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• Interleukin (IL)−1α suppresses transforming growth factor (TGF)-β1/-β2-induced extracellular matrix production, remodeling and myofibroblast differentiation in healthy lung fibroblasts. • No differences in the response of healthy lung fibroblasts to TGF-β1 or TGF-β2 treatments, or their inhibition by IL-1α in healthy lung fibroblasts. • IL-1α regulates TGF-β signaling through the down regulation of TGF-β receptor II and tumour necrosis factor receptor associated factor-6. • TGF-β1/-β2 are unable to inhibit IL-1α-induced IL-6, IL-8 and thymic stromal lymphopoietin release by healthy lung fibroblasts. Lung fibroblasts play a central role in maintaining lung homeostasis and facilitating repair through the synthesis and organization of the extracellular matrix (ECM). This study investigated the cross-talk between interleukin-1 alpha (IL-1α) and transforming growth factor-β (TGF-β) signaling, two key regulators in tissue repair and fibrosis, in the context of lung fibroblast repair in the healthy lung. Stimulation of lung fibroblasts with TGF-β1 and TGF-β2 induced collagen-I and fibronectin protein expression (p < 0.05), a response inhibited with co-treatment with IL-1α (p < 0.05). Additionally, TGF-β1 and TGF-β2 induced myofibroblast differentiation, and collagen-I gel contraction, which were both suppressed by IL-1α (p < 0.05). In contrast, interleukin (IL)-6, IL-8 and thymic stromal lymphopoietin induced by IL-1α, were unaffected by TGF-β1 or TGF-β2. Mechanistically, IL-1α administration led to the suppression of TGF-β1 and TGF-β2 signaling, through downregulation of mRNA and protein for TGF-β receptor II and the downstream adaptor protein TRAF6, but not through miR-146a that is known to be induced by IL-1α. IL-1α acts as a master regulator, modulating TGF-β1 and TGF-β2-induced ECM production, remodeling, and myofibroblast differentiation in human lung fibroblasts, playing a vital role in balancing tissue repair versus fibrosis. Further research is required to understand the dysregulated cross-talk between IL-1α and TGF-β signaling in chronic lung diseases and the exploration of therapeutic opportunities. Primary human lung fibroblasts (PHLF) were treated with media control, or 1 ng/ml IL-1α with or without 50 ng/ml TGF-β1 or TGF-β2 for 1, 6 and 72 h. Cell lysates were assessed for the expression of ECM proteins and signaling molecules by western blot, miRNA by qPCR, mRNA by RNA sequencing and cell supernatants for cytokine production by ELISA. PHLFs were also seeded in non-tethered collagen-I gels to measure contraction, and myofibroblast differentiation using confocal microscopy. [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]

The prevalence of fragrances in various hygiene products contributes to their sensorial allure. However, fragrances can induce sensitization in the skin or respiratory system, and the mechanisms involved in this process are incompletely understood. This study investigated the intricate mechanisms underlying the fragrance's effects on sensitization response, focusing on the interplay between CYP450 enzymes, a class of drug‐metabolizing enzymes, and the adaptive immune system. Specifically, we assessed the expression of CYP450 enzymes and cytokine profiles in culture of BEAS‐2B and mature dendritic cells (mDC) alone or in co‐culture stimulated with 2 mM of a common fragrance, cinnamyl alcohol (CA) for 20 h. CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2A13 were analyzed by RT‐PCR and IL‐10, IL‐12p70, IL‐18, IL‐33, and thymic stromal lymphopoietin (TSLP) by Cytometric Bead Array (CBA). Through RT–PCR analysis, we observed that CA increased CYP1A2 and CYP1B1 expression in BEAS‐2B, with a further increased in BEAS‐2B‐mDC co‐culture. Additionally, exposure to CA increased IL‐12p70 levels in mDC rather than in BEAS‐2B‐mDC co‐culture. In regards to IL‐18, level was higher in BEAS‐2B than in BEAS‐2B‐mDC co‐culture. A positive correlation between the levels of IL‐10 and CYP1B1 was found in mDC‐CA‐exposed and between IL‐12p70 and CYP1A1 was found in BEAS‐2B after CA exposure. However, IL‐12p70 and CYP1A2 as well as IL‐18, IL‐33, and CYP1A1 levels were negative, correlated mainly in co‐culture control. These correlations highlight potential immunomodulatory interactions and complex regulatory relationships. Overall, exposure to CA enhances CYP450 expression, suggesting that CA can influence immune responses by degrading ligands on xenosensitive transcription factors. This study investigated mechanisms underlying the fragrance's effects on sensitization response through CYP450 enzymes and immune system. We quantified CYP450 enzymes and cytokines in BEAS‐2B and mature dendritic cells (mDC) alone or in co‐culture stimulated with 2 mM of cinnamyl alcohol (CA) for 20 h. Positive correlations between IL‐10 and CYP1B1 in mDC‐CA‐exposed and IL‐12p70 and CYP1A1 in BEAS‐2B‐CA‐exposed were found. These correlations highlight potential immunomodulatory interactions and regulatory relationships, suggesting that CA could influence immune responses by degrading ligands on xenosensitive transcription factors. [ABSTRACT FROM AUTHOR]

This article examines the relationship between preoperative nasal mucus thymic stromal lymphopoietin (TSLP) and the impact on quality of life in chronic rhinosinusitis with nasal polyps (CRSwNP). The study reveals that CRSwNP patients have elevated TSLP levels in their nasal mucus, which is associated with a lower quality of life and treatment resistance. The findings suggest that measuring TSLP levels in nasal mucus could be a useful noninvasive method for predicting the severity and treatment response of CRSwNP. However, further research is needed to validate these findings and explore the role of TSLP in CRSwNP. The document also includes references to three scientific articles that provide additional insights into the topic of rhinosinusitis and nasal polyps. [Extracted from the article]

TAVO101 is a humanized anti‐human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half‐life extension and attenuated effector functions. This Phase 1, double‐blinded, randomized, placebo‐controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195‐day follow‐up. TAVO101 was safe and well tolerated. The incidences and severities of treatment‐emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment‐related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half‐life of 67 days in healthy subjects. All TAVO101‐treated subjects tested negative for anti‐drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone‐induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long‐acting anti‐TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients. [ABSTRACT FROM AUTHOR]

A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-β (TGF-β)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging. [ABSTRACT FROM AUTHOR]

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]

The mechanisms underlying the development of steroid resistance in asthma remain unclear. To establish whether as well as the mechanisms by which the activation of Janus kinases (JAKs) is involved in the development of steroid resistance in asthma, murine steroid‐resistant models of the proliferation of group 2 innate lymphoid cells (ILC2s) in vitro and asthmatic airway inflammation in vivo were analysed. ILC2s in the lungs of BALB/c mice were sorted and then incubated with IL‐33, thymic stromal lymphopoietin (TSLP), and/or IL‐7 with or without dexamethasone (10 nM), the pan‐JAK inhibitor, delgocitinib (1–10 000 nM), and/or the Bcl‐xL inhibitor, navitoclax (1–100 nM), followed by the detection of viable and apoptotic cells. The anti‐apoptotic factor, Bcl‐xL was detected in ILC2s by flow cytometry. As a steroid‐resistant asthma model, ovalbumin (OVA)‐sensitized BALB/c mice were intratracheally challenged with OVA at a high dose of 500 μg four times. Dexamethasone (1 mg/kg, i.p.), delgocitinib (3–30 mg/kg, p.o.), or navitoclax (30 mg/kg, p.o.) was administered during the challenges. Cellular infiltration into the lungs was analysed by flow cytometry. Airway remodelling was histologically evaluated. The following results were obtained. (1) Cell proliferation concomitant with a decrease in apoptotic cells was induced when ILC2s were cultured with TSLP and/or IL‐7, and was potently inhibited by dexamethasone. In contrast, when the culture with TSLP and IL‐7 was performed in the presence of IL‐33, the proliferative response exhibited steroid resistance. Steroid‐resistant ILC2 proliferation was suppressed by delgocitinib in a concentration‐dependent manner. (2) The culture with IL‐33, TSLP, and IL‐7 induced the overexpression of Bcl‐xL, which was clearly inhibited by delgocitinib, but not by dexamethasone. When ILC2s were treated with navitoclax, insensitivity to dexamethasone was significantly cancelled. (3) The development of airway remodelling and the infiltration of ILC2s into the lungs in the asthma model were not suppressed by dexamethasone, but were dose‐dependently inhibited by delgocitinib. Combination treatment with dexamethasone and either delgocitinib or navitoclax synergistically suppressed these responses. Therefore, JAKs appear to play significant roles in the induction of steroid resistance by up‐regulating Bcl‐xL in ILC2s. The inhibition of JAKs and Bcl‐xL has potential as pharmacotherapy for steroid‐resistant asthma, particularly that mediated by ILC2s. [ABSTRACT FROM AUTHOR]

Introduction: Thymic stromal lymphopoietin (TSLP) is integral to inducing innate and T helper two cell inflammation that leads to clinical symptoms of asthma. SHR-1905 is a humanized immunoglobulin G1 kappa monoclonal antibody that inhibits TSLP bioactivity, developed for the treatment of severe uncontrolled asthma. This phase 1, randomized, double-blind, placebocontrolled single ascending dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous SHR-1905 in healthy subjects. Methods: Five dose cohorts were planned (50, 100, 200, 400, and 600 mg) and subjects were randomized (8:2) in each cohort to receive SHR-1905 or placebo with a follow-up period up to Day 253. Results: The majority of treatment-emergent adverse events (TEAEs) were mild and the incidence of TEAEs was comparable between the SHR-1905 and the placebo groups. The maximum serum concentration was reached 7.0-17.6 days after injection. The serum concentration of SHR-1905 increased with increasing dose level, and SHR-1905 exposure exhibited in a slightly greater-than-dose-proportional manner from 50 to 600 mg. SHR-1905 had a prolonged serum half-life around 80 days supporting every 6-month dosing. In SHR-1905 treated subjects, 15% tested positive for anti-drug antibodies post-dose with no apparent effect on corresponding PK profiles or safety. Conclusion: SHR-1905 demonstrated a good safety and tolerability profile with a long half-life in healthy subjects after a single administration in the dose range of 50-600 mg. [ABSTRACT FROM AUTHOR]

This article explores the effectiveness of tezepelumab, a monoclonal antibody, in treating non-type 2 (T2) asthma patients. Tezepelumab targets a biomarker called thymic stromal lymphopoietin (TSLP) that is involved in the non-T2 asthma pathway. Previous research has shown that tezepelumab can improve lung function, asthma control, and quality of life in uncontrolled asthma patients with low baseline blood eosinophil counts. This case series, following the Global Initiative for Asthma (GINA) guideline, provides further evidence of the positive effects of tezepelumab in non-T2 asthma patients, demonstrating improvements in lung function, asthma control, and quality of life. The document also includes a list of references related to TSLP and its interaction with the epithelium in allergy and asthma, as well as studies on the efficacy and safety of tezepelumab in treating uncontrolled asthma. Additionally, it provides a link to the Global Initiative for Asthma (GINA) main report for 2023. [Extracted from the article]

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]

Objectives To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods Using serum collected at enrolment, three alarmins (IL-33, thymic stromal lymphopoietin [TSLP] and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score and anti-cyclic citrullinated antibody positivity. Results Of 2835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (hazard ratio [HR] 0.73 per log-fold increase; 95% CI: 0.57, 0.95; P  = 0.018) and adjusted (HR 0.77; 95% CI: 0.59, 1.00; P  = 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed. Conclusion In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA. [ABSTRACT FROM AUTHOR]

The article explores the potential of vinpocetine, a phosphodiesterase 1 inhibitor, in treating atopic dermatitis (AD). The study used a mouse model of AD and found that vinpocetine improved symptoms such as skin inflammation and barrier function. It also reduced the infiltration of inflammatory cells and levels of certain cytokines in the skin. The findings suggest that vinpocetine could be a promising therapeutic option for AD, but further research is needed to understand its mechanisms and long-term effects. The research was supported by the Chung-Ang University Research Scholarship Grants in 2022. [Extracted from the article]

Anti-interleukin (IL) 5 is an effective treatment modality for inhibiting eosinophilic inflammation in patients with T2-high severe asthma. The aim of this study was to determine the clinical efficacy and serum levels of type 2 inflammatory mediators during 24 weeks of mepolizumab treatment in patients with T2-high severe asthma. Eighteen patients with T2-high severe asthma were enrolled in this study. All patients received 100 mg of mepolizumab subcutaneously every 4 weeks and were retested at 4, 12, and 24 weeks. A clinical examination, asthma control test (ACT), and spirometry were performed; fractional exhaled nitric oxide (FeNO) levels were evaluated; and blood samples were drawn at every visit. Type 2 inflammation mediator levels were measured using enzyme-linked immunosorbent assay (ELISA). The blood eosinophil level significantly decreased, the ACT score and FEV1 increased after 4 weeks of mepolizumab treatment with the same tendency after 12 and 24 weeks (p < 0.05), and the FeNO level did not change (p > 0.05). A total of 27.8% of patients reached clinical remission criteria after 24 weeks of mepolizumab treatment. IL-33 and eotaxin significantly increased (p < 0.05) while IL-5, IL-13, thymic stromal lymphopoietin (TSLP), soluble IL-5 receptor subunit alpha (sIL-5Rα), and soluble high-affinity immunoglobulin E receptor (sFcεRI) decreased, with the same tendency after 12 and 24 weeks (p < 0.05). The serum levels of immunoglobulin (Ig) E and IL-4 and IL-25 levels did not change during mepolizumab treatment compared to baseline (p > 0.05). In conclusion, treatment with mepolizumab over 24 weeks improved lung function and asthma control in T2-high severe asthma patients, with nearly one-third achieving clinical remission criteria, and affected the balance of type 2 inflammatory mediators. [ABSTRACT FROM AUTHOR]

Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse‐like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll‐like receptors and protease‐activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro‐inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders. [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]

Background: Ozone is one of the triggers of asthma, but its impact on the pathophysiology of asthma, such as via airway inflammation and airway hyperresponsiveness (AHR), is not fully understood. Thymic stromal lymphopoietin (TSLP) is increasingly seen as a crucial molecule associated with asthma severity, such as corticosteroid resistance. Methods: Female BALB/c mice sensitized and challenged with house dust mite (HDM) were exposed to ozone at 2 ppm for 3 h. Airway inflammation was assessed by the presence of inflammatory cells in bronchoalveolar lavage fluid and concentrations of cytokines including TSLP in lung. Anti-TSLP antibody was administered to mice to block the signal. Survival and adhesion of bone marrow-derived eosinophils in response to granulocyte colony-stimulating factor (G-CSF) were evaluated. Results: Ozone exposure increased eosinophilic airway inflammation and AHR in mice sensitized and challenged with HDM. In addition, TSLP, but not IL-33 and IL-25, was increased in lung by ozone exposure. To confirm whether TSLP signaling is associated with airway responses to ozone, an anti-TSLP antibody was administered, and it significantly attenuated eosinophilic airway inflammation, but not AHR. Interestingly, G-CSF, but not type 2 cytokines such as IL-4, IL-5, and IL-13, was regulated by TSLP signaling associated with eosinophilic airway inflammation, and G-CSF prolonged survival and activated eosinophil adhesion. Conclusions: The present data show that TSLP contributes to ozone-induced exacerbations of eosinophilic airway inflammation and provide greater understanding of ozone-induced severity mechanisms in the pathophysiology of asthma related to TSLP and G-CSF.

• 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]

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]

Background: No studies have investigated the systemic and local sinonasal profile of obesity‐related chronic rhinosinusitis (CRS), despite its observed association in recent retrospective studies. The objectives of our study were to assess the impact of obesity on the clinical and cytokine profile of patients with CRS and evaluate treatment response with functional endoscopic sinus surgery. Methods: This was a prospective observational study at the Cleveland Clinic that included patients with CRS (n = 54) between December 2021 and September 2022. Data collection included demographics, body mass index (BMI), comorbidities, baseline sinonasal outcome test scores, baseline radiologic scores (Lund–Mackay), postoperative sinonasal outcome test scores (at 3–4 months), and local and systemic alarmins/T‐helper cytokines. Results: Out of the 54 CRS patients, there were 20 CRS patients without nasal polyps (37%) and 34 with nasal polyps (63%). Patients were categorized based on obesity (BMI ≥ 30 kg/m2). Obese CRS patients had lower systemic alarmins (interleukin [IL]‐33 and Thymic stromal lymphopoietin (TSLP)) compared to non‐obese CRS patients (IL‐33: 744.2 ± 1164.6 pg/mL vs. 137.5 ± 320.0 pg/mL, p = 0.005; TSLP: 627.7 ± 1806.3 pg/mL vs. 28.1 ± 85.4 pg/mL, p = 0.017). CRS patients with nasal polyps with BMI ≥30 kg/m2 had higher postoperative sinonasal outcome test scores and lower levels of nasal eotaxin‐3 and IL‐33 compared to BMI <30 kg/m2 counterparts. Conclusions: In conclusion, patients with obese CRS and nasal polyps displayed diminished levels of intranasal alarmins and reduced intranasal eotaxin‐3. These results potentially imply the presence of a unique, obese type 2‐low CRS phenotype that warrants further exploration. [ABSTRACT FROM AUTHOR]

Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)‐13, two key mediators of asthma pathophysiology. In this first‐in‐human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10–400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment‐emergent adverse events were COVID‐19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose‐proportional increases in exposure and linear elimination. Mean t1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL‐13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity. [ABSTRACT FROM AUTHOR]

Eczema (atopic dermatitis, AD) is a skin disease characterized by skin barrier dysfunction due to various factors, including genetics, immune system abnormalities, and environmental triggers. Application of emollients and topical drugs such as corticosteroids and calcineurin inhibitors form the mainstay of treatments for this challenging condition. This review aims to summarize the recent advances made in phytochemical-based topical applications to treat AD and the different carriers that are being used. In this review, the clinical efficacy of several plant extracts and bioactive phytochemical compounds in treating AD are discussed. The anti-atopic effects of the herbs are evident through improvements in the Scoring Atopic Dermatitis (SCORAD) index, reduced epidermal thickness, decreased transepidermal water loss, and alleviated itching and dryness in individuals affected by AD as well as in AD mouse models. Histopathological studies and serum analyses conducted in AD mouse models demonstrated a reduction in key inflammatory factors, including thymic stromal lymphopoietin (TSLP), serum immunoglobulin E (IgE), and interleukins (IL). Additionally, there was an observed upregulation of the filaggrin (FLG) gene, which regulates the proteins constituting the stratum corneum, the outermost layer of the epidermis. Carriers play a crucial role in topical drug applications, influencing dose delivery, retention, and bioavailability. This discussion delves into the efficacy of various nanocarriers, including liposomes, ethosomes, nanoemulsions, micelles, nanocrystals, solid-lipid nanoparticles, and polymeric nanoparticles. Consequently, the potential long-term side effects such as atrophy, eruptions, lymphoma, pain, and allergic reactions that are associated with current topical treatments, including emollients, topical corticosteroids, topical calcineurin inhibitors, and crisaborole, can potentially be mitigated through the use of phytochemical-based natural topical treatments. [ABSTRACT FROM AUTHOR]

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]

Asthma is a heterogeneous disease commonly driven by allergic and/or eosinophilic inflammation, both of which may be present in severe disease. Most approved biologics for severe asthma are indicated for specific phenotypes and target individual downstream type 2 components of the inflammatory cascade. Tezepelumab, a human monoclonal antibody (immunoglobulin G2λ), binds specifically to thymic stromal lymphopoietin (TSLP), an epithelial cytokine that initiates and sustains allergic and eosinophilic inflammation in asthma. By blocking TSLP, tezepelumab has demonstrated efficacy across known asthma phenotypes and acts upstream of all current clinically used biomarkers. In a pooled analysis of the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies, compared with placebo, tezepelumab reduced the annualized asthma exacerbation rate over 52 weeks by 62% (95% confidence interval [CI]: 53, 70) in patients with perennial aeroallergen sensitization (allergic asthma); by 71% (95% CI: 62, 78) in patients with a baseline blood eosinophil count ≥300 cells/μL; and by 71% (95% CI: 59, 79) in patients with allergic asthma and a baseline blood eosinophil count ≥300 cells/μL. This review examines the efficacy and mode of action of tezepelumab in patients with allergic asthma, eosinophilic asthma and coexisting allergic and eosinophilic phenotypes. [ABSTRACT FROM AUTHOR]

Background: Pruritus is a highly burdensome symptom in patients with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa (RDEB); however, only a few studies have assessed the molecular pathogenesis of RDEB-associated pruritus. Interleukin (IL)-31 is a key cytokine implicated in pruritus associated with dermatologic diseases such as atopic dermatitis and prurigo nodularis. Objective: To investigate the role and cellular source of IL-31 in RDEB-associated pruritus. Methods: Serum and skin samples were obtained from 11 RDEB patients and 11 healthy controls. Pruritus visual analogue scale scores were determined. Serum levels of IL-31 and thymic stromal lymphopoietin (TSLP) were examined by enzymelinked immunosorbent assay (ELISA). The expression of IL-31 and other pruritus mediators in the skin were examined through immunofluorescence staining, and their correlation with pruritus severity was analysed. Results: Serum IL-31 and TSLP were elevated in RDEB patients. IL-31 expression was increased in RDEB skin and positively correlated with pruritus severity. Most of the IL-31-expressing cells were mast cells, and some were CD206(+) M2-like macrophages. The number of substance P(+) cells was also increased in the patients' skin, and most of them were mast cells. The number of substance P(+) mast cells was correlated with the number of IL-31(+) dermal infiltrates. The number of IL-4Rα-and IL-13-expressing cells and expression of TSLP and periostin increased in RDEB skin, but without a correlation to pruritus score. Conclusion: The increased production of skin IL-31 from mast cells and M2-like macrophages may be the mechanism underlying pruritus in RDEB. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory skin disease that has no cure. While the specific cause of psoriasis is unknown, interactions between immune cells and inflammatory cytokines are believed to be important in its pathogenesis. Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that profoundly affects dendritic cells (DCs) and is involved in allergy and inflammatory diseases. In some studies, its expression is higher in the skin of psoriasis patients, whereas it is increased in treated psoriasis patients when compared with untreated patients in others. Aims: To investigate the role of TSLP in the pathogenesis of psoriasis. Study Design: In vitro and in vivo study. Methods: To investigate the effect of TSLP on psoriasis in vivo, a mouse psoriasis model and shRNA targeting TSLP to reduce its expression were used. Mouse primary bone marrow dendritic cells (BMDCs) were cultured in vitro and used to investigate the signaling pathways activated by TSLP. Results: We found that reducing TSLP expression in psoriasis skin alleviated disease severity. TSLP activated the Janus kinase (JAK)/SYK pathway in psoriatic skin. In vitro studies with BMDCs demonstrated that TSLP increased DC maturation through the JAK/SYK pathway and activated DCs-secreted cytokines that stimulated CD4+ T cells to develop into T helper 17 (Th17) cells by activating STAT3 signaling. The JAK/SYK pathway inhibitor reduced the effect of TSLP on activating BMDCs and promoting Th17 differentiation by CD4+ T cells. Conclusion: These findings indicated that TSLP exerted its immunemodulating effect in psoriasis through the JAK/SYK pathway. [ABSTRACT FROM AUTHOR]

Glucocorticoids are widely used in the treatment of allergic and inflammatory diseases. Glucocorticoids have a widespread action on gene expression resulting in their pharmacological actions and also an array of adverse effects which limit their clinical use. It remains, however, to be studied which target gene effects are essential for the anti-allergic activity of glucocorticoids. Mitogenactivated protein kinase phosphatase-1 (MKP-1) inhibits proinflammatory signalling by suppressing the activity of mitogen activated protein kinase (MAP kinase) pathways. MKP-1 is one of the anti-inflammatory genes whose expression is enhanced by glucocorticoids. In the present study, we aimed to investigate the role of MKP-1 in the therapeutic effects of the glucocorticoid dexamethasone in acute allergic reaction. The effects of dexamethasone were studied in wild-type and MKP-1 deficient mice. The mice were first sensitized to ovalbumin, and the allergic reaction was then induced by a subcutaneous ovalbumin injection in the hind paw. Inflammatory edema was quantified with plethysmometer and expression of inflammatory factors was measured by quantitative reverse transcription polymerase chain reaction (RT-PCR). Dexamethasone reduced the ovalbumin-induced paw edema at 1.5, 3 and 6 h time points in wild-type mice by 70%, 95% and 89%, respectively. The effect was largely abolished in MKP-1 deficient mice. Furthermore, dexamethasone significantly attenuated the expression of ovalbumin-induced inflammatory factors cyclooxygenase-2 (COX-2); inducible nitric oxide synthase (iNOS); interleukins (IL) 1β, 6 and 13; C-C motif chemokine 11 (CCL-11); tumour necrosis factor (TNF) and thymic stromal lymphopoietin (TSLP) in wild-type mice by more than 40%. In contrast, in MKP-1 deficient mice dexamethasone had no effect or even enhanced the expression of these inflammatory factors. The results suggest that dexamethasone alleviates allergic inflammation through an MKP-1-dependent mechanism. The results also demonstrate MKP-1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin-induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP-1 enhancing compounds as potential novel anti-inflammatory and anti-allergic drugs. [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]

Our previous study demonstrated that our novel herbal remedy, a mixture of Asarum sieboldii, Platycodon grandiflorum, and Cinnamomum Cassia extracts, exhibits a therapeutic effect in 1-chloro-2,4-dinitrobenzene (DNCB)-induced mice by inhibiting the Th-2 inflammatory response upon oral administration. It also ameliorated imbalances in lipid metabolism related to the skin barrier function in keratinocytes, indicating its potential as a topical agent. This study aims to further investigate the therapeutic effects and metabolic mechanisms of its topical application. The anti-atopic effect was evaluated using dermatitis scores, histopathological analysis, and immune cell factors in DNCB-induced mice. Metabolomic profiling of serum and lesional skin was conducted to elucidate the metabolic mechanisms. The topical application significantly reduced dermatitis scores, mast cell infiltration, and serum levels of immunoglobulin E (IgE), IFN-γ, interleukin (IL)-4, IL-17, and thymic stromal lymphopoietin (TSLP), demonstrating its effectiveness in treating atopic dermatitis (AD). Serum metabolomics revealed alterations in fatty acid metabolism related to the pro-inflammatory response. In lesional skin, metabolic markers associated with oxidative stress, immune regulation, and AD symptoms were restored. This study demonstrated its potential as a topical agent in suppressing Th-2 inflammatory responses and improving metabolic abnormalities related to AD symptoms, providing crucial insights for developing natural AD treatments. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/μL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies. [ABSTRACT FROM AUTHOR]

Disruption of the airway epithelium triggers a defensive immune response that begins with the production and release of alarmin cytokines. These epithelial-derived alarmin cytokines, including thymic stromal lymphopoietin (TSLP), are produced in response to aeroallergens, viruses, and toxic inhalants. An alarmin response disproportionate to the inhaled trigger can exacerbate airway diseases such as asthma. Allergens inhaled into previously sensitized airways are known to drive a T2 inflammatory response through the polarization of T cells by dendritic cells mediated by TSLP. Harmful compounds found within air pollution, microbes, and viruses are also triggers causing airway epithelial cell release of TSLP in asthmatic airways. The release of TSLP leads to the development of inflammation which, when unchecked, can result in asthma exacerbations. Genetic and inheritable factors can contribute to the variable expression of TSLP and the risk and severity of asthma. This paper will review the various triggers and consequences of TSLP release in asthmatic airways. [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]

Ozone is one of the triggers of asthma, but its impact on the pathophysiology of asthma, such as via airway inflammation and airway hyperresponsiveness (AHR), is not fully understood. Thymic stromal lymphopoietin (TSLP) is increasingly seen as a crucial molecule associated with asthma severity, such as corticosteroid resistance. Female BALB/c mice sensitized and challenged with house dust mite (HDM) were exposed to ozone at 2 ppm for 3 h. Airway inflammation was assessed by the presence of inflammatory cells in bronchoalveolar lavage fluid and concentrations of cytokines including TSLP in lung. Anti-TSLP antibody was administered to mice to block the signal. Survival and adhesion of bone marrow-derived eosinophils in response to granulocyte colony-stimulating factor (G-CSF) were evaluated. Ozone exposure increased eosinophilic airway inflammation and AHR in mice sensitized and challenged with HDM. In addition, TSLP, but not IL-33 and IL-25, was increased in lung by ozone exposure. To confirm whether TSLP signaling is associated with airway responses to ozone, an anti-TSLP antibody was administered, and it significantly attenuated eosinophilic airway inflammation, but not AHR. Interestingly, G-CSF, but not type 2 cytokines such as IL-4, IL-5, and IL-13, was regulated by TSLP signaling associated with eosinophilic airway inflammation, and G-CSF prolonged survival and activated eosinophil adhesion. The present data show that TSLP contributes to ozone-induced exacerbations of eosinophilic airway inflammation and provide greater understanding of ozone-induced severity mechanisms in the pathophysiology of asthma related to TSLP and G-CSF. [ABSTRACT FROM AUTHOR]

This article discusses a study conducted on teenagers from the PARIS birth cohort to assess the association between basal serum tryptase (bST) levels and various allergy-related outcomes. The study found that higher bST levels were associated with sensitization, allergic morbidity, and lower control of allergic asthma. The results suggest that bST levels could be a potential tool for predicting and stratifying allergic phenotypes in early life. The study provides valuable insights into the relationship between bST levels and allergies in teenagers. [Extracted from the article]

This article discusses a case report of a 35-year-old woman with a history of atopic dermatitis and asthma who experienced outbreaks of facial and neck eczematous reactions. The patient had positive reactions to a luxury antioxidant serum product containing phloretin, a natural dihydrochalcone found in apple trees and other plants. After discontinuing the use of the cosmetic product, it took several weeks for the eczematous lesions to heal. The article highlights the importance of recognizing the potential for sensitization and allergic contact dermatitis caused by substances of plant origin in cosmetics, and suggests that simpler formulas with fewer ingredients may be more suitable for vulnerable patients with disrupted barrier skin function. [Extracted from the article]

Exercise-induced bronchoconstriction (EIB) is a common condition in athletes, both with and without asthma. It involves the narrowing of the airways during intense exercise and is prevalent among elite athletes. Identifying and monitoring EIB is crucial for determining the best treatment. Inhaled corticosteroids (ICS) can effectively control EIB when taken daily for at least three months. Achieving remission in athletes with severe asthma through targeted treatments that inhibit eosinophils and mast cells is discussed, with the loss of airway hyperresponsiveness to mannitol proposed as a marker for documenting remission. Preventing and managing EIB in athletes, especially during the Olympics, is emphasized, and the use of inhaled corticosteroids is suggested as a potential treatment to reduce the risk of EIB. [Extracted from the article]

This letter discusses a study that investigated the associations between thymic stromal lymphopoietin (TSLP) signaling, mast cells, and airway obstruction in active smokers. The study used lung tissue transcriptomics and clinical data from 213 active smokers to analyze the levels of TSLP and CRLF2 transcripts in relation to clinical features and predicted immune cell signatures. The results showed that high levels of CRLF2 transcripts were associated with lower lung function in female subjects, and both male and female subjects with high CRLF2 transcript levels had fewer M2 macrophages and more activated mast cells and neutrophils. The study suggests that further investigation is needed to understand the mechanistic link between COPD progression, TSLP signaling, and activated mast cell abundance in smokers. [Extracted from the article]

Thymic stromal lymphopoietin is a key cytokine involved in the pathogenesis of asthma and other allergic diseases. Targeting TSLP and its signaling pathways is increasingly recognized as an effective strategy for asthma treatment. This study focused on enhancing the affinity of the T6 antibody, which specifically targets TSLP, by integrating computational and experimental methods. The initial affinity of the T6 antibody for TSLP was lower than the benchmark antibody AMG157. To improve this, we utilized alanine scanning, molecular docking, and computational tools including mCSM-PPI2 and GEO-PPI to identify critical amino acid residues for site-directed mutagenesis. Subsequent mutations and experimental validations resulted in an antibody with significantly enhanced blocking capacity against TSLP. Our findings demonstrate the potential of computer-assisted techniques in expediting antibody affinity maturation, thereby reducing both the time and cost of experiments. The integration of computational methods with experimental approaches holds great promise for the development of targeted therapeutic antibodies for TSLP-related diseases. Author summary: Computer-assisted affinity maturation significantly reduces experimental time and lowers research costs. Targeting thymic stromal lymphopoietin and its signaling pathways with specific antibody drugs is widely recognized as an effective strategy for treating asthma. In our study, we successfully identified a TSLP-targeting antibody from the fully synthetic human phage antibody libraries. We integrated computer-assisted methods to enhance the antibody's affinity. These techniques enabled efficient prediction of critical amino acid residues, guiding targeted mutagenesis experiments. By combining computer-assisted approaches with experimental methods, we have successfully developed a mature method for enhancing antibody affinity. Through this research, we have obtained an antibody with high affinity for TSLP, providing a new avenue for treating asthma and other TSLP-related diseases. The computer-assisted affinity maturation strategy brings hope for speeding up the drug development process. [ABSTRACT FROM AUTHOR]

Objectives: Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs. Methods: Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model. Results: IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse. Conclusions: This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy. [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]

Allergic conjunctivitis is one of the common immune hypersensitivity disorders that affect the ocular system. The clinical manifestations of this condition exhibit variability contingent upon environmental factors, seasonal dynamics, and genetic predisposition. While our comprehension of the pathophysiological engagement of immune and nonimmune cells in the conjunctiva has progressed, the same cannot be asserted for the cytokines mediating this inflammatory cascade. In this review, we proffer a comprehensive description of interleukins 4 (IL-4), IL-5, IL-6, IL-9, IL-13, IL-25, IL-31, and IL-33, as well as thymic stromal lymphopoietin (TSLP), elucidating their pathophysiological roles in mediating the allergic immune responses on the ocular surface. Delving into the nuanced functions of these cytokines holds promise for the exploration of innovative therapeutic modalities aimed at managing allergic conjunctivitis. [ABSTRACT FROM AUTHOR]

Background: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti‐TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known. Aim: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNβ, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge. Methods: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2‐ and pro‐inflammatory cytokines, IFNβ IFNλ, and viral load were analyzed by RT‐qPCR and multiplex ELISA before and after stimulation. Results: IL‐33 expression in unstimulated BECs and IL‐33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL‐33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)‐induced IL‐4, IL‐13, and IL‐17A release from BECs was also reduced with tezepelumab whereas IFNβ and IFNλ expression and viral load were unchanged. Conclusion: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL‐33 and T2 cytokines to viral challenge without affecting anti‐viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses. [ABSTRACT FROM AUTHOR]

Introduction: Annual influenza vaccinations are recommended for adolescents and adults with moderate to severe asthma. This study investigated the effect of tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, on the humoral immune response to the quadrivalent seasonal influenza vaccine in patients with moderate to severe asthma. Methods: VECTOR was a phase 3b, randomized, multicenter, double-blind, parallel-group, placebo-controlled study. Adolescents (aged 12–17 years) and young adults (aged 18–21 years) with moderate to severe asthma were enrolled across 15 centers in the USA. Patients received tezepelumab 210 mg or placebo subcutaneously at weeks 0, 4, 8, and 12, and a single dose of inactivated quadrivalent seasonal influenza vaccine at week 12 before receiving study treatment. Immediately before vaccination and at 4 weeks postvaccination (week 16), strain-specific antibody responses were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Safety was assessed. Results: Seventy patients were randomized to tezepelumab (n = 35) or placebo (n = 35). There were no meaningful differences in HAI or MN antibody responses between treatment groups at week 16. HAI assay geometric mean fold rises (GMFRs) for influenza strains were 1.76–7.34 for tezepelumab and 1.46–4.75 for placebo. MN assay GMFRs were 4.00–14.56 for tezepelumab and 3.56–10.62 for placebo. In the HAI assay, a fourfold or larger rise in antibody titer from weeks 12 to 16 occurred in 15.2–78.8% and 15.2–51.5% of tezepelumab and placebo recipients, respectively, and 97.0–100% of patients in both treatment groups achieved an antibody titer of at least 40 at week 16. No unexpected safety findings occurred. Conclusion: There was no observed suppression of the humoral immune response after influenza vaccination in adolescents and young adults with moderate to severe asthma treated with tezepelumab. Therefore, the influenza vaccine can be administered to this patient population during tezepelumab treatment. ClinicalTrials.gov identifier: NCT05062759 [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) are a type of innate immune cells that produce a large amount of IL‐5 and IL‐13 and two cytokines that are crucial for various processes such as allergic airway inflammation, tissue repair and tissue homeostasis. It is known that damaged epithelial‐derived alarmins, such as IL‐33, IL‐25 and thymic stromal lymphopoietin (TSLP), are the predominant ILC2 activators that mediate the production of type 2 cytokines. In recent years, abundant studies have found that many factors can regulate ILC2 development and function. Hormones synthesized by the body's endocrine glands or cells play an important role in immune response. Notably, ILC2s express hormone receptors and their proliferation and function can be modulated by multiple hormones during allergic airway inflammation. Here, we summarize the effects of multiple hormones on ILC2‐driven allergic airway inflammation and discuss the underlying mechanisms and potential therapeutic significance. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous inflammatory disease of the airways, affecting many children, adolescents, and adults worldwide. Up to 10% of people with asthma have severe disease, associated with a higher risk of hospitalizations, greater healthcare costs, and poorer outcomes. Patients with severe asthma generally require high-dose inhaled corticosteroids and additional controller medications to achieve disease control; however, many patients remain uncontrolled despite this intensive treatment. The treatment of severe uncontrolled asthma has improved with greater understanding of asthma pathways and phenotypes as well as the advent of targeted biologic therapies. Tezepelumab, a monoclonal antibody, blocks thymic stromal lymphopoietin, an epithelial cytokine that has multifaceted effects on the initiation and persistence of asthma inflammation and pathophysiology. Unlike other biologic treatments, tezepelumab has demonstrated efficacy across severe asthma phenotypes, with the magnitude of effects varying by phenotype. Here we describe the anti-inflammatory effects and efficacy of tezepelumab across the most relevant phenotypes of severe asthma. Across clinical studies, tezepelumab reduced annualized asthma exacerbation rates versus placebo by 63– 71% in eosinophilic severe asthma, by 58– 68% in allergic severe asthma, by 67– 71% in allergic and eosinophilic severe asthma, by 34– 49% in type 2-low asthma, and by 31– 41% in oral corticosteroid-dependent asthma. Furthermore, in all these asthma phenotypes, tezepelumab demonstrated higher efficacy in reducing exacerbations requiring hospitalizations or emergency department visits versus placebo. In patients with severe uncontrolled asthma, who commonly have multiple drivers of inflammation and disease, tezepelumab may modulate airway inflammation more extensively, as other available biologics block only specific downstream components of the inflammatory cascade. Plain Language Summary: Asthma is characterized by an immune response leading to airway inflammation. People with severe asthma may react to different triggers and develop different types of airway inflammation. In patients with asthma, a protein called thymic stromal lymphopoietin (TSLP) plays an important role in the immune response that leads to the signs and symptoms of asthma. TSLP is released by the airway lining in response to different asthma triggers, driving an immune chain reaction, leading to airway narrowing and tightening, increased airway inflammation, worsening asthma symptoms, and asthma attack. Tezepelumab is a monoclonal antibody (a type of protein) that prevents TSLP from attaching to its receptor, thereby blocking its activity, reducing airway inflammation and asthma symptoms. Tezepelumab is an add-on medicine for the treatment of people aged 12 years or older with severe asthma that is not controlled with their current medicines. In this article, we discuss how tezepelumab may work in different types of asthma, for example allergic asthma, eosinophilic asthma, and T2-low asthma. We also describe how effective tezepelumab is in these different asthma types, through the reduction of asthma attacks and improvement in lung function, symptom control, and quality of life, leading to fewer emergency department visits and hospitalizations for asthma. [ABSTRACT FROM AUTHOR]

Heterogeneity characterises inflammatory diseases and different phenotypes and endotypes have been identified. Both innate and adaptive immunity contribute to the immunopathological mechanism of these diseases and barrier damage plays a prominent role triggering type 2 inflammation through the alarmins system, such as anti-Thymic Stromal Lymphopoietin (TSLP). Treatment with anti-TSLP monoclonal antibodies showed efficacy in severe asthma and clinical trials for other eosinophilic diseases are ongoing. The aim of this perspective review is to analyse current advances and future applications of TSLP inhibition to control barrier damage. [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]