P75NTR+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-kappa B activity. The findings strongly indicate that p75(NTR+)CD64(+) neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.