Neutrophils are the earliest and most abundant immune cells to infiltrate the myocardium after myocardial ischemia/reperfusion (MI/R) injury. To date, the literature presents contradictory findings regarding the detrimental versus beneficial roles of neutrophils in MI/R. Activation of STING (Stimulator of Interferon Genes) signaling drives the expression of proinflammatory cytokines and type I interferons in immune cells. Here, we sought to investigate the role of neutrophil-intrinsic STING signaling during MI/R. Neutrophil-specific deletion of Sting resulted in significantly impaired cardiac function after MI/R, accompanied by reduced activation of NF-κB pathways in cardiac neutrophils, diminished early neutrophil recruitment to the myocardium, and defective neutrophil clearance. Immunostaining demonstrated decreased apoptosis in STING-deficient neutrophils, while flow cytometry showed reduced efferocytosis of these neutrophils by macrophages. Consistent with this, there was a reduction in anti-inflammatory macrophages within the myocardium 72 hours after MI/R. STING signaling in neutrophils is cardioprotective during MI/R by promoting efficient neutrophil clearance and facilitating the resolution of inflammation through the induction of anti-inflammatory macrophage polarization. Collectively, this work supports the concept that selectively targeting neutrophil effector function, rather than employing broad immunosuppression, represents a promising therapeutic strategy for MI/R.
Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is ubiquitously expressed and contributes to cardiovascular, metabolic, and gastrointestinal homeostasis. In this study, we observed ACE2 loss in organs of patients with COVID-19 and in SARS-CoV-2-infected cells. In aged, obese, and diabetic mice, SARS-CoV-2 infection caused greater morbidity, persistent pulmonary infection, intestinal and metabolic disruption, and impaired cardiac Wnt and interferon-γ signaling. ACE2-deficient obese-diabetic mice showed cardiovascular, intestinal, metabolic, and neurobehavioral abnormalities, providing a complementary model to examine ACE2-associated disruption in metabolic disease. Exploratory metabolic profiling identified shared disruptions in taurine, tryptophan, and microbiota-derived metabolites across clinical and preclinical samples. These findings identify metabolic disease as a modifier of SARS-CoV-2 susceptibility and support ACE2-associated dysregulation as one contributor to selected infection-related sequelae.
