Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production.
Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production.
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DOI：
10.1172/jci.insight.126520
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发表时间：
2019-05
期刊：
影响因子：
8
通讯作者：
Zhaoqi Yan;Wei Yang;L. Parkitny;S. Gibson;K. Lee;Forrest Collins;J. Deshane;Wayne Cheng;A. Weinmann;Hairong Wei;H. Qin;E. Benveniste
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文献类型：
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作者：
Zhaoqi Yan;Wei Yang;L. Parkitny;S. Gibson;K. Lee;Forrest Collins;J. Deshane;Wayne Cheng;A. Weinmann;Hairong Wei;H. Qin;E. Benveniste
JAK/STAT 信号通路的失调与多发性硬化症 (MS) 及其小鼠模型实验性自身免疫性脑脊髓炎 (EAE) 相关。细胞因子信号传导抑制因子 (SOCS) 负向调节 JAK/STAT 通路。我们之前报道过一种严重的、针对脑部的、非典型的 EAE，发生在骨髓细胞中缺乏 Socs3 的小鼠 (Socs3ΔLysM) 中，这与小脑中性粒细胞浸润有关。越来越多的证据表明，中性粒细胞在 MS/EAE 的病理学中有害，但其确切功能尚不清楚。在这里，我们证明来自 Socs3ΔLysM 小鼠小脑的中性粒细胞表现出过度激活的表型，在 EAE 峰值时产生过多的活性氧 (ROS)。体内 ROS 的中和可延迟非典型 EAE 的发作并减轻其严重程度。从机制上讲，Socs3 缺陷的中性粒细胞表现出 STAT3 激活增强，这是一种响应 G-CSF 的过度激活表型，并且在 G-CSF 启动后，ROS 产生增加。体内 G-CSF 的中和显着降低了非典型 EAE 表型的发生率和严重程度。总体而言，我们的工作阐明了 Socs3ΔLysM 小鼠中 G-CSF/STAT3 信号的超敏性通过增强中性粒细胞活化和增加氧化应激导致非典型 EAE，这可能解释了 G-CSF 在 MS 患者中的有害作用。
Dysregulation of the JAK/STAT signaling pathway is associated with Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE). Suppressors Of Cytokine Signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), which is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE, however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3ΔLysM mice show a hyper-activated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibit enhanced STAT3 activation, a hyper-activated phenotype in response to G-CSF, and upon G-CSF priming, increased ROS production. Neutralization of G-CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3ΔLysM mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients.