Abstract Body: Neutrophils are a critical component of the innate immune system, serving as the most abundant granulocyte in blood and the first responders to both infectious and sterile injury, including cardiovascular disease such as myocardial infarction (MI). MI, a leading cause of morbidity, results from coronary occlusion and subsequent myocardial cell death, triggering a rapid and robust inflammatory response characterized by neutrophil infiltration into the heart within hours after injury.
Once in the myocardium, activated neutrophils modulate local inflammation, tissue damage, and scar formation through degradation and removal of necrotic debris, the latter via phagocytosis. Enhanced early removal of necrotic cardiac debris correlates with reduced injury and scar size after MI. However, the underlying mechanisms that govern neutrophil function in this context remain poorly understood.
In this study, we developed a mouse model with neutrophil-specific mitochondrial dysfunction. Despite interruption of these fundamental metabolic pathways, these neutrophils surprisingly exhibited normal maturation, morphology and migration to the injured hearts of mice. Interestingly, neutrophils with perturbed mitochondrial respiration demonstrated higher levels of necrotic cardiac tissue uptake in vivo, which was also confirmed to be cell-intrinsic in culture. This effect was corroborated by reduced cardiac injury following MI in mice. Metabolomic profiling revealed that mitochondrial respiration impairment also resulted in decreased metabolism of mitochondrial metabolites, implicating shunting of neutrophil metabolism as a strategy to improve organ healing after injury.