Tiziana SCHIOPPA - Academia.edu (original) (raw)

Papers by Tiziana SCHIOPPA

International Journal of Molecular Sciences

Neutrophils, the most abundant subset of leukocytes in the blood, play a pivotal role in host res... more Neutrophils, the most abundant subset of leukocytes in the blood, play a pivotal role in host response against invading pathogens. However, in respiratory diseases, excessive infiltration and activation of neutrophils can lead to tissue damage. Tanimilast-international non-proprietary name of CHF6001—is a novel inhaled phosphodiesterase 4 (PDE4) inhibitor in advanced clinical development for the treatment of chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease where neutrophilic inflammation plays a key pathological role. Human neutrophils from healthy donors were exposed to pro-inflammatory stimuli in the presence or absence of tanimilast and budesonide—a typical inhaled corticosteroid drug-to investigate the modulation of effector functions including adherence to endothelial cells, granule protein exocytosis, release of extracellular DNA traps, cytokine secretion, and cell survival. Tanimilast significantly decreased neutrophil-endothelium adhesion, de...

Open University, 2006

Cell adaptation to hypoxia requires activation of transcriptional programs that coordinate expres... more Cell adaptation to hypoxia requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (viaangiogenesis) and metabolic adaptation (via glycolisis). During migration and invasion of normal and pathological tissues, cells may encounter different oxygen levels, due to poor or altered vascularization, and recent evidence has suggested that chemotaxis is a cell function which may be affected by oxygen availability. This thesis describes how oxygen avaibility is a determinant parameter in the setting of chemotactic responsiveness to Stromal-Derived Factor 1 (SDF-1, CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor CXCR4, in different cell types (monocytes, monocyte-derived macrophages, tumor associated macrophages, endothelial cells, cancer cells and dendritic cells) as both mRNA and protein expression, which is paralleled by increased chemotactic responsiveness to its specific ligand. Furthermore, preliminary results on dendritic cells (DC) show that hypoxia may affect their maturation (CCR7'°'/CCR5h'gh) and functions. In particular, hypoxia-derived DC do not migrate in response to the CCR7 ligand CCL 19, while they do express higher levels of pro-inflammatory cytokines (IL-12, TNF-a), as compared to normoxia-derived DC. CXCR4 induction by hypoxia is dependent on both activation of hypoxia-inducible factor 1 (HIF-la) and transcript stabilization. Our data identify the hypoxia/HIF-1/CXCR4 pathway as a relevant molecular circuit in the functional tuning of the chemokine system and provide novel insights into the mechanisms controlling cell migration in hypoxic regions, with potential relevance in the pathogenesis of human diseases, including chronic inflammatory diseases and cancer.

Frontiers in Immunology, 2022

Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases assoc... more Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to β-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7...

Methods in Cell Biology, 2021

Chemical induced carcinogenesis together with genetically engineered mouse models represent impor... more Chemical induced carcinogenesis together with genetically engineered mouse models represent important approaches for the study of the complex mechanisms involving genotype and environmental factors in cancer development, including lung cancer. The induction of lung tumor in mice with urethane (ethyl carbamate) is considered a valuable model of Kras-driven lung cancer. However, inbred mouse strains show variable susceptibility to lung tumor formation, with C57BL/6 background, widely used to study many transgenic and null mutations, highly resistant to lung carcinogenesis. Here is described a protocol of urethane-induced lung cancer effective in lung tumor induction in C57BL/6J strain. Multiple urethane injections are needed to overcome genetic resistance and induce in a reproducible manner lung carcinogenesis in C57BL/6J background mice.

An agent that inhibits the expression or activity of CCR4 for use in treating a cancer patient ha... more An agent that inhibits the expression or activity of CCR4 for use in treating a cancer patient having a solid tumor or a non-haematological tumor, comprising the tumor epithelial tumor cells expressing CCR4 on the agent that inhibits expression or CCR4 activity is: (i) an antibody that binds CCR4; (Ii) an antibody which binds to CCR4 ligands CCL17 or CCL22 of; or (iii) a CCR4 antagonist.

Frontiers in Cell and Developmental Biology, 2020

CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At ... more CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At difference from other members of this family, CCRL2 does not promote chemotaxis and shares structural features with atypical chemokine receptors (ACKRs). However, CCRL2 also differs from ACKRs since it does not bind chemokines and is devoid of scavenging functions. The only commonly recognized CCRL2 ligand is chemerin, a non-chemokine chemotactic protein. CCRL2 is expressed both by leukocytes and non-hematopoietic cells. The genetic ablation of CCRL2 has been instrumental to elucidate the role of this receptor as positive or negative regulator of inflammation. CCRL2 modulates leukocyte migration by two main mechanisms. First, when CCRL2 is expressed by barrier cells, such endothelial, and epithelial cells, it acts as a presenting molecule, contributing to the formation of a non-soluble chemotactic gradient for leukocytes expressing CMKLR1, the functional chemerin receptor. This mechanism...

Nature Microbiology, 2020

Sil.G. helped in the execution of the mouse experiments; B.F., M.M. and Gr.P. performed 16s rRNA ... more Sil.G. helped in the execution of the mouse experiments; B.F., M.M. and Gr.P. performed 16s rRNA metagenomic analysis; L.M. and W.V. designed and carried out histological analyses. G.N. performed ex-vivo stimulation of human colonic mucosa experiments; A.B. performed confocal analyses; J.T. executed metabolomic analyses; B.O. helped in the execution of in vitro experiments; K.A. and K.H. isolated F.PB1 and carried out GF experiments; S.A. and S.G. set up F. PB1 growth and supernatant production; S.C. set up H. biformis and L. lactis growth and supernatant production; G.F. performed FACS analyses; F.A. and N.S. performed phylogenetic analysis and human CRC dataset interrogation; G.P. participated with ideas and results interpretation; M.R. ideated the study, coordinated the work, and wrote the manuscript.

Cancer Immunology Research, 2019

CCRL2 is a nonsignaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that... more CCRL2 is a nonsignaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that promotes chemotaxis of leukocytes, including macrophages and natural killer (NK) cells. In addition, CCRL2 controls the inflammatory response in different pathologic settings, such as hypersensitivity, inflammatory arthritis, and experimental autoimmune encephalitis. Here, we investigated the role of CCRL2 in the regulation of lung cancer–related inflammation. The genetic deletion of Ccrl2 promoted tumor progression in urethane-induced and in KrasG12D/+/p53LoxP lung tumor mouse models. Similarly, a Kras-mutant lung tumor displayed enhanced growth in Ccrl2-deficient mice. This phenotype was associated with a reduced inflammatory infiltrate characterized by the impaired recruitment of several leukocyte populations including NK cells. Bone marrow chimeras showed that CCRL2 expression by the nonhematopoietic cell compartment was responsible for the increased tumor formation observed in Kras...

Tumori Journal, 2003

Environmental signals polarize mononuclear phagocytes which can express different functional prog... more Environmental signals polarize mononuclear phagocytes which can express different functional programmes. Fully polarized type I and type II (or alternatively activated) macrophages are the extremes of a continuum of functional states. Tumor-derived and T cell-derived cytokines stimulate tumor associated macrophages (TAM) to acquire a polarized type II phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, play a key role in subversion of adaptive immunity and in inflammatory circuits which promote tumor growth and progression.

Cellular & molecular immunology, 2018

Dendritic cells (DCs) are professional antigen-presenting cells responsible for the activation of... more Dendritic cells (DCs) are professional antigen-presenting cells responsible for the activation of specific T-cell responses and for the development of immune tolerance. Immature DCs reside in peripheral tissues and specialize in antigen capture, whereas mature DCs reside mostly in the secondary lymphoid organs where they act as antigen-presenting cells. The correct localization of DCs is strictly regulated by a large variety of chemotactic and nonchemotactic signals that include bacterial products, DAMPs (danger-associated molecular patterns), complement proteins, lipids, and chemokines. These signals function both individually and in concert, generating a complex regulatory network. This network is regulated at multiple levels through different strategies, such as synergistic interactions, proteolytic processing, and the actions of atypical chemokine receptors. Understanding this complex scenario will help to clarify the role of DCs in different pathological conditions, such as aut...

Current opinion in pharmacology, Aug 31, 2017

The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of s... more The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of soluble mediators. Different types of tumors have specific tumor microenvironments characterized by distinct chemokines and chemotactic factors that influence leukocyte recruitment. The immune cell infiltrate continuously interacts with stroma cells and influence tumor growth. Emerging evidence suggests that the regulation of the composition and the metabolic state of tumor-associated leukocytes may represent a new promising intervention strategy. Here we summarize the current knowledge on the role of tumor-associated immune cells in tumor growth and dissemination, with a specific focus on the nature of the chemotactic factors responsible for their accumulation and activation in tumors.

The Journal of clinical investigation, Jan 30, 2017

Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in... more Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the RENCA mouse model of RCC. CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cell and Th1 cytokine levels, and reduced immature myeloid cell infiltrate and blood chemokine levels. In spite of prominent changes in the myeloid compartment, the anti-CCR4 antibody did not affect RENCA tumors in T cell-deficient mice, and treatment with an anti-class II MHC antibody abrogated its antitumor activity. We concluded that the effects of the anti-CCR4 antibody required the adaptive immune system and CD4+ T cells. Moreover, CCL17-induced IFN-γ p...

Cancer Research, 2014

Tumor microenvironments posses complex chemokine networks that contribute to the extent and pheno... more Tumor microenvironments posses complex chemokine networks that contribute to the extent and phenotype of the host infiltrate. Malignant cells may gain functional chemokine receptors, often as a consequence of oncogenic mutations, allowing them to respond to distant chemokine gradients during metastasis. The chemokine receptor CCR4 was highly expressed in human renal cell carcinoma, RCC, biopsies and RCC patient plasma had abnormal levels of CCR4 ligands. However, during pre-clinical evaluation of CCR4 as a target in RCC, we found that both a small molecule CCR4 inhibitor and an anti-CCR4 antagonistic antibody had unexpected and novel anti-tumor activity in the mouse RCC RENCA model. CCR4 antagonists did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cells and Th1 cytokine levels, as well as reducing splenic MDSC infiltrate, and blood chemokine levels. Although the most prominent changes were...

Macrophages and dendritic cells infiltrate tumours. In the tumour microenvironment, mononuclear p... more Macrophages and dendritic cells infiltrate tumours. In the tumour microenvironment, mononuclear phagocytes acquire properties of polarized M2 (or alternatively activated) macrophages. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumours, play a key role in subversion of adaptive immunity and in inflammatory circuits which promote tumour growth and progression.

Proceedings of the National Academy of Sciences, 2011

The inflammatory cytokine TNF-α has been recognized as a critical tumor promoter, but the effecto... more The inflammatory cytokine TNF-α has been recognized as a critical tumor promoter, but the effector cells that mediate its action have not been fully characterized. Because B cells regulate squamous and prostate carcinogenesis, and Tnf −/− mice harbor B-cell defects, we investigated the hypothesis that B cells are important effector cells for TNF-α–mediated promotion of cancer development. Using an adoptive transfer strategy and the 7,12-dimethylbenz[α]anthracene/terephthalic acid (DMBA/TPA) two-stage model of skin carcinogenesis, we found that both B cells and TNF-α are critical for the development of DMBA/TPA-induced papilloma. Transfer of B cells from DMBA/TPA-treated wild-type mice to Tnf −/− mice rescued papilloma development to a wild-type level, a result not observed when B cells from Tnf −/− mice were transferred to Rag2 −/− mice or when TNF-α was eliminated selectively in B cells. Resistance to papilloma development in Tnf −/− mice was associated with increased IFN-γ and CD8...

The Journal of Immunology, 2010

We recently reported that human T-lymphotropic virus type 1 (HTLV-1) infection is accompanied by ... more We recently reported that human T-lymphotropic virus type 1 (HTLV-1) infection is accompanied by a high frequency of CD4 + FoxP3 + cells in the circulation. In asymptomatic carriers of HTLV-1 and in patients with HTLV-1-associated inflammatory and malignant diseases, a high FoxP3 + cell frequency correlated with inefficient cytotoxic T cell-mediated killing of HTLV-1-infected cells. In adult T cell leukemia/lymphoma (ATLL), the FoxP3 + population was distinct from the leukemic T cell clones. However, the cause of the increase in FoxP3 + cell frequency in HTLV-1 infection was unknown. In this study, we report that the plasma concentration of the chemokine CCL22 is abnormally high in HTLV-1-infected subjects and that the concentration is strongly correlated with the frequency of FoxP3 + cells, which express the CCL22 receptor CCR4. Further, we show that CCL22 is produced by cells that express the HTLV-1 transactivator protein Tax, and that the increased CCL22 enhances the migration and survival of FoxP3 + cells in vitro. Finally, we show that FoxP3 + cells inhibit the proliferation of ex vivo, autologous leukemic clones from patients with ATLL. We conclude that HTLV-1-induced CCL22 causes the high frequency of FoxP3 + cells observed in HTLV-1 infection; these FoxP3 + cells may both retard the progression of ATLL and HTLV-1-associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection, especially in ATLL.

Journal of Experimental Medicine, 2003

Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate ... more Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to stromal-derived factor 1 (CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor, CXC receptor 4 (CXCR4), in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by Hyp is dependent on both activation of the Hyp-inducible factor 1 α and transcript stabilization. In a relay multistep navigation process, the Hyp–Hyp-inducible factor 1 α–CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.