P75^NTR+CD64⁺ neutrophils promote sepsis-induced acute lung injury

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64⁺ neutrophils, which highly expressed p75 neurotrophin receptor (p75^NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75^NTR+CD64⁺ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75^NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64⁺ neutrophils. In vitro, p75^NTR+CD64⁺ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75^NTR activity by soluble p75^NTR extracellular domain peptide (p75^ECD-Fc) boosted CD64⁺ neutrophils phagocytic activity and reduced inflammatory cytokine production via regulation of the NF-κB activity. The findings strongly indicate that p75^NTR+CD64⁺ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.