变得有害，加速了疾病进展。这种转变对应于小胶质细胞表型的转变，表现出两种效应，这两种效应可以通过暂时控制NF-κB活化来分离。星形胶质细胞中的NF-κB活化在症状前阶段诱导Wnt依赖性小胶质细胞增殖，对运动神经元具有神经保护作用，而在后期阶段，星形胶质细胞NF-κB依赖性小胶质细胞活化导致加速疾病进展。值得注意的是，CB 2 R激动剂对早期小胶质细胞反应的抑制具有急性有害作用。这些数据确定星形胶质细胞作为小胶质细胞扩增和免疫应答的重要调节剂。因此，阶段依赖性小胶质细胞调节可能是ALS的有效治疗策略。
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.