Peripheral Neutrophil Activation and Extracellular Trap Formation in Amyotrophic Lateral Sclerosis

Area of Science:

• Neuroscience
• Immunology

Background:

• Peripheral neutrophil levels in amyotrophic lateral sclerosis (ALS) are inversely correlated with survival.
• Neutrophils may play a role in ALS disease progression.

Purpose of the Study:

• Characterize markers of neutrophil activation pathways in ALS.
• Evaluate associations between these markers and ALS survival.
• Identify potential mechanisms of neutrophil involvement in ALS.

Main Methods:

• Quantified spontaneous ex vivo neutrophil extracellular trap (NET) formation via image analysis.
• Measured plasma levels of neutrophil activation markers: calprotectin, matrix-metalloproteinase 9 (MMP9), and neutrophil gelatinase-associated lipocalin (NGAL).
• Assessed NET formation via double-stranded DNA (dsDNA) fluorescence assay.
• Associated markers with ALS survival using Cox proportional hazard regression, stratified by sex.

Main Results:

• Spontaneous ex vivo NET formation was significantly increased in ALS patients compared to controls.
• Plasma levels of calprotectin, MMP9, and NGAL were elevated in ALS patients.
• Calprotectin, MMP9, and NGAL levels were not associated with ALS survival.
• Elevated dsDNA levels, indicative of NET formation, were associated with poorer ALS survival, specifically in females.

Conclusions:

• Neutrophil function is demonstrably altered in individuals with ALS.
• NET formation represents a potential mechanism by which neutrophils contribute to ALS pathogenesis.
• The association between NETs and survival suggests a particular role for this pathway in female ALS patients.