Targeting a specific subset of neutrophils to mitigate cardiac reperfusion injury

Ischemia reperfusion (IR)-induced oxidative stress and inflammation contribute to morbidity and mortality of acute coronary syndrome. Ischemia results in profound hypoxia and tissue dysfunction and subsequent reperfusion further aggravates ischemic cardiac tissue damage. In cardiac IR injury, neutrophils are involved both in causing cardiomyocyte death and in preserving heart tissue homeostasis. We tested the hypothesis that neutrophil subpopulations show distinct functions in the pathogenesis of cardiac IR injury and that their functional heterogeneity can be exploited in subset-specific pharmacological intervention to prevent IR-induced myocardial tissue damage and functional deterioration. Cardiac IR-injury in a mouse model was characterized by the presence of two distinct heart-inflammatory subsets of neutrophils, one that specifically endocytosed albumin nanoparticles (ANP^high) and one that endocytose few or no ANP (ANP^low). The two subsets had very distinct inflammatory phenotypes. ANP^high neutrophils expressed significantly greater amounts of inflammatory mediators, such as Il-1b and Ccl3, than ANP^low neutrophils. Targeting the Spleen tyrosine kinase (Syk) specifically in ANP^high neutrophils post IR reduced cardiac neutrophilic and mononuclear inflammation and drastically decreased infarct size, and prevented the deterioration of cardiac function. Targeting the Syk pathway specifically in a defined subset of neutrophils is a feasible therapy for cardiac IR injury.