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 (CD16int Neu) in sepsis patients and slightly elevated in mature Neu (CD16hi Neu). ProBDNF expression in CD16int Neu showed promising diagnostic value for sepsis, with a specific positive correlation with disease severity, prognosis, and organ dysfunction. CD16hi 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 CD16int Neu may be a promising biomarker of sepsis. Targeting proBDNF in CD16hi Neu has the potential to control mitochondrial hyperactivation during sepsis.