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Accession IconSRP168313

Deficiency of Socs3 Leads to Brain-targeted EAE via Enhanced Neutrophil Activation and Production of Reactive Oxygen Species

Organism Icon Mus musculus
Sample Icon 12 Downloadable Samples
Technology Badge IconIllumina HiSeq 2500

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Description
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 (Socs3?LysM), 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 Socs3?LysM 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 Socs3?LysM 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. Overall design: Bone marrow cells were isolated from the femurs of Socs3fl/fl or Socs3?LysM mice. Red blood cells were lysed by incubation in ACK lysis buffer for 1 min. CD45+CD11b+Ly6G+ neutrophils were flow sorted and stimulated with or without G-CSF (10 ng/ml) for 8 hours. Total RNA was purified from cells using Trizol reagent extraction, and 500 ng–2 µg of RNA was sent to GENEWIZ (South Plainfield, NJ) for RNA-seq and bioinformatics analysis.
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