Search Results (156)

Background: Atopic dermatitis (AD) is a persistent and recurring skin disease characterized by epidermal barrier dysfunction, immune dysregulation, and elevated expression of proinflammatory mediators. We investigated the anti-inflammatory potential of polynucleotides (PN), highly purified DNA biopolymers isolated from salmonid gonads, in keratinocyte and macrophage activation models. Methods: RAW 264.7 macrophages were stimulated with lipopolysaccharide (LPS), whereas HaCaT keratinocytes were stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). The effects of PN treatment on the production or expression of inflammatory mediators, cytokines, and chemokines were evaluated. Changes in the phosphorylation of mitogen-activated protein kinases (MAPKs) and Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and in the nuclear localization of nuclear factor-κB (NF-κB) were also assessed. Results: In LPS-activated RAW 264.7 macrophages, PN treatment significantly suppressed nitric oxide production and downregulated the expression of inducible nitric oxide synthase (iNOS), TNF-α, IL-1β, and IL-8, accompanied by reduced NF-κB nuclear translocation. In TNF-α/IFN-γ-stimulated HaCaT keratinocytes, PN treatment markedly decreased the secretion levels of IL-6, IL-1β, and thymic stromal lymphopoietin. Moreover, PN treatment markedly reduced T-cell-recruiting chemokines, including MDC/CCL22, TARC/CCL17, RANTES/CCL5, and IL-8. Signaling analyses demonstrated that PN treatment attenuated the phosphorylation of key MAPKs (ERK, JNK, and p38) and the JAK1/STAT3 axis. Furthermore, PN treatment markedly reduced NF-κB nuclear translocation. Conclusions: These in vitro findings indicate that the anti-inflammatory effects of PN are associated with reduced activation of multiple core signaling pathways governing cytokine and chemokine responses, supporting further investigation of PN in AD and other chronic inflammatory skin diseases. Full article

Although airway organoids provide a physiologically relevant platform for modeling human airway inflammation, their utility is often limited by substantial heterogeneity in epithelial differentiation and functional responsiveness across Matrigel domes. Here, we present a non-destructive, imaging-guided framework to predict epithelial cytokine responses and enable the selection of functionally consistent airway organoid domes. Mature human airway organoids were stimulated with house dust mite (HDM) extract and dome-level inflammatory responsiveness was quantified by RT-qPCR for thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33). Both cytokines exhibited wide dome-to-dome variability and showed a significant positive correlation, indicating coordinated allergic inflammatory regulation. Meanwhile, bright-field dome images were analyzed to segment individual organoids, define robust regions of interest, and extract quantitative morphological and texture descriptors based on gray-level co-occurrence matrix features. Organoid-level descriptors were aggregated into a single dome-level feature vector using distributional statistics, thereby capturing both central tendency and heterogeneity within each dome. Using these engineered dome-level features, we trained a deep tabular learning model (TabNet) to classify qPCR-defined inflammatory responsiveness. The resulting model achieved strong and consistent cross-validated performance for both targets, reaching balanced accuracies of 0.910 for TSLP and 0.833 for IL-33, demonstrating that bright-field phenotypes contain predictive signatures of cytokine activation. This approach provides a scalable enrichment strategy for robustly responsive organoid–Matrigel domes without destructive assay. It improves reproducibility in organoid-based airway inflammation studies and supports standardized dome selection for downstream mechanistic and translational applications. Full article

Chronic lung diseases, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and idiopathic pulmonary fibrosis, are clinically distinct but share epithelial injury, host-defense, inflammatory, and remodeling processes. We integrated European-ancestry genome-wide association study (GWAS) summary statistics for these four diseases using genomic structural equation modeling to construct a multivariate chronic lung disease (mvCLD) factor. Variant-level association testing was combined with genomic control assessment, locus annotation, GWAS-by-subtraction, fine-mapping, transcriptomic prioritization, pathway enrichment, single-cell spatial mapping, and heritability partitioning. For discovery, across 6,255,777 autosomal variants, mvCLD identified 2067 genome-wide significant variants, 30 loci, and 53 lead variants. Five lead variants were genome-wide significant for mvCLD but not for any component disease and showed high-confidence fine-mapping support. For gene prioritization, transcriptomic and gene-level analyses prioritized 21 candidate genes, including ORMDL3, GSDMB, IL18RAP, IL18R1, IL1R1, SMAD3, and CLEC16A. In exploratory functional analyses, enrichment analyses converged on interleukin, cytokine-receptor, JAK-STAT, interleukin-4/interleukin-13, thymic stromal lymphopoietin, asthma, and lung fibrosis pathways. Exploratory single-cell spatial mapping, based on a mouse embryonic atlas, showed the strongest overall enrichment in the lung annotation, although cross-dataset cell-type and tissue analyses did not reach significance after false discovery rate correction; heritability partitioning implicated conserved and active regulatory elements. These findings support a shared epithelial–immune and cytokine-regulatory genetic architecture across major chronic lung diseases and nominate biologically coherent candidate genes and pathways for future functional and translational studies. Full article

Background and Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease of the nasal and paranasal sinus mucosa, associated with significant impairment in quality of life, frequent postoperative recurrence, and repeated need for systemic glucocorticosteroid therapy. Despite the availability of biologics targeting IL-4/IL-13, IL-5, and IgE, a subset of patients shows incomplete or insufficient clinical response. In this context, upstream targeting of epithelial alarmins, particularly thymic stromal lymphopoietin (TSLP), has emerged as a potential therapeutic strategy. To critically review current evidence on the role of TSLP in CRSwNP and to evaluate available data on the mechanism of action, clinical efficacy, and therapeutic potential of tezepelumab in severe and recurrent disease. Materials and Methods: A narrative review was conducted using PubMed, Scopus, and Web of Science. Studies published between 2016 and 2026 were included, comprising experimental research, phase II–III clinical trials, systematic reviews, and international guidelines. Results: TSLP functions as an epithelial alarmin that initiates and amplifies type 2 inflammation via dendritic cell activation, Th2 polarization, and activation of type 2 innate lymphoid cells (ILC2). Data suggests that tezepelumab, a monoclonal antibody targeting TSLP, may reduce inflammation and regulate the immune system. Evidence from asthma populations and relevant CRSwNP subgroups indicates potential improvements in nasal polyp score, congestion, olfactory function and quality of life. It is our understanding that the safety profile appears comparable to placebo, with no new safety concerns having been identified in long-term studies. Conclusions: Tezepelumab is a promising biologic that targets inflammation in CRSwNP. It may benefit severe, recurrent, treatment-resistant disease by modulating immune pathways. However, evidence is indirect and limited, and more trials are needed to define its efficacy, identify biomarkers, and clarify its role in treatment algorithms. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by substantial clinical and immunological heterogeneity. Once considered primarily a disorder of epidermal barrier dysfunction, AD is now recognized as a complex systemic inflammatory condition involving dysregulated immune responses, epithelial-derived signaling, neuroimmune interactions, and diverse molecular endotypes. Advances in molecular immunology have substantially improved understanding of the cytokine networks underlying disease pathogenesis and have accelerated the transition toward precision medicine approaches in AD. This narrative review summarizes current evidence regarding the immunopathogenesis of AD, focusing on the interplay between classical and emerging cytokine pathways, biomarker development, and recent therapeutic innovations. While interleukin (IL)-4 and IL-13 remain central drivers of type 2 inflammation and barrier impairment, additional mediators including IL-31, IL-33, IL-22, thymic stromal lymphopoietin (TSLP), and OX40/OX40L signaling, and the emerging Th9/IL-9 axis contribute to chronic inflammation, neuroimmune activation, epidermal remodeling, pruritus, and disease heterogeneity. Comparative evaluation of these pathways supports the identification of distinct immunological endotypes relevant to disease stratification and targeted therapy. The review further discusses current and emerging biomarkers associated with disease severity, therapeutic responsiveness, and inflammatory profiling, including cytokine signatures, serum biomarkers, and transcriptomic approaches. Recent advances in biologic therapies, Janus kinase (JAK) inhibitors, and novel cytokine-targeted interventions are discussed within the context of a precision medicine framework integrating immunological profiling, molecular endotyping, and mechanism-based therapeutic innovation. Continued advances in biomarker discovery, multi-omics technologies, and predictive therapeutic algorithms are expected to further refine disease stratification and support increasingly individualized management strategies for patients with AD. Full article

Background/Objectives: Tezepelumab targets thymic stromal lymphopoietin and has broad efficacy in severe asthma, yet real-world evidence on patient-reported trigger burden remains limited. We assessed 12-month outcomes after tezepelumab, focusing on clinical remission, biomarkers, and trigger profiling as complementary dimensions of response. Methods: In this multicenter longitudinal real-world observational cohort based on routine clinical follow-up and Severe Asthma Network in Italy (SANI) registry data, 43 adults with severe asthma treated with tezepelumab at four Italian SANI reference centers were evaluated at baseline and, when available, after 1, 3, 6, and 12 months. Outcomes included exacerbations, lung function, type 2 biomarkers, the Asthma Control Test, SNOT-22, trigger categories, Asthma Trigger Inventory (ATI) scores, and SANI-defined clinical remission. Results: Among 22 patients with 12-month follow-up data, mean annualized exacerbations decreased from 4.30 ± 2.77 to 0.36 ± 0.49 (p < 0.001), and 14/22 (63.6%) were exacerbation-free. Asthma control improved, whereas FEV1 remained stable. FeNO and blood eosinophils decreased at selected time points. The number of reported trigger categories was lower at 6 months (p < 0.001), and physical exertion, smoke, irritants, and infection-related ATI domains improved longitudinally. Complete clinical remission was achieved in 5/22 patients (22.7%). Conclusions: Tezepelumab was associated with reduced exacerbations, improved asthma control, and lower patient-reported trigger burden. Structured trigger profiling may provide an exploratory patient-centered dimension for assessing treatment response in severe asthma. Full article

Asthma is characterized by persistent airway epithelial dysfunction and remodelling of the reticular basement membrane (RBM). In healthy airways, the RBM is primarily composed of the extracellular matrix (ECM) proteins laminin and collagen-IV, but in remodelled asthmatic airways, the RBM has increased deposition of collagen-I, -III and fibronectin. Here, we systematically compared the effects of collagen-I, -III, -IV, fibronectin, laminin, and bovine serum albumin (BSA) control on bronchial epithelial cells (BECs) from six healthy controls and seven individuals with asthma. Epithelial attachment, spreading and barrier function were assessed in real time over 72 h using electrical cell–substrate impedance sensing. Cell culture supernatants were analyzed for release of epithelial cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-6, IL-8, and IL-11 using ELISA. BECs from both control and asthma donors had faster cell attachment, spreading, and barrier formation on collagen-I, -III, -IV, and fibronectin compared to laminin and BSA. BECs from both control and asthma donors cultured on collagen -I and -III produced more TSLP, but had no effect on IL-6, IL-8, and IL-11 expression. In summary, remodelling of the RBM in asthma may promote epithelial barrier formation whilst simultaneously enhancing epithelial-derived Th2 inflammation through increased TSLP release. Full article

Representing a pathology frequently encountered in the clinical pediatric practice, non-IgE-mediated food allergy is characterized by delayed immune-mediated adverse reactions to foods. Various genetic and environmental factors play complex and incompletely elucidated roles in the development of this type of allergic pathology. In the present research, we aimed to assess the associations of the TSLP gene single-nucleotide polymorphisms (SNPs) rs3806933 and rs10062929 with the risk of non-IgE-mediated food allergy, as well as with other characteristics of these patients. The study included 87 Romanian patients with non-IgE-mediated food allergy and 115 healthy controls. The two SNPs were genotyped using Real-Time PCR TaqMan Allelic Discrimination Assays. No associations were identified between rs3806933 or rs10062929 and the risk of non-IgE-mediated food allergy. The frequency of the minor allele C of rs3806933 was lower in children with atopic dermatitis (35.4% vs. 46.8%), a positive family history of atopic disease (39.0% vs. 47.8%), and elevated levels of total IgE (39.2% vs. 45.7%), but not statistically significant. Full article

Background: Asthma is a heterogeneous chronic airway disease characterized by inflammation, airflow obstruction, hyperresponsiveness, and remodeling. Severe eosinophilic asthma is driven by eosinophilic inflammation, which contributes to tissue damage, recurrent exacerbations, and progressive impairment of airway structure and function. Eosinophils play a central role through the release of cytokines, cytotoxic granule proteins, and extracellular traps, and their persistence in the airways is sustained by type 2 inflammatory pathways, particularly interleukin-5-mediated signaling. A better understanding of eosinophil biology has promoted the development of targeted therapies, including anti-interleukin-5/interleukin-5 receptor agents and biologics that indirectly modulate eosinophilic inflammation, such as anti-interleukin-4 receptor alpha and anti-thymic stromal lymphopoietin antibodies. Aim: This narrative review summarizes the immunopathology of eosinophilic asthma and links eosinophil biology to current and emerging pharmacological strategies. We discuss biologics that directly target the IL-5/IL-5 receptor axis, as well as agents that indirectly modulate eosinophilic inflammation, including IL-4 receptor alpha and TSLP blockade. We also review the clinical positioning of available biologics, focusing on blood eosinophils, FeNO, exacerbation history, oral corticosteroid exposure, lung function, type 2 comorbidities, treatment response, remission and switching. Conclusions: Overall, eosinophilic inflammation remains a central therapeutic target and a key component of precision medicine in severe asthma, but biologic selection should be individualized and reassessed through multidomain clinical outcomes. Full article

Background: Eosinophilic chronic rhinosinusitis (ECRS) is characterized by refractory nasal polyps and severely impaired mucociliary clearance (MCC). The molecular mechanisms underlying the modulation of mucociliogenesis following IL-4/13 blockade with dupilumab remain poorly understood, notwithstanding its proven clinical efficacy. Methods: Bulk RNA Barcoding and sequencing (BRB-seq) was performed on nasal polyp tissues collected from healthy controls (n = 6), patients with non-ECRS (n = 8), and patients with ECRS both before and four weeks after dupilumab treatment (n = 9) to identify the early molecular drivers underlying ciliary regeneration. Comprehensive gene-set scoring systems were developed to evaluate multiciliogenesis master regulators, master regulators of core/ciliary planar cell polarity (PCP) and PCP components. Interaction scores for epithelial-derived cytokines—thymic stromal lymphopoietin (TSLP), IL-25, and IL-33—were calculated based on ligand and cognate receptor subunit expression. Results: The ciliary master regulatory hierarchy (e.g., FOXJ1, RFX2/3), PCP components (CELSR1 and the ciliogenesis and planar polarity effector (CPLANE) module: FUZ, INTU, WDPCP), and structural ciliogenesis pathways were robustly restored following IL-4/13 blockade. The TSLP interaction score correlated with global mucosal damage, serving as a trigger for compensatory multiciliogenesis. The pre-treatment IL-33 interaction score emerged as a significant predictor of transcriptomic ciliary recovery (p < 0.05). DNASE1L3—the primary endonuclease for degrading eosinophilic extracellular traps (EETs)—remained persistently downregulated post-treatment. Conclusions: IL-4/13 blockade successfully restores the structural and directional “hardware” of the respiratory epithelium but fails to rectify the enzymatic “software” required for mucus degradation. This “residual molecular scar” may explain the persistent mucus hyperviscosity observed in some ECRS patients even after clinical polyp resolution. Full article

Sensory neurons at barrier tissues were once seen as passive detectors of environmental stimuli. However, in the last five years, increasing evidence has challenged this view, redefining these cells as active immune sentinels that directly affect tissue immunity in the skin, lungs, and gastrointestinal tract. Nociceptors and pruriceptors express various immune-sensing receptors, including Toll-like receptors, cytokine receptors, and alarmin sensors, which allow them to directly detect pathogens, allergens, and tissue damage. When activated, sensory neurons quickly release neuropeptides such as calcitonin gene-related peptide (CGRP), substance P, vasoactive intestinal peptide (VIP), and PACAP (pituitary adenylate cyclase-activating polypeptide), which guide immune cell recruitment, activation, and resolution. Reciprocally, immune-derived mediators, including IL-33, IL-31, thymic stromal lymphopoietin (TSLP), IL-4/IL-13, and TNF-α, modulate neuronal excitability and plasticity, forming bidirectional neuroimmune circuits that control inflammation, host defense, pain, and itch. Landmark studies published in 2024–2025, including neuronal control of gut Treg function and the identification of sensory nerve immune niches, have further refined this framework and revealed tissue-specific circuit specialization. This review synthesizes recent insights from molecular, cellular, and systems levels into the sensory neuroimmune axis, emphasizes its protective versus pathogenic roles, and critically evaluates emerging therapeutic strategies and safety concerns, positioning sensory neuroimmunology as a unifying framework for tissue barrier homeostasis and disease. Full article

Eosinophils are multifunctional granulocytes that reside constitutively within mucosal tissues, where they engage in bidirectional communication with the epithelial cells lining the respiratory and gastrointestinal (GI) tracts. Once regarded solely as terminal effectors of the type 2 immunity, eosinophils are now recognized as key regulators of epithelial homeostasis and barrier integrity. Epithelial cells initiate crosstalk by releasing the alarm cytokines such as interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and IL-25, which drive eosinophil recruitment, activation, and tissue retention. Conversely, eosinophils modulate epithelial function through the release of granule proteins, cytokines, and growth factors with both damaging and reparative consequences. In the airway, this crosstalk underpins the pathogenesis of eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), in part via eosinophil-derived mediators that disrupt tight junction integrity and fuel remodeling. In the GI tract, homeostatic eosinophils support villous architecture, epithelial turnover, and goblet cell differentiation through microbiota-driven IL-33 signals and neuropeptide-mediated neuroimmune pathways, whereas dysregulated crosstalk promotes eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD). This review synthesizes recent research to delineate the molecular mechanisms of eosinophil–epithelial crosstalk across mucosal compartments, highlight tissue-specific differences and shared mechanistic themes, and discuss the implications of these findings for targeted therapy. Full article

Background/Objectives: Thymic stromal lymphopoietin (TSLP) is central to the pathogenesis of atopic dermatitis (AD) and a promising therapeutic target. However, developing small-molecule TSLP inhibitors is challenging due to the difficulty in disrupting the TSLP-TSLPR interface. This study aimed to explore naturally sourced blockers of the TSLP-TSLPR interaction and identify novel candidate compounds for AD treatment. Methods: HuT78 cells were stimulated with PMA, ionomycin, and TSLP to establish an AD model. Inflammatory cytokines were measured by qRT-PCR and ELISA. JAK/STAT signaling was analyzed by Western blot. In female BALB/c mice, DNCB-induced AD-like skin lesions were topically treated with test compounds, followed by histopathological and immunohistochemical assessment. Results: Eight compounds were screened, and their key structural features were elucidated via structure–activity relationship (SAR) analysis. Among them, kaempferol-7-O-glucoside (K-7-G) emerged as the most potent candidate. It interfered with the TSLP-TSLPR interaction, selectively inhibited TSLP-mediated JAK2/STAT5 phosphorylation, and significantly downregulated IL-4 (p < 0.0001) and IL-13 (p < 0.001) levels. Topical application of 1% K-7-G significantly alleviated AD-like symptoms in a mouse model, decreasing dorsal skin thickness, dermatitis score, and scratching frequency while restoring the expression of filaggrin, loricrin, and occludin (p < 0.0001). Meanwhile, it significantly reduced key inflammatory mediators in a concentration-dependent manner, including TSLP, IL-4, IL-13, TNF-α, IFN-γ, and IgE. Conclusions: This study demonstrates that K-7-G is a novel natural TSLP inhibitor capable of blocking the TSLP-TSLPR signaling pathway and effectively improving AD symptoms. Further research may explore its therapeutic potential in other inflammatory diseases. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by epidermal barrier dysfunction and dysregulated immune responses, particularly an imbalance between T helper type 1 (Th1) and type 2 (Th2) cytokines. Natural products with immunomodulatory activity have attracted increasing attention as potential strategies for regulating allergic inflammation. In this study, we investigated the immunomodulatory effects of bioprocessed black rice bran (BRB-F) and bioprocessed balloon flower root (BFR-F). In vitro assays using human B cells, mast cells, and keratinocytes were conducted to evaluate IgE production, mast cell degranulation, and epithelial inflammatory mediator release. The efficacy of the BRB-F:BFR-F mixture was further evaluated in BALB/c mice with 2,4-dinitrochlorobenzene (DNCB)/Dermatophagoides farinae extract (DFE)-induced AD-like dermatitis. BRB-F and BFR-F suppressed IgE production, attenuated mast cell degranulation and thymic stromal lymphopoietin (TSLP) release, and reduced keratinocyte-derived inflammatory mediators (thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and IL-6). In mice, dietary supplementation with the BRB-F:BFR-F mixture (10–80 mg/kg/day) dose-dependently improved clinical skin lesions and histopathological changes, with serum IgE reduced by up to 87.1% at the highest dose. The treatment significantly suppressed Th2 cytokine mRNA expression in ear tissue (IL-4, IL-5, and IL-13) by 37.2%, 32.7%, and 34.0%, respectively, compared with the positive control. In contrast, splenic Th1 cytokine mRNA expression (IL-2, IL-12, and IFN-γ) was partially restored by 37.1%, 22.5%, and 18.7%, respectively. These findings indicate that BRB-F and BFR-F modulate multiple immune pathways and help restore Th1/Th2 immune balance, suggesting their potential as functional materials for regulating immune dysregulation associated with AD. Full article

Microorganisms residing on the skin play a crucial role in maintaining both the integrity of the skin barrier and immune function. This study examined the effects of culture supernatants from canine-derived Bifidobacterium animalis subsp. lactis DS008 on canine keratinocytes in vitro. To induce cytokine production, canine progenitor epidermal keratinocytes (CPEK) were indirectly co-cultured with Malassezia pachydermatis using an insert well system to prevent direct cell-to-yeast contact, and CPEK were supplemented with 0.1%, 1%, and 10% of DS008 supernatants. mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-13, thymic stromal lymphopoietin (TSLP), IL-31, and keratin 10 were analyzed by real-time PCR. The protein concentrations of TSLP and IL-31 were measured by ELISA. Additionally, DS008 supernatants were applied to reconstructed canine epidermis (RCE) models exposed to lipopolysaccharide to evaluate changes in epidermal architecture. Treatment with DS008 supernatants showed significant reductions in mRNA expression of TNF-α, IL-13, TSLP, and IL-31, as well as decreased protein levels of TSLP and IL-31. Furthermore, keratin 10 mRNA expression was significantly increased, and RCE analysis demonstrated that DS008 supernatants ameliorated stratum corneum deformation. These findings suggest that postbiotics derived from canine-derived Bifidobacterium animalis subsp. lactis DS008 is a potential candidate with anti-inflammatory properties. Full article