Neutrophil extracellular traps released by CD177+ neutrophils aggravated inflammation and neuronal impairment post-SCI

Abstract Spinal cord injury (SCI) causes irreversible motor and sensory dysfunction. Initial mechanical injury breaches the blood-spinal cord barrier (BSCB), triggering a rapid influx of neutrophils. However, previous studies on neutrophils after SCI have been relatively limited, the function and heterogeneity of neutrophils need further study. Here, we identified 3 distinct neutrophil subclusters post-SCI using scRNA-seq in SCI mouse models. Additionally, elevated levels of CD177+ neutrophils may aggravate inflammation and neuronal impairment based on our data from SCI patients and mice models. Further in vivo and in vitro assays indicate that CD177+ neutrophils induce pro-inflammatory polarization of macrophages and microglia via neutrophil extracellular traps (NETs) formation in a peptidyl arginine deiminase 4 (PAD4) and reactive oxygen species (ROS)-dependent manner thus inducing neuronal apoptosis. Additionally, bone marrow transplantation from Cd177 knockout (KO) to Cd177 wild-type (WT) mice improved functional recovery post-SCI. These findings elucidate the role of CD177+ neutrophils in SCI-related inflammation and highlight their potential as therapeutic targets.