Targeting proBDNF in neutrophil subsets: Sepsis biomarker discovery and insights into mitochondrial hyperactivation

Sepsis, characterized by dysregulated immune responses, necessitates biomarkers and therapies. We conducted a prospective multicentric observational study involving sepsis patients and control groups. The proportions and brain-derived neurotrophic factor precursor (proBDNF) expression of blood neutrophil subsets were detected, and their clinical value was evaluated via correlation analysis and receiver operating characteristic curve analysis. ProBDNF was significantly upregulated in immature neutrophils (CD16^int Neu) in sepsis patients and slightly elevated in mature Neu (CD16^hi Neu). ProBDNF expression in CD16^int Neu showed promising diagnostic value for sepsis, with a specific positive correlation with disease severity, prognosis, and organ dysfunction. CD16^hi Neu from sepsis patients presented hyperactivated mitochondria, as shown by their increased mitochondrial membrane potential and length, which was reversed by neutralizing proBDNF. ProBDNF expression in circulating CD16^int Neu may be a promising biomarker of sepsis. Targeting proBDNF in CD16^hi Neu has the potential to control mitochondrial hyperactivation during sepsis.