Targeting mitochondrial complex I of CD177⁺ neutrophils alleviates lung ischemia-reperfusion injury.

Abstract

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality following lung transplantation, with neutrophils playing a central role in its inflammatory pathology. Here, we employ single-cell RNA sequencing and spatial transcriptomics to investigate neutrophil subtypes in the lung ischemia-reperfusion injury (IRI) model. We identify CD177⁺ neutrophils as an activated subpopulation that significantly contributes to lung injury and serves as an early biomarker for predicting severe PGD in human lung transplant recipients (area under the curve [AUC] = 0.871). CD177⁺ neutrophils exhibit elevated oxidative phosphorylation and increased mitochondrial complex I activity, driving inflammation and the formation of neutrophil extracellular traps. Targeting mitochondrial function with the complex I inhibitor IACS-010759 reduces CD177⁺ neutrophil activation and alleviates lung injury in both mouse IRI and rat left lung transplant models. These findings provide a comprehensive landscape of CD177⁺ neutrophil-driven inflammation in lung IRI and highlight its potential value for future early diagnosis and therapeutic interventions.