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Among the non-coding RNAs, the aberrant expression of microRNAs (miRNAs) is well described in the oncology field. It is clear that the altered expression of miRNAs is crucial for a variety of processes such as proliferation, apoptosis, motility, angiogenesis and metastasis insurgence. Considering these aspects, RNA-based therapies and the use of miRNAs as non-invasive biomarkers for early diagnosis are underlined as promising opportunities against cancer death. In the era of precision medicine, significant progress in next-generation sequencing (NGS) techniques has broadened knowledge regarding the miRNAs expression profile in cancer tissues and in the blood of cancer patients. In this scenario, pre-clinical and clinical studies suggested that the members of the miR-584 family, i.e., miR-584-5p and -3p, are prominent players in cancer development and progression. Under some conditions, these miRNAs are under-expressed in cancer tissues acting as tumor suppressors, while in other conditions, they are overexpressed, acting as oncogenes increasing the aggressive behavior of cancer cells. The aim of this review is to provide a comprehensive and up-to-date overview on the expression, upstream genes, molecular targets and signaling pathways influenced by the miR-584 family (i.e., miR-584-3p and -5p) in various human solid and hematological cancers. To achieve this goal, 64 articles on this topic are discussed. Among these articles, 55 are focused on miR-584-5p, and it is outlined how this miRNA could be used in future applications as a potential new therapeutic strategy and diagnostic tool.
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Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Biomarcadores Tumorais/genética , Transdução de Sinais/genética , AnimaisRESUMO
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.
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Proliferação de Células , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Carcinoma Anaplásico da Tireoide/imunologia , Neoplasias da Glândula Tireoide/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Neutrófilos/patologia , Espécies Reativas de Oxigênio/imunologia , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
In this study we investigated the effects of snake venom Group IA secreted phospholipase A2 (svGIA) on the release of inflammatory and angiogenic mediators from human lung macrophages (HLMs). HLMs were incubated with lipopolysaccharide (LPS) or svGIA with or without macrophage-polarizing stimuli (IL-4, IL-10, IFN-γ or the adenosine analogue NECA). M2-polarizing cytokines (IL-4 and IL-10) inhibited TNF-α, IL-6, IL-12, IL-1ß, CXCL8 and CCL1 release induced by both LPS and svGIA. IL-4 inhibited also the release of IL-10. IFN-γ reduced IL-10 and IL-12 and increased CCL1 release by both the LPS and svGIA-stimulated HLMs, conversely IFN-γ reduced IL-1ß only by svGIA-stimulated HLMs. In addition, IFNγ promoted TNF-α and IL-6 release from svGIA-stimulated HLMs to a greater extent than LPS. NECA inhibited TNF-α and IL-12 but promoted IL-10 release from LPS-stimulated HLMs according to the well-known effect of adenosine in down-regulating M1 activation. By contrast NECA reduced TNF-α, IL-10, CCL1 and IL-1ß release from svGIA-activated HLM. IL-10 and NECA increased both LPS- and svGIA-induced vascular endothelial growth factor A (VEGF-A) release. By contrast, IL-10 reduced angiopoietin-1 (ANGPT1) production from activated HLMs. IFN-γ and IL-4 reduced VEGF-A and ANGPT1 release from both LPS- and svGIA-activated HLMs. Moreover, IL-10 inhibited LPS-induced ANGPT2 production. In conclusion, we demonstrated a fine-tuning modulation of svGIA-activated HLMs differentially exerted by the classical macrophage-polarizing cytokines.
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Fosfolipases A2 do Grupo IB/metabolismo , Pulmão/metabolismo , Macrófagos/metabolismo , Angiopoietina-1/metabolismo , Animais , Diferenciação Celular , Quimiocina CCL1/metabolismo , Citocinas/metabolismo , Humanos , Inflamação , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Monócitos/citologia , Neovascularização Patológica , Serpentes , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
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Regulação da Expressão Gênica , Cardiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Cardiopatias/patologia , Humanos , Miócitos Cardíacos/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossínteseRESUMO
During tumorigenesis, miRNAs with unbalanced expression profiles can increase the threat of disease progression. Here, we focus on the role of miR-331-5p in the pathogenesis of thyroid cancer (TC). In vitro studies were conducted using TC cell lines after the forced expression and silencing of miR-331-5p. Cell proliferation and viability were analyzed via cell counts and colorimetric assays. Cell motility was analyzed via wound healing assays, Transwell migration and invasion assays, and Matrigel Matrix assays. The putative targets of miR-331-5p were unveiled via label-free proteomic screening and then verified using Western blot and luciferase assays. Expression studies were conducted by interrogating The Cancer Genome Atlas (TCGA). We found that ectopic miR-331-5p expression reduces TC cell motility, while miR-331-5p silencing induces the opposite phenotype. Proteomic screening revealed eight putative downregulated targets of miR-331-5p, among which BID was confirmed as a direct target. TCGA data showed the downregulation of miR-331-5p and the upregulation of BID in TC tissues. In summary, deregulation of the miR-331-5p/BID axis could enhance the aggressiveness of TC cell lines, providing new insights into the mechanisms of the progression of this disease and suggesting a potential role of the component factors as possible biomarkers in TC tissues.
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PURPOSE: Since cancer-related miRNAs expression are affected by physical activity/exercise, they represent an attractive tool to monitor this response in healthy and in cancer subjects. Here, we aim to update the literature regarding the benefit of this axis in oncology field. METHOD: We systematically questioned the literature according to PRISMA guidelines defining our questions by PICO tool and carrying out the risk of bias and quality assessment by NOS. RESULTS: Among 751 records risen from the initial search, 28 studies resulted eligible. The majority of studies regarded breast cancer, while others were initially conducted in healthy subjects and afterwards authors speculated on the relationship between exercise-modulated miRNAs and cancer. CONCLUSION: Physical activity/exercise induces beneficial effects in the cancer prevention, prognosis and treatments. Among the miRNAs modulated by physical activity/exercise, miR-21, let-7 and miR-133 families resulted the most promising in this field.
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Neoplasias da Mama , MicroRNAs , Humanos , Feminino , MicroRNAs/genética , Exercício Físico/fisiologia , Neoplasias da Mama/terapia , PrognósticoRESUMO
The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, migration, epithelial-to-mesenchymal transition and stemness. Moreover, agonists of CB1 and CB2 receptors inhibit angiogenesis and lymphangiogenesis in vitro and in vivo. Low-grade inflammation is a hallmark of cancer in the tumor microenvironment (TME), which contains a plethora of innate and adaptive immune cells. These cells play a central role in tumor initiation and growth and the formation of metastasis. CB2 and, to a lesser extent, CB1 receptors are expressed on a variety of immune cells present in TME (e.g., T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, eosinophils). The activation of CB receptors modulates a variety of biological effects on cells of the adaptive and innate immune system. The expression of CB2 and CB1 on different subsets of immune cells in TME and hence in tumor development is incompletely characterized. The recent characterization of the human cannabinoid receptor CB2-Gi signaling complex will likely aid to design potent and specific CB2/CB1 ligands with therapeutic potential in cancer.
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Endocanabinoides/imunologia , Neoplasias , Receptor CB1 de Canabinoide/imunologia , Receptor CB2 de Canabinoide/imunologia , Microambiente Tumoral/imunologia , Autofagia , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine highly expressed by epithelial cells and several innate and adaptive immune cells. TSLP exerts its biological effects by binding to a heterodimeric complex composed of TSLP receptor (TSLPR) and IL-7Rα. In humans, there are two TSLP isoforms: the short form (sfTSLP), constitutively expressed, and the long form (lfTSLP), which is upregulated in inflammation. TSLP has been implicated in the induction and progression of several experimental and human cancers. Primary human lung macrophages (HLMs), monocyte-derived macrophages (MDMs), and peripheral blood monocytes consitutively expressed sfTSLP mRNA. Incubation of HLMs, MDMs, and monocytes with lipopolysaccharide (LPS) or IL-4, but not with IL-13, induced TSLP release from HLMs. LPS, but not IL-4 or IL-13, induced CXCL8 release from HLMs. LPS, IL-4 alone or in combination with IL-13, induced the expression of lfTSLP, but not of sfTSLP from HLMs. Preincubation of HLMs with IL-4, alone or in combination with IL-13, but not IL-13 alone, synergistically enhanced TSLP release from LPS-activated macrophages. By contrast, IL-4, alone or in combination with IL-13, inhibited LPS-induced CXCL8 release from HLMs. Immunoreactive TSLP was detected in lysates of HLMs, MDMs, and monocytes. Incubation of HLMs with TSLP induced the release of proinflammatory (TNF-α), angiogenic (VEGF-A, angiopoietin 2), and lymphangiogenic (VEGF-C) factors. TSLP, TSLPR, and IL-7Rα were expressed in intratumoral and peritumoral areas of human lung cancer. sfTSLP and lfTSLP mRNAs were differentially expressed in peritumoral and intratumoral lung cancer tissues. The TSLP system, expressed in HLMs, MDMs, and monocytes, could play a role in chronic inflammatory disorders including lung cancer.
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Adenocarcinoma de Pulmão/metabolismo , Citocinas/metabolismo , Neoplasias Pulmonares/metabolismo , Ativação de Macrófagos , Macrófagos Alveolares/metabolismo , Microambiente Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Idoso , Proteínas Angiogênicas/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/farmacologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfangiogênese , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Transdução de Sinais , Linfopoietina do Estroma do TimoRESUMO
Hereditary angioedema (HAE) is a rare genetic disease, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. HAE may be further classified into HAE with C1-inhibitor deficiency (C1-INH-HAE) and HAE with normal C1-INH activity (nlC1-INH-HAE), mostly due to mutations leading to increased vascular permeability. Recent evidence implicates also the innate and adaptive immune responses in several aspects of angioedema pathophysiology. Monocytes/macrophages, granulocytes, lymphocytes, and mast cells contribute directly or indirectly to the pathophysiology of angioedema. Immune cells are a source of vasoactive mediators, including bradykinin, histamine, complement components, or vasoactive mediators, whose concentrations or activities are altered in both attacks and remissions of HAE. In turn, through the expression of various receptors, these cells are also activated by a plethora of molecules. Thereby, activated immune cells are the source of molecules in the context of HAE, and on the other hand, increased levels of certain mediators can, in turn, activate immune cells through the engagement of specific surface receptors and contribute to vascular endothelial processes that lead to hyperpemeability and tissue edema. In this review, we summarize recent developments in the putative involvement of the innate and adaptive immune system of angioedema.
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Angioedemas Hereditários , Bradicinina , Proteína Inibidora do Complemento C1/genética , Humanos , MutaçãoRESUMO
Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSAKIT WT and ROSA KIT D816V and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSAKIT WT, ROSAKIT D816V and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.
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Angiopoietinas/sangue , Mastocitose/metabolismo , Regulação para Cima , Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular , Feminino , Mutação com Ganho de Função , Humanos , Masculino , Mastocitose/sangue , Mastocitose/genética , Pessoa de Meia-Idade , Gravidade do Paciente , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Adulto JovemRESUMO
Neutrophils (PMNs) are innate immune cells with primary roles in inflammation and in host defense against infections. Both inflammatory and tumor angiogenesis are modulated by a sequential, coordinated production of angiogenic factors such as vascular endothelial growth factors (VEGFs), angiopoietins, hepatocyte growth factor (HGF), and chemokines. These factors are produced by several immune cells, including PMNs. Activation of cannabinoid receptor type-1 (CB1 ) and -2 (CB2 ) has been suggested as a new strategy to modulate in vitro and in vivo angiogenesis. We sought to investigate whether activation of CB1 and CB2 by CB agonists modulate LPS-mediated angiogenic activity of human PMNs. Highly purified PMNs were isolated from buffy coats of healthy donors. Cells were stimulated with CB1 and CB2 agonists/antagonists alone and/or in combination with LPS. Angiogenic factors in cell-free supernatants were measured by ELISA. The modulation of activation markers of PMNs by CB agonists was evaluated by flow cytometry. Angiogenesis in vitro was measured as tube formation by optical microscopy. Endothelial cell permeability was assessed by an in vitro vascular permeability assay. LPS-activated PMNs released VEGF-A, CXCL8, and HGF. Preincubation of PMNs with low concentrations of CB1 and CB2 agonists inhibited VEGF-A release induced by LPS, but did not affect CXCL8 and HGF production. The effects of CB agonists on VEGF-A release induced by LPS were reversed by preincubation with CB antagonists. CB agonists modulated in vitro angiogenesis and endothelial permeability induced by supernatants of LPS-activated PMNs through the reduction of VEGF-A. Neutrophils play a central role in the control of bacterial infections and in the outcome of sepsis. The latter condition is associated with an increase in circulating levels of VEGF-A. We demonstrated that low concentrations of CB agonists inhibit VEGF-A release from LPS-activated PMNs. These results suggest that CB agonists might represent a novel therapeutic strategy in patients with sepsis.
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Agonistas de Receptores de Canabinoides/farmacologia , Lipopolissacarídeos/farmacologia , Neutrófilos/metabolismo , Receptores de Canabinoides/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígenos CD/metabolismo , Canabinoides/farmacologia , Bovinos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Interleucina-8/metabolismo , Cinética , Neovascularização Fisiológica/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Quinoxalinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistasRESUMO
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.
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1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Angiopoietina-1/sangue , Proteína Inibidora do Complemento C1/metabolismo , Angioedema Hereditário Tipos I e II/imunologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/imunologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Adolescente , Adulto , Angiopoietina-1/imunologia , Angiopoietina-1/metabolismo , Angiopoietina-2/sangue , Angiopoietina-2/imunologia , Angiopoietina-2/metabolismo , Bradicinina/imunologia , Bradicinina/metabolismo , Permeabilidade Capilar/imunologia , Estudos de Casos e Controles , Proteína Inibidora do Complemento C1/genética , Feminino , Voluntários Saudáveis , Angioedema Hereditário Tipos I e II/sangue , Angioedema Hereditário Tipos I e II/genética , Humanos , Masculino , Pessoa de Meia-Idade , Exacerbação dos Sintomas , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/sangue , Fator C de Crescimento do Endotélio Vascular/imunologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/sangue , Fator D de Crescimento do Endotélio Vascular/imunologia , Fator D de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
Introduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. TSLP exerts its effects by binding to a high affinity heteromeric receptor complex composed of TSLPR and IL-7Rα. An association of polymorphisms in TSLP with airway hyperresponsiveness, IgE, eosinophilia and asthma has been documented. TSLP has been implicated in asthma pathophysiology. Tezepelumab is a first-in-class human monoclonal antibody that binds to TSLP, thus inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. Several trials are evaluating the long-term safety and the efficacy of tezepelumab in adults and adolescents with severe uncontrolled asthma.Areas covered: We provide an overview of the monoclonal antibody therapeutics market for severe uncontrolled asthma, examine the underlying pathophysiology that drives TSLP and discuss the use of tezepelumab for the treatment of severe uncontrolled asthma,Expert opinion: TSLP is a promising target for T2-high and perhaps some patients with T2-low asthma. The results of preliminary clinical trials are encouraging. Several unanswered questions concerning basic pathophysiological aspects of TSLP variants, the long-term safety and efficacy of tezepelumab with different phenotypes/endotypes of asthma should be addressed.