Stefania Loffredo

University of Naples Federico II

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Gianni Marone

University of Naples Federico II

Gilda Varricchi

University of Naples Federico II

Maria Rosaria Galdiero

University of Naples Federico II

Angelica Petraroli

University of Naples Federico II

Anne Lise Ferrara

University of Naples Federico II

Francescopaolo Granata

University of Naples Federico II

Massimo Triggiani

University of Salerno

Giuseppe Spadaro

University of Naples Federico II

Maria Bova

University of Naples Federico II

Amato de Paulis

University of Naples Federico II

Cooperative Institutions

University of Naples Federico II

190

Manchester Metropolitan University

134

Federico II University Hospital

106

Istituti di Ricovero e Cura a Carattere Scientifico

National Research Council

University of Salford

University of Milan

Inserm

Universidad de Granada

Semmelweis University

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Secreted Phospholipases A2 in Hereditary Angioedema With C1-Inhibitor Deficiency

Frontiers in Immunology (2018)

Stefania Loffredo Anne Lise Ferrara Maria Bova Francesco Borriello Chiara Suffritti

Background: Hereditary 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 (VEGFs) 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). Objective: We sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE. Methods: sPLA2 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. Results: Plasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared to 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. Conclusions: sPLA2 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.

Hereditary Angioedema

Vascular permeability

C1-inhibitor

10.3389/fimmu.2018.01721

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Citations (26)

IL-33 and Superantigenic Activation of Human Lung Mast Cells Induce the Release of Angiogenic and Lymphangiogenic Factors

Cells (2021)

Leonardo Cristinziano Remo Poto Gjada Criscuolo Anne Lise Ferrara Maria Rosaria Galdiero

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 (VH3) 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.

Superantigen

Interleukin 33

10.3390/cells10010145

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Citations (43)

Secreted phospholipases A2: A proinflammatory connection between macrophages and mast cells in the human lung

Immunobiology (2009)

Francescopaolo Granata Vincenza Nardicchi Stefania Loffredo Annunziata Frattini Rosaria Ilaria Staiano

Proinflammatory cytokine

Mast (botany)

10.1016/j.imbio.2009.06.006

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Citations (40)

Size-Based Effects of Anthropogenic Ultrafine Particles on Lysosomal TRPML1 Channel and Autophagy in Motoneuron-like Cells

International Journal of Molecular Sciences (2022)

Silvia Sapienza Valentina Tedeschi B. Apicella Francesco Palestra Carmela Russo

Background: An emerging body of evidence indicates an association between anthropogenic particulate matter (PM) and neurodegeneration. Although the historical focus of PM toxicity has been on the cardiopulmonary system, ultrafine PM particles can also exert detrimental effects in the brain. However, only a few studies are available on the harmful interaction between PM and CNS and on the putative pathomechanisms. Methods: Ultrafine PM particles with a diameter < 0.1 μm (PM0.1) and nanoparticles < 20 nm (NP20) were sampled in a lab-scale combustion system. Their effect on cell tracking in the space was studied by time-lapse and high-content microscopy in NSC-34 motor neurons while pHrodo™ Green conjugates were used to detect PM endocytosis. Western blotting analysis was used to quantify protein expression of lysosomal channels (i.e., TRPML1 and TPC2) and autophagy markers. Current-clamp electrophysiology and Fura2-video imaging techniques were used to measure membrane potential, intracellular Ca2+ homeostasis and TRPML1 activity in NSC-34 cells exposed to PM0.1 and NP20. Results: NP20, but not PM0.1, reduced NSC-34 motor neuron movement in the space. Furthermore, NP20 was able to shift membrane potential of motor neurons toward more depolarizing values. PM0.1 and NP20 were able to enter into the cells by endocytosis and exerted mitochondrial toxicity with the consequent stimulation of ROS production. This latter event was sufficient to determine the hyperactivation of the lysosomal channel TRPML1. Consequently, both LC3-II and p62 protein expression increased after 48 h of exposure together with AMPK activation, suggesting an engulfment of autophagy. The antioxidant molecule Trolox restored TRPML1 function and autophagy. Conclusions: Restoring TRPML1 function by an antioxidant agent may be considered a protective mechanism able to reestablish autophagy flux in motor neurons exposed to nanoparticles.

10.3390/ijms232113041

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Citations (4)

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

Environment International (2022)

Simone Marcella B. Apicella Agnese Secondo Francesco Palestra Giorgia Opromolla

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.

Proinflammatory cytokine

Interleukin 8

Mediator

Human lung

Alveolar macrophage

10.1016/j.envint.2022.107395

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Citations (15)

Simplexide Induces CD1d-Dependent Cytokine and Chemokine Production from Human Monocytes

PLoS ONE (2014)

Stefania Loffredo Rosaria Ilaria Staiano Francescopaolo Granata Valeria Costantino Francesco Borriello

Monocytes are major effector cells of innate immunity and recognize several endogenous and exogenous molecules due to the expression of wide spectrum of receptors. Among them, the MHC class I-like molecule CD1d interacts with glycolipids and presents them to iNKT cells, mediating their activation. Simplexide belongs to a novel class of glycolipids isolated from marine sponges and is structurally distinct from other immunologically active glycolipids. In this study we have examined the effects of simplexide on cytokine and chemokine release from human monocytes. Simplexide induces a concentration- and time-dependent release of IL-6, CXCL8, TNF-α and IL-10 and increases the expression of IL6, CXCL8 and IL10 mRNA. Cytokine and chemokine release induced by simplexide from monocytes is dependent on CD1d since: i) a CD1d antagonist, 1,2-bis (diphenylphosphino) ethane [DPPE]- polyethylene glycolmonomethylether [PEG], specifically blocks simplexide-induced activation of monocytes; ii) CD1d knockdown inhibits monocyte activation by simplexide and iii) simplexide induces cytokine production from CD1d-transfected but not parental C1R cell line Finally, we have shown that simplexide also induces iNKT cell expansion in vitro. Our results demonstrate that simplexide, apart from activating iNKT cells, induces the production of cytokines and chemokines from human monocytes by direct interaction with CD1d.

CD1D

10.1371/journal.pone.0111326

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Citations (10)

Melanoma-derived soluble mediators modulate neutrophil plasticity and the release of Neutrophil Extracellular Traps

Zenodo (CERN European Organization for Nuclear Research) (2023)

Luca Modestino Leonardo Cristinziano Marialuisa Trocchia Annagioia Ventrici Mariaelena Capone

Background: polymorphonuclear neutrophils (PMNs) are main effector cells in the inflammatory responses. The significance of PMN infiltration in tumor microenvironment remains to be clarified. Metastatic melanoma is the most lethal type of skin cancer with an increasing incidence over the last decades. Few studies investigated the role of PMNs in human melanoma. The aim of this study was to investigate the role of PMNs and their mediators in human melanoma; (2) Methods: highly purified human PMNs from healthy donors were stimulated, in vitro, with conditioned media derived from the melanoma cell lines SKMEL28 and A375 (melanoma-CM) as well as from primary melanocytes as control. PMN functions (chemotaxis, survival, activation, cell tracking, morphology and NETs release) were evaluated; (3) Results: we found that the A375 cell line produced soluble factors able to promote PMN chemotaxis, survival, activation, and to modify PMN morphological changes and kinetic properties. Furthermore, both melanoma cell lines CM induced activation and the release of neutrophil extracellular traps (NETs) from PMNs. By contrast, primary melanocytes CM did not modify any PMN biological behavior. In addition, serum levels of myeloperoxidase (MPO), matrix metalloprotease-9 (MMP-9), CXCL8/IL-8, granulocyte and monocyte colony stimulating factor (GM-CSF) and NETs components were significantly increased in advanced melanoma patients compared to healthy controls; (4) Conclusions: melanoma cell lines produce soluble factors able to ‘educate’ PMNs towards an activated functional state. Metastatic melanoma patients display increased circulating levels of neutrophil-related mediators and NETs, suggesting that a neutrophil-related signature exists in metastatic melanoma patients. Further investigations are needed to better understand the role of these “tumor-educated neutrophils” in modifying melanoma cell behavior.

Neutrophil Extracellular Traps

10.5281/zenodo.7794048

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Citations (0)

164 Treatment of Acquired Angioedema with the Bradykinin Receptor Antagonist Icatibant

World Allergy Organization Journal (2012)

M.C. Siani Angelica Petraroli Maria Bova Stefania Loffredo Massimo Triggiani

Background Complement-mediated acquired angioedema (AAE) is a rare condition characterized by an increased degradation of C1-esterase inhibitor (C1-INH) associated with lymphoproliferative disorders (AAE type I) or caused by autoantibodies against C1-INH (AAE type II). Reduced C1-INH activity leads to uncontrolled bradykinin formation and to angioedema symptoms. There is no established treatment for AAE. Replacement with plasma-derived C1-INH is effective in most patients with life-threatening attack; however, icatibant, a bradykinin B2 receptor antagonist, may represent an alternative treatment.

Icatibant

Hereditary Angioedema

B2 receptor

Bradykinin receptor

10.1097/01.wox.0000411921.50578.c8

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Citations (1)

The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition

International Journal of Molecular Sciences (2019)

Gilda Varricchi Stefania Loffredo Giancarlo Marone Luca Modestino Poupak Fallahi

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.

Immune checkpoint

10.3390/ijms20163934

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Citations (89)

Signaling events involved in cytokine and chemokine production induced by secretory phospholipase A₂ in human lung macrophages

European Journal of Immunology (2006)

Francescopaolo Granata Annunziata Frattini Stefania Loffredo Annalisa Del Prete Silvano Sozzani

Abstract Secretory phospholipases A 2 (sPLA 2 ) are enzymes released during inflammatory reactions. These molecules activate immune cells by mechanisms either related or unrelated to their enzymatic activity. We examined the signaling events activated by group IA (GIA) and group IB (GIB) sPLA 2 in human lung macrophages leading to cytokine/chemokine production. sPLA 2 induced the production of cytokines (TNF‐α, IL‐6 and IL‐10) and chemokines (CCL2, CCL3, CCL4 and CXCL8), whereas no effect was observed on IL‐12, CCL1, CCL5 and CCL22. sPLA 2 induced the phosphorylation of the MAPK p38 and ERK1/2, and inhibition of these kinases by SB203580 and PD98059, respectively, reduced TNF‐α and CXCL8 release. Suppression of sPLA 2 enzymatic activity by a site‐directed inhibitor influenced neither cytokine/chemokine production nor activation of MAPK, whereas alteration of sPLA 2 secondary structure suppressed both responses. GIA activated the phosphatidylinositol 3‐kinase (PI3 K)/Akt system and a specific inhibitor of PI3 K (LY294002) reduced sPLA 2 ‐induced release of TNF‐α and CXCL8. GIA promoted phosphorylation and degradation of IκB and inhibition of NF‐κB by MG‐132 and 6‐amino‐4‐phenoxyphenylethylamino‐quinazoline suppressed the production of TNF‐α and CXCL8. These results indicate that sPLA 2 induce the production of cytokines and chemokines in human macrophages by a non‐enzymatic mechanism involving the PI3 K/Akt system, the MAPK p38 and ERK1/2 and NF‐κB.

Interleukin 8

CCL5

LY294002

10.1002/eji.200535567

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Citations (67)