GALDIERO is CO-FIRST AUTHOR. Phagocytes as Corrupted Policemen in Cancer-Related Inflammation

Inflammation is a key component of the tumor microenvironment. Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) are prototypic inflammatory cells in cancer-related inflammation. Macrophages provide a first line of resistance against infectious agents but in the ecological niche of cancer behave as corrupted policemen. TAMs promote tumor growth and metastasis by direct interactions with cancer cells, including cancer stem cells, as well as by promoting angiogenesis and tissue remodeling and suppressing effective adaptive immunity. In addition, the efficacy of chemotherapy, radiotherapy, and checkpoint blockade inhibitors is profoundly affected by regulation of TAMs. In particular, TAMs can protect and rescue tumor cells from cytotoxic therapy by orchestrating a misguided tissue repair response. Following extensive preclinical studies, there is now proof of concept that targeting tumor-promoting macrophages by diverse strategies (e.g., Trabectedin, anti-colony-stimulating factor-1 receptor antibodies) can result in antitumor activity in human cancer and further studies are ongoing. Neutrophils have long been overlooked as a minor component of the tumor microenvironment, but there is evidence for an important role of TANs in tumor progression. Targeting phagocytes (TAMs and TANs) as corrupted policemen in cancer may pave the way to innovative therapeutic strategies complementing cytoreductive therapies and immunotherapy

The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity

Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers

hereditary angioedema attack what happens to vasoactive mediators

Abstract Hereditary angioedema is a disabling, life-threatening condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) leading to bradykinin accumulation and recurrent episodes of edema attack. Vascular leakage is a complex process sustained by the coordinated production of several permeabilizing factors including vascular endothelial growth factors (VEGFs), angiopoietins (ANGPTs) and phospholipase A2 enzymes (PLA2). We previously reported that patients with C1-INH-HAE in remission have increased plasma levels of VEGFs, ANGPTs and secreted PLA2. In this study, we sought to analyze plasma levels of these mediators in 15 patients with C1-INH-HAE during the acute attack compared to remission. Plasma concentrations of VEGF-A, VEGF-C and VEGF-D were not altered during attack compared to remission. Moreover, VEGF-D concentrations were not altered also in remission phase compared to controls. Concentrations of ANGPT1, a vascular stabilizer, were increased during attacks compared to symptoms-free periods, whereas ANGPT2 levels were not altered. The ANGPT2/ANGPT1 ratio was decreased during angioedema attacks. Platelet activating factor acetylhydrolase activity was increased in patients with C1-INH-HAE in remission compared to controls and was decreased during angioedema attacks. Our results emphasize the complexity by which several vasoactive mediators are involved not only in the pathophysiology of C1-INH-HAE, but also during angioedema attacks and its resolution

Mast Cells in Early Rheumatoid Arthritis

NIHR Transitional Research Fellowshi

Epigenetics: an Opportunity to Shape Innate and Adaptive Immune Responses

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 decision 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. This article is protected by copyright. All rights reserved

Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency

BackgroundHereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s).ObjectiveWe sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE.MethodssPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay.ResultsPlasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro.ConclusionsPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets

Size-based effects of anthropogenic ultrafine particles on activation of human lung macrophages

The anthropogenic particulate matter (PM), suspended air dust that can be inhaled by humans and deposited in the lungs, is one of the main pollutants in the industrialized cities atmosphere. Recent studies have shown that PM has adverse effects on respiratory diseases. These effects are mainly due to the ultrafine particles (PM0.1, PM < 100 nm), which, thanks to their PM size, are efficiently deposited in nasal, tracheobronchial, and alveolar regions. Pulmonary macrophages are a heterogeneous cell population distributed in different lung compartments, whose role in inflammatory response to injury is of particular relevance. In this study, we investigated the effect of PM0.1 on Human Lung Macrophages (HLMs) activation evaluated as proinflammatory cytokines and chemokine release, Reactive Oxygen Species (ROS) production and intracellular Ca2+concentration ([Ca2+]i). Furthermore, PM0.1, after removal of organic fraction, was fractionated in nanoparticles both smaller (NP20) and bigger (NP100) than 20 nm by a properlydeveloped analytical protocol, allowed isolating their individual contribution. Interestingly, while PM0.1 and NP20 induced stimulatory effects on HLM cytokines release, NP100 had not effect. In particular, PM0.1 induced IL-6, IL-1β, TNF-α, but not CXCL8, release from HLMs. Moreover, PM0.1, NP20 and NP100 did not induce β-glucuronidase release, a preformed mediator contained in HLMs. The long time necessary for cytokines release (18 h) suggested that PM0.1 and NP20 could induce ex-novo production of the tested mediators. Accordingly, after 6 h of incubation, PM0.1 and NP20 induced mRNA expression of IL-6, TNF-α and IL-1β. Moreover, NP20 induced ROS production and [Ca2+]i increase in a time-dependent manner, without producing cytotoxicity. Collectively, the present data highlight the main proinflammatory role of NP20 among PM fractions. This is particularly of concern because this fraction is not currently covered by legal limits as it is not easily measured at the exhausts by the available technical methodologies, suggesting that it is mandatory to search for new monitoring techniques and strategies for limiting NP20 formation

Clinical significance and functional roles of tumor-associated neutrophils in colorectal cancer

Immune cells actively take part to the tumor microenvironment, where they play several roles in the multistep process of carcinogenesis. Among the tumor-infiltrating immune cells, myeloid cells represent a "double-edged sword" for cancer. Indeed, they can both promote or inhibit cancer initiation and progression. Neutrophils have long been viewed as short-lived cells, pivotal for the elimination of extracellular pathogens, with a limited role in the orchestration of the immune response. However, recent lines of evidence have challenged this limited point of view, revealing a number of unexpected functions for neutrophils in several pathological contexts. Indeed, neutrophils were also found among inflammatory cells infiltrating cancer tissues, such as colorectal cancer (CRC). Today, the functional roles of neutrophils in cancer and the association between neutrophil infiltration, clinicopathological features and outcome of CRC patients remain to be clarified. Here, we found that neutrophils are recruited within CRC tissues through a spatiotemporal dynamism. Infiltration of neutrophils increased from stage I to stage III CRC and decreased at stage IV. In a large cohort of stage III CRC, neutrophil infiltration was preferentially found in the intratumoral compartment compared with the invasive margin. Higher density of neutrophils within the tumor was found to be an independent prognostic factor for better patients' outcome (n=128, Stage I-Stage IV CRC) and a predictive factor for 5-FluoroUracyle chemotherapy response in Stage III CRC patients (n=178). Moreover, CRC cell lines released soluble factors, which promoted neutrophil chemotaxis and survival. In turn, neutrophils displayed a cytostatic activity towards CRC cell lines. Our data suggest that neutrophils are critical components of antitumor immunity and that neutrophil infiltration within tumors could be a useful predictive marker to identify patients with cancer who would likely benefit from chemotherapy. Therefore, neutrophils have to be considered as central participants in the regulation of the innate and adaptive immune responses, with important roles in the resolution or exacerbation of various pathologies, including cancer