RESUMEN
Cardiac macrophages represent a functionally diverse population of cells involved in cardiac homeostasis, repair, and remodeling. With recent advancements in single-cell technologies, it is possible to elucidate specific macrophage subsets based on transcriptional signatures and cell surface protein expression to gain a deep understanding of macrophage diversity in the heart. The use of fate-mapping technologies and parabiosis studies have provided insight into the ontogeny and dynamics of macrophages identifying subsets derived from embryonic and adult definitive hematopoietic progenitors that include tissue-resident and bone marrow monocyte-derived macrophages, respectively. Within the heart, these subsets have distinct tissue niches and functional roles in the setting of homeostasis and disease, with cardiac resident macrophages representing a protective cell population while bone marrow monocyte-derived cardiac macrophages have a context-dependent effect, triggering both proinflammatory tissue injury, but also promoting reparative functions. With the increased understanding of the clinical relevance of cardiac macrophage subsets, there has been an increasing need to detect and measure cardiac macrophage compositions in living animals and patients. New molecular tracers compatible with positron emission tomography/computerized tomography and positron emission tomography/ magnetic resonance imaging have enabled investigators to noninvasively and serially visualize cardiac macrophage subsets within the heart to define associations with disease and measure treatment responses. Today, advancements within this thriving field are poised to fuel an era of clinical translation.
Asunto(s)
Macrófagos , Miocardio , Animales , Macrófagos/metabolismo , Humanos , Miocardio/metabolismo , Miocardio/citologíaRESUMEN
RATIONALE: The innate immune response contributes to cardiac injury in myocardial ischemia/reperfusion (MI/R). Neutrophils are an important early part of the innate immune response to MI/R. Adenosine, an endogenous purine, is a known innate immune modulator and inhibitor of neutrophil activation. However, its delivery to the heart is limited by its short half-life (<30 s) and off-target side effects. CD39 and CD73 are anti-inflammatory homeostatic enzymes that can generate adenosine from phosphorylated adenosine substrate such as ATP released from injured tissue. OBJECTIVE: We hypothesize that hydrogel-delivered CD39 and CD73 target the local early innate immune response, reduce neutrophil activation, and preserve cardiac function in MI/R injury. METHODS AND RESULTS: We engineered a poly(ethylene) glycol (PEG) hydrogel loaded with the adenosine-generating enzymes CD39 and CD73. We incubated the hydrogels with neutrophils in vitro and showed a reduction in hydrogen peroxide production using Amplex Red. We demonstrated availability of substrate for the enzymes in the myocardium in MI/R by LC/MS, and tested release kinetics from the hydrogel. On echocardiography, global longitudinal strain (GLS) was preserved in MI/R hearts treated with the loaded hydrogel. Delivery of purinergic enzymes via this synthetic hydrogel resulted in lower innate immune infiltration into the myocardium post-MI/R, decreased markers of macrophage and neutrophil activation (NETosis), and decreased leukocyte-platelet complexes in circulation. CONCLUSIONS: In a rat model of MI/R injury, CD39 and CD73 delivered via a hydrogel preserve cardiac function by modulating the innate immune response.
Asunto(s)
Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Ratas , Animales , Hidrogeles/uso terapéutico , Corazón , Miocardio , Adenosina , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Polietilenglicoles/uso terapéuticoRESUMEN
Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/inmunología , Ferroptosis/inmunología , Trasplante de Corazón , Daño por Reperfusión Miocárdica/inmunología , Miocardio/inmunología , Infiltración Neutrófila , Neutrófilos/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 4/inmunología , Proteínas Adaptadoras del Transporte Vesicular/genética , Animales , Ciclohexilaminas/farmacología , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Noqueados , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Neutrófilos/patología , Fenilendiaminas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Receptor Toll-Like 4/genética , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/genética , Función Ventricular Izquierda/inmunologíaRESUMEN
The increase of physician ownership and use of in-office advanced diagnostic imaging equipment (magnetic resonance imaging, positron emission tomography, and computed axial tomography) has led to concerns about overuse, quality, and increased costs. The requirement that a physician or non-physician practitioner furnishing diagnostic testing services (1) enroll as an independent diagnostic testing facility (IDTF) for each practice location furnishing these services and (2) comply with the performance standards of 42 C.F.R. section 410.33 would represent a major step toward curbing potential advanced diagnostic imaging self-referral overutilization, improving quality, and lowering costs.