Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart.

BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.

Bone marrow adipocytes fuel emergency hematopoiesis after myocardial infarction.

After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the balance between glycolysis and mitochondrial metabolism regulates hematopoietic stem cell homeostasis, metabolic cues may influence emergency myelopoiesis. Here, we show in humans and female mice that hematopoietic progenitor cells increase fatty acid metabolism after MI. Blockade of fatty acid oxidation by deleting carnitine palmitoyltransferase (Cpt1A) in hematopoietic cells of Vav1Cre/+Cpt1Afl/fl mice limited hematopoietic progenitor proliferation and myeloid cell expansion after MI. We also observed reduced bone marrow adiposity in humans, pigs and mice following MI. Inhibiting lipolysis in adipocytes using AdipoqCreERT2Atglfl/fl mice or local depletion of bone marrow adipocytes in AdipoqCreERT2iDTR mice also curbed emergency hematopoiesis. Furthermore, systemic and regional sympathectomy prevented bone marrow adipocyte shrinkage after MI. These data establish a critical role for fatty acid metabolism in post-MI emergency hematopoiesis.

CDC-derived extracellular vesicles reprogram inflammatory macrophages to an arginase 1-dependent proangiogenic phenotype.

Macrophages play a pivotal role in tissue repair following myocardial infarction (MI). In response to injury, they exist along a spectrum of activation states tightly regulated by their microenvironment. Cardiosphere-derived cells (CDCs) have been shown to mediate cardioprotection via modulation of the macrophage response. Our study was designed to gain mechanistic insight into the role of CDC-derived extracellular vesicles (EVs) in modulating macrophage phenotypes and operant signaling pathways to better understand their potential contribution to immunomodulatory cardioprotection. We found that CDC-derived EVs alter the functional phenotype of macrophages, modifying levels of phagocytosis and efferocytosis without changing viability or proliferation. Interestingly, extracellular vesicles differentially regulate several M1/M2 genes dependent on macrophage activation before EV treatment but consistently upregulate arginase 1 regardless of macrophage origin or polarization state. CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation and independent of VEGF-A. In addition, EV-dependent arginase 1 upregulation downregulates nitric oxide (NO) secretion in activated macrophages. These data suggest a novel urea-cycle-dependent mechanism in macrophages that promotes angiogenesis and provides additional mechanistic insight into the potential contribution of CDC-derived extracellular vesicles in immunomodulatory cardioprotection.NEW & NOTEWORTHY We hypothesized that in the window of therapeutic extracellular vesicle (EV) administration, inflammatory M1 macrophages are likely the primary target of cardiosphere-derived cell (CDC)-derived EVs. The effect of CDC-EVs on this population, however, is currently unknown. In this study, we demonstrate that CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation. These results provide insight into an immunomodulatory mechanism of CDC-EVs in a more physiologically relevant model of post-myocardial infarction (post-MI) macrophage polarization.

Therapeutic Potential of Engineered Extracellular Vesicles.

Extracellular vesicles (EVs) comprise a heterogeneous group of small membrane vesicles, including exosomes, which play a critical role in intracellular communication and regulation of numerous physiological processes in health and disease. Naturally released from virtually all cells, these vesicles contain an array of nucleic acids, lipids and proteins which they transfer to target cells within their local milieu and systemically. They have been proposed as a means of "cell-free, cell therapy" for cancer, immune disorders, and more recently cardiovascular disease. In addition, their unique properties of stability, biocompatibility, and low immunogenicity have prompted research into their potential as therapeutic delivery agents for drugs and small molecules. In this review, we aim to provide a comprehensive overview of the current understanding of extracellular vesicle biology as well as engineering strategies in play to improve their therapeutic potential.