The vascular endothelial growth factor (VEGF), a homodimeric vasoactive glycoprotein, is the key mediator of angiogenesis. Angiogenesis, the formation of new blood vessels, is responsible for a wide variety of physio/pathological processes, including cardiovascular diseases (CVD). Cardiomyocytes (CM), the main cell type present in the heart, are the source and target of VEGF-A and express its receptors, VEGFR1 and VEGFR2, on their cell surface. The relationship between VEGF-A and the heart is double-sided. On the one hand, VEGF-A activates CM, inducing morphogenesis, contractility and wound healing. On the other hand, VEGF-A is produced by CM during inflammation, mechanical stress and cytokine stimulation. Moreover, high concentrations of VEGF-A have been found in patients affected by different CVD, and are often correlated with an unfavorable prognosis and disease severity. In this review, we summarized the current knowledge about the expression and effects of VEGF-A on CM and the role of VEGF-A in CVD, which are the most important cause of disability and premature death worldwide. Based on clinical studies on angiogenesis therapy conducted to date, it is possible to think that the control of angiogenesis and VEGF-A can lead to better quality and span of life of patients with heart disease.

Neutrophil functions have long been regarded as limited to acute inflammation and the defense against microbes. The role(s) of neutrophils in cancer remain poorly understood. Neutrophils infiltrate tumors and are key effector cells in the orchestration of inflammatory responses. Thyroid cancer (TC) is the most recurrent endocrine malignant tumor and is responsible for 70% of deaths due to endocrine cancers. No studies are so far available on the role of neutrophils in TC. Our purpose was to study the involvement of tumor-associated neutrophils in TC. Highly purified human neutrophils (>99%) from healthy donors were stimulated in vitro with conditioned media derived from TC cell lines TPC1 and 8505c (TC-CMs). Neutrophil functions (e.g., chemotaxis, activation, plasticity, survival, gene expression, and protein release) were evaluated. TC-derived soluble factors promoted neutrophil chemotaxis and survival. Neutrophil chemotaxis toward a TC-CM was mediated, at least in part, by CXCL8/IL-8, and survival was mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, each TC-CM induced morphological changes and activation of neutrophils (e.g., CD11b and CD66b upregulation and CD62L shedding) and modified neutrophils’ kinetic properties. Furthermore, each TC-CM induced production of reactive oxygen species, expression of proinflammatory and angiogenic mediators (CXCL8/IL-8, VEGF-A, and TNF-α), and a release of matrix metalloproteinase 9 (MMP-9). Moreover, in TC patients, tumor-associated neutrophils correlated with larger tumor size. TC cell lines produce soluble factors able to “educate” neutrophils toward an activated functional state. These data will advance the understanding of the molecular and cellular mechanisms of innate immunity in TC.

Neutrophils are key effector cells that orchestrate inflammatory responses in the tumor microenvironment. Although neutrophil extracellular DNA traps (NETs) entrap and kill pathogens, they also contribute to chronic inflammation and cancer progression. Thyroid cancer (TC) is the most frequently occurring cancer of the endocrine system, accounting for 70% of deaths due to endocrine tumors. Although anaplastic TC (ATC) is rare among TCs, it is highly lethal. We demonstrated in a recent study that tumor-infiltrating neutrophil density correlated with TC size. Moreover, TC-derived soluble mediators modulate the human neutrophil phenotype. Our study aimed to investigate the involvement of NETs in human TC. Highly purified neutrophils from healthy donors were primed in vitro with a papillary TC or ATC cell line conditioned medium (CM) or with a normal thyroid CM as control. NET release was quantified using a High-Content Imaging System. Neutrophil viability was assessed by flow cytometry. Fluorescence microscopy, flow cytometry, and PCR were performed to determine the mitochondrial origin of ATC-induced NETs. ATC CM–primed neutrophils were cocultured with ATC cells to determine the effects exerted by NETs on cell proliferation. ATC CM induce NET release, whereas papillary TC or normal thyroid CM did not. ATC CM–induced NET production occurred in a reactive oxygen species–dependent and cell death–independent manner and was associated with mitochondrial reactive oxygen species production; the NETs contained mitochondrial DNA. ATC CM–primed neutrophils promoted ATC cell proliferation in a NET-dependent manner.

Secreted phospholipases A2 (sPLA2s) are extracellular enzymes that catalyze the release of free fatty acids and lysophospholipids from membrane phospholipids and also bind to different receptors (e.g. PLA2R1 or integrins). To date, 12 mammalian sPLA2s have been identified, which play a critical role in pathophysiological processes including inflammation and cancer. sPLA2sactivate immune cells such as human neutrophils (PMNs) by enzymatic activity or receptor-mediated mechanisms. In addition, human PMNs synthesize and store human group V (hGV) and X (hGX) sPLA2s in their granules, but only the former is released upon cellular activation. We investigated the effects of sPLA2son the release of pro-angiogenic and anti-angiogenic factors by PMNs. We found that exogenous hGV and hGX sPLA2s induce the release of vascular endothelial growth factor (VEGF-A), Angiopoietin 1 (Ang1) and CXCL8/IL-8. Only hGV induces the secretion of the anti-angiogenic isoform of VEGF-A, namely VEGF-A165b. While the release of VEGF-A, Ang1 and CXCL8/IL-8 was likely mediated by hGV enzymatic activity and/or binding to PLA2R1 and heparan sulfate proteoglycans, the release of VEGF-A165b requires the interaction with αVβ3 and α4β1 integrins. We also provide evidence that endogenous hGV released by N-Formyl-Met-Leu-Phe (fMLF)-activated PMNs is involved in the release of angiogenic factors. The translational relevance of these data is supported by our findings that hGV expression is increased in human samples of lung cancer which are infiltrated by PMNs. Overall, our results suggest that the hGV-neutrophil axis may play a relevant role in the modulation of cancer-related inflammation and angiogenesis.

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post‐translational modifications and the regulation of chromatin accessibility by non‐coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental‐driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage‐specific transcription factors and maintenance of cell type‐specific epigenetic modifications, referred to as ‘epigenetic memory’, dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as ‘trained immunity’. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are strategically located in different compartments of human lung, where they play a role in several inflammatory disorders and cancer. Immunoglobulin superantigens (e.g., protein A of Staphylococcus aureus and protein L of Peptostreptococcus magnus) bind to the variable regions of either the heavy (V_H3) or light chain (κ) of IgE. IL-33 is a cytokine expressed by epithelial cells that exerts pleiotropic functions in the lung. The present study investigated whether immunoglobulin superantigens protein A and protein L and IL-33 caused the release of inflammatory (histamine), angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The results show that protein A and protein L induced the rapid (30 min) release of preformed histamine from HLMCs. By contrast, IL-33 did not induce the release of histamine from lung mast cells. Prolonged incubation (12 h) of HLMCs with superantigens and IL-33 induced the release of VEGF-A and VEGF-C. Preincubation with IL-33 potentiated the superantigenic release of histamine, angiogenic and lymphangiogenic factors from HLMCs. Our results suggest that IL-33 might enhance the inflammatory, angiogenic and lymphangiogenic activities of lung mast cells in pulmonary disorders.