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Article ; Online: Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis.

Ferrara, Anne Lise / Liotti, Antonietta / Pezone, Antonio / De Rosa, Veronica

Trends in endocrinology and metabolism: TEM

2022 Volume 33, Issue 7, Page(s) 507–521

Abstract: The ability of the immune system to discriminate external stimuli from self-components - namely immune tolerance - occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, ... ...

Abstract	The ability of the immune system to discriminate external stimuli from self-components - namely immune tolerance - occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4
MeSH term(s)	Chromatin/metabolism ; Epigenesis, Genetic ; Forkhead Transcription Factors/genetics ; Humans ; Immune Tolerance ; T-Lymphocytes, Regulatory/metabolism
Chemical Substances	Chromatin ; Forkhead Transcription Factors
Language	English
Publishing date	2022-05-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2022.04.002
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Article ; Online: Cytokine dysregulation despite immunoglobulin replacement therapy in common variable immunodeficiency (CVID).

Poto, Remo / Pecoraro, Antonio / Ferrara, Anne Lise / Punziano, Alessandra / Lagnese, Gianluca / Messuri, Carla / Loffredo, Stefania / Spadaro, Giuseppe / Varricchi, Gilda

Frontiers in immunology

2023 Volume 14, Page(s) 1257398

Abstract: Introduction: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy ( ... ...

Abstract	Introduction: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) can prevent severe infections but not underlying immune dysregulation. Methods: In this study, we evaluated the serum concentrations of proinflammatory (TNF-α, IL-1β, IL-6) and immunoregulatory cytokines (IL-10), as well as lipopolysaccharide (LPS) and soluble CD14 (sCD14) in CVID individuals with infectious only (INF-CVID), and those with additional systemic autoimmune and inflammatory disorders (NIC-CVID), and healthy donors (HD). Results: Our results showed increased serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 in both INF-CVID and NIC-CVID subjects compared to HD. However, elevations of TNF-α, IL-1β, IL-6, and IL-10 were significantly more marked in NIC-CVID than INF-CVID. Additionally, LPS concentrations were increased only in NIC-CVID but not in INF-CVID compared to HD. Circulating levels of sCD14 were significantly increased in NIC-CVID compared to both INF-CVID and HD. Discussion: These findings indicate persistent cytokine dysregulation despite IgRT in individuals with CVID. Moreover, the circulating cytokine profile reveals the heterogeneity of immune dysregulation in different subgroups of CVID subjects.
MeSH term(s)	Humans ; Cytokines ; Interleukin-10 ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Lipopolysaccharides ; Lipopolysaccharide Receptors ; Common Variable Immunodeficiency ; Immunoglobulins
Chemical Substances	Cytokines ; Interleukin-10 (130068-27-8) ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Lipopolysaccharides ; Lipopolysaccharide Receptors ; Immunoglobulins
Language	English
Publishing date	2023-09-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1257398
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Article ; Online: TSLP is localized in and released from human lung macrophages activated by T2-high and T2-low stimuli: relevance in asthma and COPD.

Canè, Luisa / Poto, Remo / Palestra, Francesco / Pirozzi, Marinella / Parashuraman, Seetharaman / Iacobucci, Ilaria / Ferrara, Anne Lise / La Rocca, Antonello / Mercadante, Edoardo / Pucci, Piero / Marone, Gianni / Monti, Maria / Loffredo, Stefania / Varricchi, Gilda

European journal of internal medicine

2024

Abstract: Background: Macrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine ... ...

Abstract	Background: Macrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by bronchial epithelial cells, plays a key role in asthma and COPD pathobiology. TSLP exists in two variants: the long form (lfTSLP) and a shorter TSLP isoform (sfTSLP). We aimed to localize TSLP in human lung macrophages (HLMs) and investigate the mechanisms of its release from these cells. We also evaluated the effects of the two variants of TSLP on the release of angiogenic factor from HLMs. Methods: We employed immunofluorescence and Western blot to localize intracellular TSLP in HLMs purified from human lung parenchyma. HLMs were activated by T2-high (IL-4, IL-13) and T2-low (lipopolysaccharide: LPS) immunological stimuli. Results: TSLP was detected in HLMs and subcellularly localized in the cytoplasm. IL-4 and LPS induced TSLP release from HLMs. Preincubation of macrophages with brefeldin A, known to disrupt the Golgi apparatus, inhibited TSLP release induced by LPS and IL-4. lfTSLP concentration-dependently induced the release of vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor, from HLMs. sfTSLP neither activated nor interfered with the activating property of lfTSLP on macrophages. Conclusions: Our results highlight a novel immunologic circuit between HLMs and TSLP. Given the central role of macrophages in airway inflammation, this autocrine loop holds potential translational relevance in understanding innovative aspects of the pathobiology of asthma and chronic inflammatory lung disorders.
Language	English
Publishing date	2024-02-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1038679-8
ISSN	1879-0828 ; 0953-6205
ISSN (online)	1879-0828
ISSN	0953-6205
DOI	10.1016/j.ejim.2024.02.020
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Article ; Online: Angiopoietins, vascular endothelial growth factors and secretory phospholipase A

Varricchi, Gilda / Poto, Remo / Ferrara, Anne Lise / Gambino, Giuseppina / Marone, Gianni / Rengo, Giuseppe / Loffredo, Stefania / Bencivenga, Leonardo

European journal of internal medicine

2022 Volume 106, Page(s) 111–119

Abstract: Background: Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. A proportion of patients with HF have a normal ventricular ejection fraction (EF), referred to as HF with preserved EF (HFpEF), as opposed to ... ...

Abstract	Background: Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. A proportion of patients with HF have a normal ventricular ejection fraction (EF), referred to as HF with preserved EF (HFpEF), as opposed to patients with HF with reduced ejection fraction (HFrEF). HFpEF currently accounts for about 50% of all HF patients, and its prevalence is rising. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A Methods: The aim of this study was to analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA Results: The concentration of ANGPT1 was reduced in HFrEF compared to HFpEF patients and healthy controls. ANGPT2 levels were increased in both HFrEF and HFpEF subjects compared to controls. The ANGPT2/ANGPT1 ratio was increased in HFrEF patients compared to controls. The concentrations of both VEGF-A and VEGF-C did not differ among the three groups examined. VEGF-D was increased in both HFrEF and HFpEF patients compared to controls. Plasma activity of sPLA Conclusions: Our results indicate that three different classes of proinflammatory regulators of vascular permeability and smoldering inflammation are selectively altered in HFrEF or HFpEF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings.
MeSH term(s)	Humans ; Stroke Volume ; Heart Failure ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor D ; Vascular Endothelial Growth Factor C ; Angiopoietins ; Endothelial Cells ; Prognosis ; Phospholipases A2, Secretory ; Phospholipases
Chemical Substances	Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor D ; Vascular Endothelial Growth Factor C ; Angiopoietins ; Phospholipases A2, Secretory (EC 3.1.1.4) ; Phospholipases (EC 3.1.-)
Language	English
Publishing date	2022-10-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1038679-8
ISSN	1879-0828 ; 0953-6205
ISSN (online)	1879-0828
ISSN	0953-6205
DOI	10.1016/j.ejim.2022.10.014
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Article ; Online: Thymic Stromal Lymphopoietin (TSLP) Is Cleaved by Human Mast Cell Tryptase and Chymase.

Canè, Luisa / Poto, Remo / Palestra, Francesco / Iacobucci, Ilaria / Pirozzi, Marinella / Parashuraman, Seetharaman / Ferrara, Anne Lise / Illiano, Amalia / La Rocca, Antonello / Mercadante, Edoardo / Pucci, Piero / Marone, Gianni / Spadaro, Giuseppe / Loffredo, Stefania / Monti, Maria / Varricchi, Gilda

International journal of molecular sciences

2024 Volume 25, Issue 7

Abstract: Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) ... ...

Abstract	Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play key roles in asthma. We evaluated the early proteolytic effects of tryptase and chymase released by HLMCs on TSLP by mass spectrometry. We also investigated whether TSLP and its fragments generated by these enzymes induce angiogenic factor release from HLMs. Mass spectrometry (MS) allowed the identification of TSLP cleavage sites caused by tryptase and chymase. Recombinant human TSLP treated with recombinant tryptase showed the production of 1-97 and 98-132 fragments. Recombinant chymase treatment of TSLP generated two peptides, 1-36 and 37-132. lfTSLP induced the release of VEGF-A, the most potent angiogenic factor, from HLMs. By contrast, the four TSLP fragments generated by tryptase and chymase failed to activate HLMs. Long-term TSLP incubation with furin generated two peptides devoid of activating property on HLMs. These results unveil an intricate interplay between mast cell-derived proteases and TSLP. These findings have potential relevance in understanding novel aspects of asthma pathobiology.
MeSH term(s)	Humans ; Tryptases ; Chymases ; Thymic Stromal Lymphopoietin ; Angiogenesis Inducing Agents ; Serine Proteases ; Cytokines ; Asthma
Chemical Substances	Tryptases (EC 3.4.21.59) ; Chymases (EC 3.4.21.39) ; Thymic Stromal Lymphopoietin (GT0IL38SP4) ; Angiogenesis Inducing Agents ; Serine Proteases (EC 3.4.-) ; Cytokines
Language	English
Publishing date	2024-04-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25074049
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Article: The broad spectrum of cardiotoxicities from immunotherapies.

Iengo, Martina / Topa, Ester / Cuomo, Alessandra / Marone, Giancarlo / Poto, Remo / Varricchi, Gilda / Cristinziano, Leonardo / Galdiero, Maria Rosaria / Ferrara, Anne Lise / Loffredo, Stefania / Formisano, Luigi / Troiani, Teresa / Mercurio, Valentina / Tocchetti, Carlo Gabriele

Frontiers in cardiovascular medicine

2023 Volume 10, Page(s) 1259620

Language	English
Publishing date	2023-09-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2023.1259620
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Article ; Online: Thymic stromal lymphopoietin (TSLP) is a substrate for tryptase in patients with mastocytosis.

Marcella, Simone / Petraroli, Angelica / Canè, Luisa / Ferrara, Anne Lise / Poto, Remo / Parente, Roberta / Palestra, Francesco / Cristinziano, Leonardo / Modestino, Luca / Galdiero, Maria Rosaria / Monti, Maria / Marone, Gianni / Triggiani, Massimo / Varricchi, Gilda / Loffredo, Stefania

European journal of internal medicine

2023 Volume 117, Page(s) 111–118

Abstract: Mastocytosis is a heterogeneous disease associated to uncontrolled proliferation and increased density of mast cells in different organs. This clonal disorder is related to gain-of-function pathogenic variants of the c-kit gene that encodes for KIT ( ... ...

Abstract	Mastocytosis is a heterogeneous disease associated to uncontrolled proliferation and increased density of mast cells in different organs. This clonal disorder is related to gain-of-function pathogenic variants of the c-kit gene that encodes for KIT (CD117) expressed on mast cell membrane. Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, which plays a key role in allergic disorders and several cancers. TSLP is a survival and activating factor for human mast cells through the engagement of the TSLP receptor. Activated human mast cells release several preformed mediators, including tryptase. Increased mast cell-derived tryptase is a diagnostic biomarker of mastocytosis. In this study, we found that in these patients serum concentrations of TSLP were lower than healthy donors. There was an inverse correlation between TSLP and tryptase concentrations in mastocytosis. Incubation of human recombinant TSLP with sera from patients with mastocytosis, containing increasing concentrations of tryptase, concentration-dependently decreased TSLP immunoreactivity. Similarly, recombinant β-tryptase reduced the immunoreactivity of recombinant TSLP, inducing the formation of a cleavage product of approximately 10 kDa. Collectively, these results indicate that TSLP is a substrate for human mast cell tryptase and highlight a novel loop involving these mediators in mastocytosis.
MeSH term(s)	Humans ; Thymic Stromal Lymphopoietin ; Tryptases/metabolism ; Cytokines/metabolism ; Mastocytosis/metabolism ; Mast Cells/metabolism
Chemical Substances	Thymic Stromal Lymphopoietin (GT0IL38SP4) ; Tryptases (EC 3.4.21.59) ; Cytokines
Language	English
Publishing date	2023-07-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1038679-8
ISSN	1879-0828 ; 0953-6205
ISSN (online)	1879-0828
ISSN	0953-6205
DOI	10.1016/j.ejim.2023.07.026
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Article ; Online: Pathways of Neutrophil Granulocyte Activation in Hereditary Angioedema with C1 Inhibitor Deficiency.

Kajdácsi, Erika / Veszeli, Nóra / Mező, Blanka / Jandrasics, Zsófia / Kőhalmi, Kinga Viktória / Ferrara, Anne Lise / Cervenak, László / Varga, Lilian / Farkas, Henriette

Clinical reviews in allergy & immunology

2021 Volume 60, Issue 3, Page(s) 383–395

Abstract: Hereditary angioedema (HAE) with C1-inhibitor deficiency belongs to bradykinin-mediated angioedemas. It is characterized by recurrent subcutaneous and/or submucosal swelling episodes (HAE attacks) and erythema marginatum skin rash as a pre-attack ( ... ...

Abstract	Hereditary angioedema (HAE) with C1-inhibitor deficiency belongs to bradykinin-mediated angioedemas. It is characterized by recurrent subcutaneous and/or submucosal swelling episodes (HAE attacks) and erythema marginatum skin rash as a pre-attack (prodromal) phase. HAE attacks were shown to be accompanied by peripheral blood neutrophilia. We aimed to find molecular mechanisms that may explain the distinct role of neutrophil granulocytes in HAE. Plasma levels of blood cells and factors related to neutrophil activation (cytokines, chemokines, chemotactic factors, enzymes, and neutrophil extracellular trap) were measured in plasma samples obtained from patients during symptom-free periods (n = 77), during prodromal phase (n = 8) and attacks (n = 14), during a spontaneously resolved attack (n = 1), and in healthy controls (n = 79). Higher counts of white blood cells, lymphocytes, and neutrophil granulocytes were found in symptom-free patients compared with controls; these cell counts were elevated further during HAE attacks. The level of chemokine (C-C motif) ligand 5, monocyte chemoattractant protein-1, and myeloperoxidase were also higher in the symptom-free patients than in the controls. Levels of monocyte chemoattractant protein-1, leukotriene B4, neutrophil elastase, and myeloperoxidase were elevated during attacks. During erythema marginatum, white blood cells and monocyte count and levels of interleukin 8 were elevated compared with symptom-free period. Similar changes were detected during the attack follow-up. We conclude that the activation of NGs in symptom-free periods and a further increase observed during attacks suggests that NGs may be involved in the pathomechanism of HAE with C1-INH deficiency.
MeSH term(s)	Angioedemas, Hereditary/diagnosis ; Chemokine CCL2 ; Complement C1 Inhibitor Protein ; Erythema ; Humans ; Neutrophil Activation ; Neutrophils ; Peroxidase ; Skin Diseases, Genetic
Chemical Substances	Chemokine CCL2 ; Complement C1 Inhibitor Protein ; Peroxidase (EC 1.11.1.7)
Language	English
Publishing date	2021-02-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1239045-8
ISSN	1559-0267 ; 1080-0549
ISSN (online)	1559-0267
ISSN	1080-0549
DOI	10.1007/s12016-021-08847-4
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Article ; Online: SARS-CoV-2 Spike Protein Activates Human Lung Macrophages.

Palestra, Francesco / Poto, Remo / Ciardi, Renato / Opromolla, Giorgia / Secondo, Agnese / Tedeschi, Valentina / Ferrara, Anne Lise / Di Crescenzo, Rosa Maria / Galdiero, Maria Rosaria / Cristinziano, Leonardo / Modestino, Luca / Marone, Gianni / Fiorelli, Alfonso / Varricchi, Gilda / Loffredo, Stefania

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: COVID-19 is a viral disease caused by SARS-CoV-2. This disease is characterized primarily, but not exclusively, by respiratory tract inflammation. SARS-CoV-2 infection relies on the binding of spike protein to ACE2 on the host cells. The virus uses the ... ...

Abstract	COVID-19 is a viral disease caused by SARS-CoV-2. This disease is characterized primarily, but not exclusively, by respiratory tract inflammation. SARS-CoV-2 infection relies on the binding of spike protein to ACE2 on the host cells. The virus uses the protease TMPRSS2 as an entry activator. Human lung macrophages (HLMs) are the most abundant immune cells in the lung and fulfill a variety of specialized functions mediated by the production of cytokines and chemokines. The aim of this project was to investigate the effects of spike protein on HLM activation and the expression of ACE2 and TMPRSS2 in HLMs. Spike protein induced CXCL8, IL-6, TNF-α, and IL-1β release from HLMs; promoted efficient phagocytosis; and induced dysfunction of intracellular Ca
MeSH term(s)	Humans ; COVID-19/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2/metabolism ; Lung/metabolism ; Macrophages/metabolism
Chemical Substances	spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2023-02-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24033036
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Article ; Online: Melanoma-derived soluble mediators modulate neutrophil biological properties and the release of neutrophil extracellular traps.

Modestino, Luca / Cristinziano, Leonardo / Trocchia, Marialuisa / Ventrici, Annagioia / Capone, Mariaelena / Madonna, Gabriele / Loffredo, Stefania / Ferrara, Anne Lise / Romanelli, Marilena / Simeone, Ester / Varricchi, Gilda / Rossi, Francesca Wanda / de Paulis, Amato / Marone, Gianni / Ascierto, Paolo Antonio / Galdiero, Maria Rosaria

Cancer immunology, immunotherapy : CII

2023 Volume 72, Issue 10, Page(s) 3363–3376

Abstract: Polymorphonuclear neutrophils (PMNs) are the main effector cells in the inflammatory response. The significance of PMN infiltration in the tumor microenvironment remains unclear. Metastatic melanoma is the most lethal skin cancer with an increasing ... ...

Abstract	Polymorphonuclear neutrophils (PMNs) are the main effector cells in the inflammatory response. The significance of PMN infiltration in the tumor microenvironment remains unclear. Metastatic melanoma is the most lethal skin cancer with an increasing incidence over the last few decades. This study aimed to investigate the role of PMNs and their related mediators in human melanoma. Highly purified human PMNs from healthy donors were stimulated in vitro with conditioned media (CM) derived from the melanoma cell lines SKMEL28 and A375 (melanoma CM), and primary melanocytes as controls. PMN biological properties (chemotaxis, survival, activation, cell tracking, morphology and NET release) were evaluated. We found that the A375 cell line produced soluble factors that promoted PMN chemotaxis, survival, activation and modification of morphological changes and kinetic properties. Furthermore, in both melanoma cell lines CM induced chemotaxis, activation and release of neutrophil extracellular traps (NETs) from PMNs. In contrast, the primary melanocyte CM did not modify the biological behavior of PMNs. In addition, serum levels of myeloperoxidase, matrix metalloprotease-9, CXCL8/IL-8, granulocyte and monocyte colony-stimulating factor and NETs were significantly increased in patients with advanced melanoma compared to healthy controls. Melanoma cell lines produce soluble factors able to "educate" PMNs toward an activated functional state. Patients with metastatic melanoma display increased circulating levels of neutrophil-related mediators and NETs. Further investigations are needed to better understand the role of these "tumor-educated neutrophils" in modifying melanoma cell behavior.
MeSH term(s)	Humans ; Neutrophils/pathology ; Extracellular Traps ; Chemotaxis ; Melanoma/pathology ; Tumor Microenvironment
Language	English
Publishing date	2023-07-31
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-023-03493-5
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