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Alarmin cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) function as danger signals to trigger host immunity in response to tissue injury caused by pathogenic factors such as parasitic infections. Parasitic diseases also provide an excellent context to study their functions and mechanisms. Numerous studies have indicated that alarmin cytokine released by non-immune cells such as epithelial and stromal cells induce the hosts to initiate a type 2 immunity that drives parasite expulsion but also host pathology such as tissue injury and fibrosis. By contrast, alarmin cytokines especially IL-33 derived from immune cells such as dendritic cells may elicit an immuno-suppressive milieu that promotes host tolerance to parasites. Additionally, the role of alarmin cytokines in parasite infections is reported to depend on species of parasites, cellular source of alarmin cytokines, and immune microenvironment, all of which is relevant to the parasitic sites or organs. This narrative review aims to provide information on the crucial and diverse role of alarmin cytokines in parasitic infections involved in different organs including intestine, lung, liver and brain. [ABSTRACT FROM AUTHOR]

Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial–mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the influence of osthole (OS) on asthma-induced airway epithelial cell apoptosis and inflammation by restraining Th2 differentiation through suppressing TSLP/NF-κB. Methods: An asthma mouse model and an inflammation cell model were constructed with ovalbumin (OVA) and lipopolysaccharide (LPS), respectively. CD4 + T cells were treated with IL-4 to induce Th2 differentiation. Model mice were treated with OS (15,40 mg/kg) for 7 days, and 10 µg/mL OS was added to cell treatment groups. The levels of relevant indices were detected by RT‒qPCR, HE and Masson staining, Western blotting, ELISA and flow cytometry. Results: In a mouse asthma model, TSLP expression was elevated, and the NF-κB pathway was activated. Therefore, OS could restrain the apoptosis and inflammation of airway epithelial cells. Downstream mechanistic studies revealed that OS can suppress Th2 differentiation by restraining the level of TSLP and NF-κB nuclear translocation, thus facilitating the proliferation of airway epithelial cells, restraining their apoptosis and inflammation, and alleviating airway inflammation in asthmatic mice. Conclusion: OS can inhibit Th2 differentiation by inhibiting the TSLP and NF-κB pathways, which can reduce the apoptosis and inflammation of airway epithelial cells caused by asthma. [ABSTRACT FROM AUTHOR]

This study investigates the mechanism through which paeoniflorin inhibits TSLP expression to regulate dendritic cell activation in corticosteroid-dependent dermatitis treatment. Utilizing databases like TCMSP, we identified paeoniflorin's components, targets, and constructed networks. Molecular docking and gene enrichment analysis helped pinpoint key targets and pathways affected by paeoniflorin. In vitro and in vivo models were used to study CD80, CD86, cytokines, T-cell activation, skin lesions, histopathological changes, TSLP, CD80, and CD86 expression. Our study revealed paeoniflorin's active constituent targeting IL-6 in corticosteroid-dependent dermatitis. In vitro experiments demonstrated reduced TSLP expression, CD80, CD86, and cytokine secretion post-paeoniflorin treatment. In vivo, paeoniflorin significantly decreased skin lesion severity, cytokine levels, TSLP, CD80, and CD86 expression. The study highlights paeoniflorin's efficacy in inhibiting TSLP expression and suppressing dendritic cell activation in corticosteroid-dependent dermatitis, suggesting its potential as a therapeutic intervention. Additionally, it offers insights into the complex molecular mechanisms underlying paeoniflorin's anti-inflammatory properties in treating corticosteroid-dependent dermatitis. [ABSTRACT FROM AUTHOR]

Background: In recent years, there has been a growing interest in the utilization of biologic therapies for the management of asthma. Both TSLP and IgE are important immune molecules in the development of asthma, and they are involved in the occurrence and regulation of inflammatory response. Methods: A comprehensive search of PubMed and Web of Science was conducted to gather information on anti-TSLP antibody and anti-IgE antibody. Results: This investigation elucidates the distinct mechanistic roles of Thymic Stromal Lymphopoietin (TSLP) and Immunoglobulin E (IgE) in the pathogenesis of asthma, with a particular emphasis on delineating the therapeutic mechanisms and pharmacological properties of monoclonal antibodies targeting IgE and TSLP. Through a meticulous examination of clinical trials involving paradigmatic agents such as omalizumab and tezepelumab, we offer valuable insights into the potential treatment modalities for diseases with shared immunopathogenic pathways involving IgE and TSLP. Conclusion: The overarching objective of this comprehensive study is to delve into the latest advancements in asthma therapeutics and to provide guidance for future investigations in this domain. [ABSTRACT FROM AUTHOR]

Ayman Mubarak,1 Mahfoudh Alqoufail,1 Saeedah Almutairi,1 Bahauddeen Alrfaei,2 Abdulaziz Almotairi,3 Ibrahim Aziz,1 Taghreed N Almanaa,1 Mostafa A Abdel-Maksoud,1 Mohamed A Farrag,1 Allolo D Aldreiwish,4 Maaweya E Awadalla,5 Bandar Alosaimi,5 Wael Alturaiki4 1Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia; 2Stem Cells Unit, Department of Cellular Therapy, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Science, MNGHA, Riyadh, Saudi Arabia; 3College of Medicine, Almaarefa University, Riyadh, Saudi Arabia; 4Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Saudi Arabia; 5Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi ArabiaCorrespondence: Wael Alturaiki, Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Saudi Arabia, Email w.alturaiki@mu.edu.saPurpose: Thymic stromal lymphopoietin (TSLP) is a proinflammatory cytokine produced by epithelial cells that is involved in the activation of allergic disorders. To date, no study has examined TSLP induction during Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Herein, we aimed to study the effects of the recombinant spike protein of MERS-CoV on TSLP production. Additionally, the effects of recombinant human TSLP (rhTSLP) on B cell survival and antibody production were investigated.Patients and Methods: B cells were separated using the Human B Cell Enrichment Kit, and B cell survival was measured using the WST-1 Assay Kit. Enzyme-linked immunosorbent assay (ELISA) was used to measure TSLP levels in the sera of both MERS-CoV-infected (n=4; median age, 53 years) and healthy individuals (n=5; median age, 35 years).Results: We showed that the group of infected patients had significantly higher levels of TSLP than healthy controls (37.6 pg/mL vs 19.8 pg/mL, &ast;p< 0.05). The levels of TSLP in A549 cells were remarkably increased after 48 h of stimulation with recombinant full-length spike protein (rSP) (32.2 pg/mL, p=0.01). B cell survival was greatly enhanced by rhTSLP alone or in combination with rSP (0.02 vs 0.046, and 0.045; &ast;&ast;p< 0.01, respectively). Our data also showed a significant synergistic effect of rhTSLP and rSP on the augmented response of IgG antibodies against the spike protein of MERS-CoV compared with unstimulated cells (0.156 vs 0.22; &ast;p< 0.05).Conclusion: TSLP production is induced in vivo after MERS-CoV infection and in vitro after treatment with the rSP of MERS-CoV, which has a significant effect on the survival of B cells. Our data suggest that TSLP can be used as a strong mucosal adjuvant for vaccine development against MERS-CoV infection. However, further investigation is required to study the functional role of TSLP in MERS-CoV infection.Keywords: MERS-CoV, TSLP, recombinants spike protein, B cells

Abstract Objective The aim of this study was to investigate the influence of osthole (OS) on asthma-induced airway epithelial cell apoptosis and inflammation by restraining Th2 differentiation through suppressing TSLP/NF-κB. Methods An asthma mouse model and an inflammation cell model were constructed with ovalbumin (OVA) and lipopolysaccharide (LPS), respectively. CD4 + T cells were treated with IL-4 to induce Th2 differentiation. Model mice were treated with OS (15,40 mg/kg) for 7 days, and 10 µg/mL OS was added to cell treatment groups. The levels of relevant indices were detected by RT‒qPCR, HE and Masson staining, Western blotting, ELISA and flow cytometry. Results In a mouse asthma model, TSLP expression was elevated, and the NF-κB pathway was activated. Therefore, OS could restrain the apoptosis and inflammation of airway epithelial cells. Downstream mechanistic studies revealed that OS can suppress Th2 differentiation by restraining the level of TSLP and NF-κB nuclear translocation, thus facilitating the proliferation of airway epithelial cells, restraining their apoptosis and inflammation, and alleviating airway inflammation in asthmatic mice. Conclusion OS can inhibit Th2 differentiation by inhibiting the TSLP and NF-κB pathways, which can reduce the apoptosis and inflammation of airway epithelial cells caused by asthma.

Allergic rhinitis (AR) is an inflammatory disease of the upper respiratory tract (nasal mucosa). AR affects up to 40% of the world’s population; in the Russian Federation, the incidence is 18% to 30%, depending on the region. Despite the fact that AR is not a severe pathology, it causes significant economic burden. Another threat associated with this disease is that in 40% of cases, patients with AR eventually develop a more severe disabling pathology – AD. Widespread prevalence and significant economic disadvantages caused by AR determine the importance of developing new ways of prevention and control of this disease, as the existing methods of therapy are insufficient. However, the search for new ways of therapy is impossible without a detailed investigation of the molecular mechanisms of AR pathogenesis. For a long time it was considered that this allergic inflammation is formed by Th2-dependent mechanism with involvement of Th2-lymphocytes, B-cells and eosinophils and pro-inflammatory cytokines: IL-4, IL-5 and IL-13. However, experimental evidence has now accumulated on the role of epithelial cells of the respiratory tract and the proinflammatory cytokines they secrete (IL-25, IL-33 and TSLP) in the pathogenesis of AR and AD. IL-25 has been shown to induce the production of IL-4, IL-5 and IL-13, directing a Th2-type immune response. At the same time, mice with inactivated IL-25 developed barely any Th2-immune response. Inactivation of IL-33 significantly reduces inflammation (mediated by eosinophils) of the respiratory tract. Mice knockout for the cytokine receptor TSLP did not develop nasal hyperreactivity in response to allergen, but the level of nasal mucosal inflammation remained high. Currently, work is actively progressing on the development of new drugs capable of specifically blocking the activity of the listed cytokines; first of all, drugs based on neutralizing monoclonal antibodies. However, there are other technologies that can be used to regulate the activity of genes, such as the technology based on the RNA interference. It can be used to suppress the expression of any gene with a known nucleotide sequence, including genes encoding pro-inflammatory cytokines.Considering the above, the aim of this work was to design synthetic miRNA molecules and study their ability to specifically block the expression of genes encoding proinflammatory cytokines IL-25 and TSLP in experiments in vitro.

Abstract Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

Specific molecular and inflammatory endotypes have been identified for chronic respiratory disorders, including asthma and COPD (chronic obstructive pulmonary disease). These endotypes correspond with clinical aspects of disease, enabling targeted medicines to address certain pathophysiologic pathways, often referred to as “precision medicine”. With respect to bronchiectasis, many comorbidities and underlying causes have been identified. Inflammatory endotypes have also been widely studied and reported. Additionally, several genes have been shown to affect disease progression. However, the lack of a clear classification has also hampered our understanding of the disease’s natural course. The aim of this review is, thus, to summarize the current knowledge on biomarkers and actionable targets of this complex pathologic condition and to point out unmet needs, which are required in the design of effective diagnostic and therapeutic trials.

Abstract Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein–protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.

Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects. [ABSTRACT FROM AUTHOR]

[Display omitted] The cytokine TSLP promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown. This study investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss. RNA-sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single-cell RNA-sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro. This study found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single-cell RNA-sequencing revealed that TSLP recruited distinct T-cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro. This study proposes that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss. [ABSTRACT FROM AUTHOR]

Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a main global epidemic increasing as population age and affecting approximately 10% of subjects over 45 years. COPD is a heterogeneous inflammatory disease with several endo-phenotypes and clinical presentations. Although neutrophilic inflammation is canonically considered a hallmark of COPD, eosinophilic inflammation can also be present in a subgroup of patients. Several other immune cells and cytokines play a key role in orchestrating and perpetuating the inflammatory pathways in COPD, making them attractive targets for treating this disorder. Recent studies have started to evaluate the possible role of type 2 (T2) inflammation and epithelial-derived alarmins (TSLP and IL-33) in COPD. Two phase III randomized clinical trials (RCTs) showed a modest reduction in exacerbations in COPD patients with eosinophilic phenotype treated with mepolizumab (anti-IL-5) or benralizumab (anti-IL-5Rα). A phase III RCT showed a 30% reduction in exacerbations in COPD patients with ≥ 300 eosinophils/μL treated with dupilumab (anti-IL-4Rα). These results suggest that blocking a single cytokine (e.g., IL-5) or its main target (i.e., IL-5Rα) is less promising than blocking a wider spectrum of cytokines (i.e., IL-4 and IL-13) in COPD. TSLP and IL-33 are upstream regulators of T2-high and T2-low immune responses in airway inflammation. Several ongoing RCTs are evaluating the efficacy and safety of anti-TSLP (tezepelumab), anti-IL-33 (itepekimab, tozorakimab), and anti-ST2 (astegolimab) in patients with COPD, who experience exacerbations. In conclusion, targeting T2 inflammation or epithelial-derived alarmins might represent a step forward in precision medicine for the treatment of a subset of COPD. [ABSTRACT FROM AUTHOR]

Thymic Stromal Lymphopoietin (TSLP) is an important cytokine that invokes early immune responses. TSLP, an IL-7-like cytokine encoded by the TSLP gene, activates JAK1 and JAK2 signaling pathways, stimulating dendritic cells to induce inflammatory Th2 cells. This cytokine is associated with pruritus in various cutaneous disorders, particularly atopic dermatitis. Varying levels of the cytokine TSLP have been demonstrated in studies of different cutaneous disorders. Pharmacological treatment targeting TSLP has been explored recently, particularly in the realm of atopic dermatitis. This review explores the relation of TSLP to cutaneous diseases, highlighting its potential as a biomarker for monitoring disease progression in discoid lupus erythematosus (DLE). The pharmacological therapy involving TSLP is discussed, along with the potential role of TSLP promotion in the treatment of alopecia areata. This overview examines the background, structure, and functions of TSLP, with a focus on its association with cutaneous disorders and a special focus on the impact of the atopic march. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein–protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases. Synopsis: A potent small molecule TSLPR inhibitor was identified as a novel therapeutic option for atopic diseases. The small molecule BP79 effectively abrogates TSLP-triggered immune reactions at low micromolar concentrations in human skin and lungs. BP79 can be topically applied and, thus, provides significant advantages over the current TSLP antibodies. A human-based atopic disease drug discovery platform was developed with the potential to facilitate preclinical development of atopy-targeting drugs. A potent small molecule TSLPR inhibitor was identified as a novel therapeutic option for atopic diseases. [ABSTRACT FROM AUTHOR]

Yukmijihwang-tang (YJT) is a blend of six herbal ingredients that has long been used in Asia for various diseases, including diabetes mellitus and mental decline. Here, we assessed the prophylactic efficacy of YJT in a murine model of asthma induced by ovalbumin (OVA). Male C57BL/6 mice underwent sensitization followed by an airway challenge with OVA for 1 h. YJT (100 or 300 mg/kg once daily) was administered orally for 6 days. Our analyses revealed that YJT significantly reduced inflammatory cell counts in bronchoalveolar lavage fluid (BALF), decreased the concentrations of interleukin (IL)-4, IL-5, and IL-13 in BALF, and lowered the relative mRNA levels of thymic stromal lymphopoietin (TSLP) and tumor necrosis factor α (TNFα) in lung tissues. Histological analyses showed that YJT substantially decreased inflammation and mucus hypersecretion in the bronchial airway. YJT also effectively reduced oxidative stress, as evidenced by improved levels of malondialdehyde (MDA), total glutathione, glutathione reductase (GR), and reduced glutathione (GSH). YJT also markedly suppressed the phosphorylation of nuclear factor-kappa B (NF-κB) in lung tissues. Together, these results show that YJT effectively inhibits respiratory inflammation, mucus hypersecretion, and oxidative stress induced by OVA, suggesting its potential for asthma treatment. [ABSTRACT FROM AUTHOR]

Allergic diseases, affecting millions worldwide, have shown a progressive increase in recent years. Existing anti-allergy drugs primarily target symptoms and downstream reactions, necessitating the exploration of novel therapeutics addressing the root causes in the allergy pathway. Thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33), classified as upstream cytokines, play pivotal roles in initiating type-2 immunity and are implicated in allergic diseases. However, small molecule antagonists for both TSLP and IL-33 proteins are still in early development and not yet available as treatments for allergic diseases. This study focuses on identifying natural small molecules that can inhibit both TSLP and IL-33 proteins. The study employed structure-based virtual screening to identify potential dual inhibitors of TSLP and IL-33 from the ZINC database. Through the use of Autodock Vina in PyRx software, virtual screening was conducted to predict the binding mode and binding affinity of these compounds. Molecular dynamics simulations utilizing GROMACS and binding free energy calculations (MM/PBSA) were performed to evaluate the stability and strength of interactions between the identified compounds and the target proteins. Additionally, bioavailability and toxicity analyses were carried out to evaluate the safety and pharmacokinetic properties of the compounds. The study successfully pinpointed three promising compounds, namely ZINC01105767 and ZINC08764679 (fused heterocyclic compounds), and ZINC33833100 (a limonin analogue), as potential dual inhibitors of both TSLP and IL-33 proteins. Molecular dynamics simulations confirmed the structural stability of these complexes, and the analysis of RMSD, RMSF, Rg, and SASA indicated strong interactions. Furthermore, the bioavailability analysis revealed drug-like properties, and toxicity analysis suggested that the compounds are non-mutagenic and non-tumorigenic. ZINC01105767, ZINC08764679, and ZINC33833100 represent promising lead candidates for the treatment of allergic diseases, particularly being heterocyclic compounds with benzoxalyl coumarin, and chromone moieties, which have shown effectiveness in allergic disease treatment.The comprehensive computational analysis provides valuable insights into the structural stability, structural integrity, compactness, folding properties and safety profiles of these compounds, highlighting their potential as anti-allergy agents. Among three dual candidate inhibitors, based on the MM/PBSA based binding free energy analysis, ZINC01105767 emerged as the most promising dual inhibitor, demonstrating the strongest binding affinity with a binding free energy of −43.31 kcal/mol in case of TSLP and −29.87 kcal/mol in case of IL-33. This suggests a potent interaction with both TSLP and IL-33 proteins, indicating its potential as a dual inhibitor targeting these pathways simultaneously. This study paves the way for further investigations and experimental validations, ultimately contributing to the development of more effective therapies for allergic diseases. [ABSTRACT FROM AUTHOR]

• Human lung macrophages (HLMs) are a key source of TSLP in airway diseases. • TSLP is selectively localized in the cytoplasm of HLMs. • Both Type-2 high and Type-2 low stimuli induce TSLP release from HLMs. • Long form TSLP (lfTSLP) stimulates VEGF-A release from HLMs. • Short form TSLP neither activates nor interferes with the activating TSLP property. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus. AD is harmful to both children and adults, but its pathogenic mechanism has yet to be fully elucidated. The development of mouse models for AD has greatly contributed to its study and treatment. Among these models, the exogenous drug-induced mouse model has shown promising results and significant advantages. Until now, a large amount of AD-related research has utilized exogenous drug-induced mouse models, leading to notable advancements in research. This indicates the crucial significance of applying such models in AD research. These models exhibit diverse characteristics and are highly complex. They involve the use of various strains of mice, diverse types of inducers, and different modeling effects. However, there is currently a lack of comprehensive comparative studies on exogenous drug-induced AD mouse models, which hinders researchers' ability to choose among these models. This paper provides a comprehensive review of the features and mechanisms associated with various exogenous drug-induced mouse models, including the important role of each cytokine in AD development. It aims to assist researchers in quickly understanding models and selecting the most suitable one for further investigation. [Display omitted] • Exogenous-drugs induced mouse models are very helpful in studying the pathogenesis of AD in humans. • Hapten-induced mouse models are cost-effective but time-consuming. • OVA-induced mouse models are widely applicable. • MC903-induced mouse models are ideal for rapid AD modelling. [ABSTRACT FROM AUTHOR]

The epithelial barriers of the skin, gut, and respiratory tract are critical interfaces between the environment and the host, and they orchestrate both homeostatic and pathogenic immune responses. The mechanisms underlying epithelial barrier dysfunction in allergic and inflammatory conditions, such as atopic dermatitis, food allergy, eosinophilic oesophagitis, allergic rhinitis, chronic rhinosinusitis, and asthma, are complex and influenced by the exposome, microbiome, individual genetics, and epigenetics. Here, we review the role of the epithelial barriers of the skin, digestive tract, and airways in maintaining homeostasis, how they influence the occurrence and progression of allergic and inflammatory conditions, how current treatments target the epithelium to improve symptoms of these disorders, and what the unmet needs are in the identification and treatment of epithelial disorders. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies. [ABSTRACT FROM AUTHOR]

Alarmin cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) function as danger signals to trigger host immunity in response to tissue injury caused by pathogenic factors such as parasitic infections. Parasitic diseases also provide an excellent context to study their functions and mechanisms. Numerous studies have indicated that alarmin cytokine released by non-immune cells such as epithelial and stromal cells induce the hosts to initiate a type 2 immunity that drives parasite expulsion but also host pathology such as tissue injury and fibrosis. By contrast, alarmin cytokines especially IL-33 derived from immune cells such as dendritic cells may elicit an immuno-suppressive milieu that promotes host tolerance to parasites. Additionally, the role of alarmin cytokines in parasite infections is reported to depend on species of parasites, cellular source of alarmin cytokines, and immune microenvironment, all of which is relevant to the parasitic sites or organs. This narrative review aims to provide information on the crucial and diverse role of alarmin cytokines in parasitic infections involved in different organs including intestine, lung, liver and brain.

Chronic pain is a universal public health problem with nearly one third of global human involved, which causes significant distressing personal burden. After painful stimulus, neurobiological changes occur not only in peripheral nervous system but also in central nervous system where somatosensory cortex is important for nociception. Being an ion channel, transient receptor potential vanilloid 1 (TRPV1) act as an inflammatory detector in the brain. Thymic stromal lymphopoietin (TSLP) is a potent neuroinflammation mediator after nerve injury. Bleomycin is applied to treat dermatologic diseases, and its administration elicits local painful sensation. However, whether bleomycin administration can cause chronic pain remains unknown. In the present study, we aimed to investigate how mice develop chronic pain after receiving repeated bleomycin administration. In addition, the relevant neurobiological brain changes after noxious stimuli were clarified. C57BL/6 mice aged five- to six-weeks were randomly classified into two group, PBS (normal) group and bleomycin group which bleomycin was intradermally administered to back five times a week over a three-week period. Calibrated forceps testing was used to measure mouse pain threshold. Western blots were used to assess neuroinflammatory response; immunofluorescence assay was used to measure the status of neuron apoptosis, glial reaction, and neuro-glial communication. Bleomycin administration induced mechanical nociception and activated both TRPV1 and TSLP/TSLPR/pSTAT5 signals in mouse somatosensory cortex. Through these pathways, bleomycin not only activates glial reaction but also causes neuronal apoptosis. TRPV1 and TSLP/TSLPR/pSTAT5 signaling had co-labeled each other by immunofluorescence assay. Taken together, our study provides a new chronic pain model by repeated intradermal bleomycin injection by activating TRPV1 and glial reaction-mediated neuroinflammation via TSLP/TSLPR/pSTAT5 signals.

Human respiratory syncytial virus (RSV) is one of the common causes of respiratory illnesses and hospitalizations among infants and young children worldwide, yet an effective vaccine remains unavailable. Cytokines that can activate B-cells and stimulate antibody production, such as thymic stromal lymphopoietin (TSLP), could be used to produce robust and long-lasting mucosal responses to respiratory virus infection. TSLP cytokine is expressed by many immune and non-immune cells, for example airway epithelial cells and mediates a crucial role in activating and maturing dendritic cells and T helper 2 cells. TSLP also promotes cytokine production from activated Th2 cells, such as IL-5, that enhance antibody class switching recombination to IgA, which can protect against viral respiratory infections at the mucosal surfaces. This review is focused on the effect of TSLP on local B-cell responses and IgA antibody production during respiratory viral infections. We suggest that mucosal vaccines could provide better protection against RSV. A novel RSV mucosal vaccine that uses TSLP as an immunostimulant with the RSV Fusion protein (RSV-F) could enhance the local adaptive immune response, generating extended lasting tissue resident memory cells and block early RSV replication, and increase viral clearance from airways. However, additional investigations are required to determine the challenges and limitations of utilizing TSLP cytokine as an immunostimulant combined with RSV-F as it may lead to excessive Th2 immune responses.

Background: Thymic stromal lymphopoietin (TSLP) is a cytokine initially implicated to be associated with allergic disorders inducing Th2 response. Emerging studies have shown that TSLP is also involved in autoimmune diseases. In psoriasis, TSLP acts in synergy with T cell-derived CD40L to promote the release of IL-23 from dendritic cells. IL-23 is responsible for the inappropriate immune reaction and keratinocyte proliferation in psoriasis. Targeting TSLP could be a novel therapeutic approach in the treatment of psoriasis. Objective: To compare the serum levels of TSLP between patients with psoriasis and healthy individuals. Materials and Methods: A prospective hospital-based case-control study was carried out on 38 patients with psoriasis. The severity of psoriasis was graded into mild, moderate, and severe according to PASI. A total of 30 healthy individuals with matched age and sex were taken as controls. 5 ml of venous blood was collected, centrifuged, and the collected serum was stored at -80°C until quantitative assessment by sandwich enzyme-linked immunosorbent assay (ELISA) technique. Results: TSLP has been found to be significantly elevated in the sera of cases (0.1380178 pg/ml) than in controls (0.1125974 pg/ml). There was also a significant proportionate increase in the mean TSLP with the mean PASI score. Limitations: The sample size was small and we could not follow-up the cases to study the changes in TSLP levels with remission of the lesions. Conclusion: We found that serum TSLP was elevated in psoriasis patients and correlated with disease severity, indicating a possible pathogenetic role.

As the burden of mild asthma is not well understood, the significance of expanding research in the group of patients with mild asthma is emphasized. Thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33) are involved in the pathogenesis of atopy and the immune response to inhaled environmental insults, such as allergens, in asthmatic patients. Objectives: The objective of this study was to explore the correlation between specific polymorphisms within the genes encoding TSLP and IL-33, as well as the concentrations of TSLP and IL-33 in the serum, and the occurrence of pediatric mild asthma. Methods: The analysis encompassed 52 pediatric patients diagnosed with mild bronchial asthma, including both atopic and non-atopic cases, and a control group of 26 non-asthmatic children. Recruitment was conducted through a comprehensive questionnaire. Parameters such as allergic sensitization, serum levels of circulating TSLP and IL-33, and the identification of single-nucleotide polymorphisms in TSLP (rs11466750 and rs2289277) and IL-33 (rs992969 and rs1888909) were assessed for all participants. Results: Significantly lower mean serum TSLP concentrations were observed in asthmatic subjects compared to the control group, with atopic asthma patients showing even lower TSLP levels than non-atopic counterparts. No significant differences were found in mean serum IL-33 concentrations between the two groups. Considering the allele model, for both tested SNPs of IL-33, we observed that patients with asthma, atopic asthma, and atopy statistically less frequently possess the risk allele. Conclusions: Our study findings suggest that IL-33 and TSLP do not serve as ideal biomarkers for mild asthma in children. Their effectiveness as biomarkers might be more relevant for assessing disease severity rather than identifying asthma in pediatric patients. Further research focusing on the association between TSLP and IL-33 gene polymorphisms and asthma is expected to significantly advance disease management. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is a cytokine initially implicated to be associated with allergic disorders inducing Th2 response. Emerging studies have shown that TSLP is also involved in autoimmune diseases. In psoriasis, TSLP acts in synergy with T cell‑derived CD40L to promote the release of IL‑23 from dendritic cells. IL‑23 is responsible for the inappropriate immune reaction and keratinocyte proliferation in psoriasis. Targeting TSLP could be a novel therapeutic approach in the treatment of psoriasis. Objective: To compare the serum levels of TSLP between patients with psoriasis and healthy individuals. Materials and Methods: A prospective hospital‑based case‑control study was carried out on 38 patients with psoriasis. The severity of psoriasis was graded into mild, moderate, and severe according to PASI. A total of 30 healthy individuals with matched age and sex were taken as controls. 5 ml of venous blood was collected, centrifuged, and the collected serum was stored at ‑80°C until quantitative assessment by sandwich enzyme‑linked immunosorbent assay (ELISA) technique. Results: TSLP has been found to be significantly elevated in the sera of cases (0.1380178 pg/ml) than in controls (0.1125974 pg/ml). There was also a significant proportionate increase in the mean TSLP with the mean PASI score. Limitations: The sample size was small and we could not follow‑up the cases to study the changes in TSLP levels with remission of the lesions. Conclusion: We found that serum TSLP was elevated in psoriasis patients and correlated with disease severity, indicating a possible pathogenetic role. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signaling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signaling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signaling induces TSLP mRNA expression via the PERK-C/EBP homologous protein (CHOP) signaling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP that is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma. NEW & NOTEWORTHY: TSLP is an epithelial-derived cytokine and a key regulator in the pathogenesis of severe uncontrolled asthma. We demonstrate a novel mechanism by which endoplasmic reticulum stress signaling upregulates airway epithelial TSLP mRNA expression via the PERK-CHOP signaling pathway and enhances TLR3-mediated TSLP protein secretion. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation. [ABSTRACT FROM AUTHOR]

The effect of RV-16 on the lung endothelium has not yet been fully defined. It has been suggested that infection of lung endothelial cells with RV-16 drives the production of proinflammatory cytokines. Aim The study's main objective was to investigate lung endothelial cells' antiviral response in vitro to RV-16 infection in the context of modulation the concentration of thymic stromal lymphopoietin (TSLP), which has not been assessed yet. TSLP has been also determined in cell cultures exposed to the virus and stimulated with IL-33 in the presence of antibodies towards the IL-33 receptor (ST2). Material and methods Human lung microvascular endothelial cells (HMVEC-L) were infected with RV-16 or infected with this virus and stimulated with IL-33 in the presence or absence of anti-ST2 antibodies. In the supernatant TSLP level was determined using an enzyme imunoassay (ELISA). Results The TLSP level in cell cultures infected with RV-16, at 72 hours of incubation, was significantly lower compared to the cell culture in medium alone. Stimulation of cells infected with RV-16 with IL-33, in the presence or absence of anti-ST2 antibodies, did not influence the TSLP production and secretion. Conclusions RV-16 infection of lung endothelial cells is associated with decreased TSLP synthesis and release. IL-33 does not significantly affect the response of RV-16-infected lung endothelial cells in the context of TSLP synthesis and release. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome‐wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix–loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor β expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow‐up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling. [ABSTRACT FROM AUTHOR]

This study delves into the critical role of alarmins in chronic spontaneous urticaria (CSU), focusing on their impact on disease severity and the quality of life (QoL) of patients. We investigated the alterations in alarmin levels in CSU patients and their correlations with the Urticaria Activity Score (UAS7) and the Dermatology Life Quality Index (DLQI). We analyzed serum levels of interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoietin (TSLP) in 50 CSU patients, comparing these to 38 healthy controls. The study examined the relationship between alarmin levels and clinical outcomes, including disease severity and QoL. Elevated levels of IL-33 and TSLP in CSU patients (p < 0.0001) highlight their potential role in CSU pathogenesis. Although IL-25 showed higher levels in CSU patients, this did not reach statistical significance (p = 0.0823). Crucially, IL-33's correlation with both UAS7 and DLQI scores underscores its potential as a biomarker for CSU diagnosis and severity assessment. Of the alarmins analyzed, IL-33 emerges as particularly significant for further exploration as a diagnostic and prognostic biomarker in CSU. Its substantial correlation with disease severity and impact on QoL makes it a compelling candidate for future research, potentially serving as a target for therapeutic interventions. Given these findings, IL-33 deserves additional investigation to confirm its role and effectiveness as a biomarker and therapeutic target in CSU. [ABSTRACT FROM AUTHOR]

Influenza B viruses (IBV) cocirculate with influenza A viruses (IAV) and cause periodic epidemics of disease, yet antibody and cellular responses following IBV infection are less well understood. Using the ferret model for antisera generation for influenza surveillance purposes, IAV resulted in robust antibody responses following infection, whereas IBV required an additional booster dose, over 85% of the time, to generate equivalent antibody titers. In this study, we utilized primary differentiated ferret nasal epithelial cells (FNECs) which were inoculated with IAV and IBV to study differences in innate immune responses which may result in differences in adaptive immune responses in the host. FNECs were inoculated with IAV (H1N1pdm09 and H3N2 subtypes) or IBV (B/Victoria and B/Yamagata lineages) and assessed for 72 h. Cells were analyzed for gene expression by quantitative real-time PCR, and apical and basolateral supernatants were assessed for virus kinetics and interferon (IFN), respectively. Similar virus kinetics were observed with IAV and IBV in FNECs. A comparison of gene expression and protein secretion profiles demonstrated that IBV-inoculated FNEC expressed delayed type-I/II IFN responses and reduced type-III IFN secretion compared to IAVinoculated cells. Concurrently, gene expression of Thymic Stromal Lymphopoietin (TSLP), a type-III IFN-induced gene that enhances adaptive immune responses, was significantly downregulated in IBV-inoculated FNECs. Significant differences in other proinflammatory and adaptive genes were suppressed and delayed following IBV inoculation. Following IBV infection, ex vivo cell cultures derived from the ferret upper respiratory tract exhibited reduced and delayed innate responses which may contribute to reduced antibody responses in vivo. IMPORTANCE Influenza B viruses (IBV) represent nearly one-quarter of all human influenza cases and are responsible for significant clinical and socioeconomic impacts but do not pose the same pandemic risks as influenza A viruses (IAV) and have thus received much less attention. IBV accounts for greater severity and deaths in children, and vaccine efficacy remains low. The ferret can be readily infected with human clinical isolates and demonstrates a similar course of disease and immune responses. IBV, however, generates lower antibodies in ferrets than IAV following the challenge. To determine whether differences in initial innate responses following infection may affect the development of robust adaptive immune responses, ferret respiratory tract cells were isolated, infected with IAV/IBV, and compared. Understanding the differences in the initial innate immune responses to IAV and IBV may be important in the development of more effective vaccines and interventions to generate more robust protective immune responses. [ABSTRACT FROM AUTHOR]

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Thymic stromal lymphopoietin (TSLP) is a primarily epithelial‐derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1–24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as ‘high TSLP’ or ‘low TSLP’ for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I–III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I–III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro‐inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro‐inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre‐activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro‐inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long‐term impact of viral respiratory illnesses during early infancy and beyond childhood. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is critical in developing allergic responses, including atopic dermatitis (AD). We systematically reviewed the literature to complete a meta-analysis to quantitatively summarize the levels of serum TSLP in AD. The study was prospectively registered in the PROSPERO database (ID = CRD42021242628). The PUBMED, SCOPUS, and Cochrane Library databases were reviewed, and original articles investigating serum TSLP in AD patients were included. Differences in TSLP levels of AD patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed by applying the Newcastle‒Ottawa Scale. Fourteen studies, which included 1,032 AD patients and 416 controls, were included. Meta-analysis showed that TSLP levels were significantly higher in the AD group than in the control group (SMD = 2.21, 95% CI 1.37–3.06, p < 0.001). Stratification by geographical region, age, disease severity, TSLP determination method, sample size, and study quality revealed significantly elevated TSLP levels in European AD patients (SMD = 3.48, 95% CI 1.75–5.21, p < 0.0001), adult AD patients (SMD = 4.10, 95% CI 2.00–6.21, p < 0.0001), child AD patients (SMD = 0.83, 95% CI 0.08–1.59, p = 0.031), and all severity groups with AD compared with the control group (mild: SMD = 1.15, 95% CI 0.14–2.16, p = 0.025; moderate: SMD = 2.48, 95% CI 0.33–4.62, p = 0.024; and severe: SMD = 8.28, 95% CI 4.82–11.74, p = 2.72e−6). Noticeably, adults showed higher serum TSLP levels than children with AD, and serum TSL levels increased according to AD severity. In conclusion, our meta-analysis demonstrates that circulating TSLP levels are elevated in patients with AD. Future studies are warranted to further elucidate the sources of heterogeneity. [ABSTRACT FROM AUTHOR]

Purpose of Review: Compelling evidence over the past decade supports the central role of epithelial barrier dysfunction in the pathophysiology of eosinophilic esophagitis (EoE). The purpose of this review is to summarize the genetic, environmental, and immunologic factors driving epithelial barrier dysfunction, and how this impaired barrier can further promote the inflammatory response in EoE. Recent Findings: Common environmental exposures, such as detergents, may have a direct impact on the esophageal epithelial barrier. In addition, the effects of IL-13 on barrier dysfunction may be reduced by 17β-estradiol, Vitamin D, and the short chain fatty acids butyrate and propionate, suggesting novel therapeutic targets. Summary: There are many genetic, environmental, and immunologic factors that contribute to epithelial barrier dysfunction in EoE. This leads to further skewing of the immune response to a "Th2" phenotype, alterations in the esophageal microbiome, and penetration of relevant antigens into the esophageal mucosa, which are central to the pathophysiology of EoE. [ABSTRACT FROM AUTHOR]

Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.

• Mastocytosis is a clonal disorder of mast cells. • TSLP is a cytokine involved in allergic disorders and cancer. • Mast cell-derived tryptase is increased in mastocytosis. • TSLP is a substrate for human mast cell tryptase. • TSLP-tryptase is a novel loop involved in mastocytosis. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Combined exposure to the alarmins TSLP, IL-33 and IL-25 enhances mast cell-dependent contractions of human bronchi Keywords: airway hyperresponsiveness; anti-IgE; asthma; histamine; IL-33; prostaglandin D2; TSLP EN airway hyperresponsiveness anti-IgE asthma histamine IL-33 prostaglandin D2 TSLP 1062 1066 5 10/09/23 20231001 NES 231001 Key Messages Combined pretreatment with TSLP, IL-33 and IL-25 (epithelial alarmins) enhanced IgE-triggered contraction in isolated human bronchi. The release of histamine in response to IgE-mediated stimulation increased only in the alarmin mix pretreated group, indicating that, as shown for PGD SB 2, sb the alarmin mix enhanced the IgE-triggered release of histamine, presumably by increasing mast cell reactivity. Airway hyperresponsiveness, asthma, histamine, IL-33, anti-IgE, TSLP, prostaglandin D2. [Extracted from the article]

Therapeutic strategies that enhance regulatory T (Treg) cell proliferation or suppressive function hold promise for the treatment of autoimmune and inflammatory diseases. We previously reported that the topical application of the vitamin D3 analog MC903 systemically expands Treg cells by stimulating the production of thymic stromal lymphopoietin (TSLP) from the skin. Using mice lacking TSLP receptor expression by dendritic cells (DCs), we hereby show that TSLP receptor signaling in DCs is required for this Treg expansion in vivo. Topical MC903 treatment of ear skin selectively increased the number of migratory DCs in skin‐draining lymph nodes (LNs) and upregulated their expression of co‐stimulatory molecules. Accordingly, DCs isolated from skin‐draining LNs but not mesenteric LNs or spleen of MC903‐treated mice showed an enhanced ability to promote Treg proliferation, which was driven by co‐stimulatory signals through CD80/CD86 and OX40 ligand. Among the DC subsets in the skin‐draining LNs of MC903‐treated mice, migratory XCR1−CD11b+ type 2 and XCR1−CD11b− double negative conventional DCs promoted Treg expansion. Together, these data demonstrate that vitamin D3 stimulation of skin induces TSLP expression, which stimulates skin migratory DCs to expand Treg cells. Thus, topical MC903 treatment could represent a convenient strategy to treat inflammatory disorders by engaging this pathway. [ABSTRACT FROM AUTHOR]

The aim of this study was to establish the role of thymic stromal lymphopoietin (TSLP) in the intra-amniotic host response of women with spontaneous preterm labor (sPTL) and birth. Amniotic fluid and chorioamniotic membranes (CAM) were collected from women with sPTL who delivered at term (n = 30) or preterm without intra-amniotic inflammation (n = 34), with sterile intra-amniotic inflammation (SIAI, n = 27), or with intra-amniotic infection (IAI, n = 17). Amnion epithelial cells (AEC), Ureaplasma parvum , and Sneathia spp. were also utilized. The expression of TSLP, TSLPR, and IL-7Rα was evaluated in amniotic fluid or CAM by RT-qPCR and/or immunoassays. AEC co-cultured with Ureaplasma parvum or Sneathia spp. were evaluated for TSLP expression by immunofluorescence and/or RT-qPCR. Our data show that TSLP was elevated in amniotic fluid of women with SIAI or IAI and expressed by the CAM. TSLPR and IL-7Rα had detectable gene and protein expression in the CAM; yet, CRLF2 was specifically elevated with IAI. While TSLP localized to all layers of the CAM and increased with SIAI or IAI, TSLPR and IL-7Rα were minimal and became most apparent with IAI. Co-culture experiments indicated that Ureaplasma parvum and Sneathia spp. differentially upregulated TSLP expression in AEC. Together, these findings indicate that TSLP is a central component of the intra-amniotic host response during sPTL. [ABSTRACT FROM AUTHOR]

The role of type 2 inflammation has been progressively associated with many diseases, including severe asthma, atopic dermatitis, nasal polyposis, eosinophilic granulomatosis with polyangiitis, and, recently, eosinophilic esophagitis. Despite this, the association between asthma and esophagitis is still poorly known, and this is probably because of the low prevalence of each disease and the even lower association between them. Nonetheless, observations in clinical trials and, subsequently, in real life, have allowed researchers to observe how drugs acting on type 2 inflammation, initially developed and marketed for severe asthma, could be effective also in treating eosinophilic esophagitis. For this reason, clinical trials specifically designed for the use of drugs targeted to type 2 inflammation were also developed for eosinophilic esophagitis. The results of clinical trials are presently promising and envisage the use of biologicals that are also likely to be employed in the field of gastroenterology in the near future. This review focuses on the use of biologicals for type 2 inflammation in cases of combined severe asthma and eosinophilic esophagitis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a common skin disease caused by genetic susceptibility, environmental factors, immune response, and skin barrier dysfunction. Kaempferol is a natural flavonoid widely found in tea, vegetables, and fruits and has been reported to have excellent anti-inflammation activity. However, the therapeutic effect of kaempferol on atopic dermatitis is unclear. This study aimed to elucidate the effect of kaempferol on skin inflammation in atopic dermatitis. The suppressive effect of kaempferol administration on skin inflammation was examined using MC903-induced atopic dermatitis-like skin inflammation mouse model. Quantification of skin dermatitis and transepidermal water loss was performed. A histopathological study was performed to examine thymic stromal lymphopoietin expression, cornified envelope proteins such as filaggrin, loricrin, and involucrin, and the numbers of infiltrating inflammatory cells, including lymphocytes, macrophages, and mast cells in the dermatitis area. The expressions of IL-4 and IL-13 were investigated by qPCR and flow cytometry analysis using skin tissues. The expression of HO-1 was investigated by western blot and qPCR. Kaempferol therapy significantly suppressed MC903-induced dermatitis, TEWL, TSLP, and HO-1 expression, and infiltration of inflammatory cells. Kaempferol therapy improved the decreased expressions of filaggrin, loricrin, and involucrin in MC903-induced dermatitis skin site. The expressions of IL-4, and IL-13 were partially decreased in kaempferol-treated mice. Kaempferol might improve MC903-induced dermatitis via suppression of type 2 inflammation and improvement of barrier dysfunction by inhibition of TSLP expression and oxidative stress. Kaempferol might have the potential to be a new treatment for atopic dermatitis. • Kaempferol improved AD-like dermatitis in mouse. • Kaempferol inhibited TSLP expression in AD mouse model. • Kaempferol inhibited oxidative stress in AD mouse model. • Kaempferol suppressed type 2 inflammation in AD mouse model. [ABSTRACT FROM AUTHOR]

The epithelium-associated cytokine thymic stromal lymphopoietin (TSLP) can induce OX40L and CCL17 expression by myeloid dendritic cells (mDCs), which contributes to aberrant Th2-type immune responses. Herein, we report that such TSLP-induced Th2-type immune response can be effectively controlled by Dectin-1, a C-type lectin receptor expressed by mDCs. Dectin-1 stimulation induced STAT3 activation and decreased the transcriptional activity of p50-RelB, both of which resulted in reduced OX40L expression on TSLP-activated mDCs. Dectin-1 stimulation also suppressed TSLP-induced STAT6 activation, resulting in decreased expression of the Th2 chemoattractant CCL17. We further demonstrated that Dectin-1 activation was capable of suppressing ragweed allergen (Amb a 1)-specific Th2-type T cell response in allergy patients ex vivo and house dust mite allergen (Der p 1)-specific IgE response in non-human primates in vivo. Collectively, this study provides a molecular explanation of Dectin-1-mediated suppression of Th2-type inflammatory responses and suggests Dectin-1 as a target for controlling Th2-type inflammation.