Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production

Area of Science:

• Immunology
• Neuroscience
• Molecular Biology

Background:

• The JAK/STAT signaling pathway is implicated in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE).
• Suppressors Of Cytokine Signaling (SOCS) proteins, particularly SOCS3, are critical negative regulators of the JAK/STAT pathway.
• Previous studies identified a severe, brain-specific EAE form in mice lacking SOCS3 in myeloid cells (Socs3ΔLysM), characterized by cerebellar neutrophil infiltration.

Purpose of the Study:

• To investigate the role and function of neutrophils in the atypical EAE observed in Socs3ΔLysM mice.
• To elucidate the underlying mechanisms of neutrophil hyper-activation and their contribution to EAE pathogenesis.
• To explore the therapeutic potential of targeting neutrophil-derived reactive oxygen species (ROS) and G-CSF signaling in EAE.

Main Methods:

• Generated and analyzed Socs3ΔLysM mice exhibiting an atypical EAE phenotype.
• Characterized neutrophil phenotype, including reactive oxygen species (ROS) production, in the cerebellum during EAE.
• Assessed the impact of in vivo neutralization of ROS and Granulocyte-Colony Stimulating Factor (G-CSF) on EAE severity and onset.
• Investigated the molecular mechanisms of SOCS3 deficiency in neutrophils, focusing on STAT3 activation and response to G-CSF.

Main Results:

• Neutrophils from Socs3ΔLysM mice displayed a hyper-activated phenotype with excessive ROS production at the peak of EAE.
• In vivo neutralization of ROS significantly delayed EAE onset and reduced disease severity.
• Socs3-deficient neutrophils showed enhanced STAT3 activation and hyper-responsiveness to G-CSF, leading to increased ROS production upon G-CSF priming.
• In vivo neutralization of G-CSF markedly reduced the incidence and severity of the atypical EAE.

Conclusions:

• Hypersensitivity to G-CSF/STAT3 signaling in SOCS3-deficient neutrophils drives atypical EAE through enhanced activation and oxidative stress.
• Neutrophil-derived ROS and G-CSF signaling are critical contributors to EAE pathogenesis.
• Targeting neutrophil activation, ROS production, or G-CSF signaling may represent a viable therapeutic strategy for MS and related inflammatory neurological diseases.