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Accumulating evidence has shown that long-term exposure to particulate matter with aerodynamic diameter of less than 2.5 μm (PM2.5) causes Th1/Th2 imbalance and increases the risk of allergic asthma (AA) in children. However, the mechanism underlying such effect remains elusive. Here, an AA mouse model was developed by intranasal administration of ovalbumin (OVA) and uncovered that OVA-sensitized mice exhibited pathological damage of lung tissues, mucus production, augmented serum IgE levels, enhanced Th2 cells and associated cytokine levels, and diminished Th1 cells and associated cytokine levels. Meanwhile, OVA induction led to upregulation of SRSF1 in mice. Moreover, shRNA-mediated knockdown of SRSF1 suppressed AA and Th1/Th2 imbalance in OVA-sensitized mice. After PM2.5 exposure, AA and Th1/Th2 imbalance were exacerbated and SRSF1 expression was increased in OVA-sensitized mice. Mechanistic experiments demonstrated that PM2.5-mediated inhibition of ALKBH5 expression augmented SRSF1 m6A modification in human bronchial epithelial cells treated with house dust mite. In this process, the m6A-reading protein YTHDF1 bound to SRSF1 mRNA and increased its stability. Furthermore, ALKBH5 overexpression neutralized PM2.5-aggravated Th1/Th2 imbalance in OVA-sensitized mice. Altogether, PM2.5 fosters Th1/Th2 imbalance in pediatric asthma by increasing SRSF1 m6A methylation through ALKBH5 downregulation., Competing Interests: Declarations. Ethics approval and consent to participate: The current study was performed with the approval of the Animal Ethics Committee of The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan children’s hospital). The animal experiments have been carried out in accordance with the ARRIVE guidelines. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s) under exclusive licence to International Society of Biometeorology.)

The epithelial barrier, previously regarded only as a physical defense, is now understood to play a vital role in immune responses and the regulation of inflammation. Allergic rhinitis (AR) is a prevalent chronic inflammatory condition of the nasal mucosa, with House Dust Mite (HDM) identified as a significant inhalant allergen that can impair this barrier. IL-24 has emerged as a key cytokine in allergic diseases, involved in maintaining epithelial cell homeostasis. Nevertheless, the underlying mechanisms of these effects remain inadequately understood. This study explores HDM-induced IL-24 secretion and mucosal barrier impairment using patient and animal tissue samples. Our results confirm that HDM sensitization triggers inflammatory changes in the nasal cavity, with IL-24 acting as a key mediator of type 2 inflammation and AR severity. HDM enhances IL-24 secretion via the P38 MAPK pathway and transcription factor AP-1, while IL-24 downregulates occludin and ZO-1 expression through the STAT1/STAT3 signaling pathway, compromising barrier function and increasing permeability. Furthermore, IL-24 promotes IL-33 secretion, further exacerbating the inflammatory response in AR. These findings clarify the mechanisms of epithelial barrier disruption in HDM-sensitized allergic rhinitis and suggest that modulating the IL-24 signaling pathway may serve as a promising therapeutic strategy to restore barrier integrity in AR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Airway epithelial cells constitute the first line of defense against external noxious stimuli and play crucial roles in the release of epithelial inflammatory cytokines (IL33, IL25 and TSLP), initiating airway allergic inflammatory diseases such as asthma. IL33 plays critical physiological processes in T2-endotype asthma. However, the mechanisms by which allergen exposure triggers IL33 release from airway epithelial cells remain unclear., Methods: Integrated bioinformatic analysis and transcriptional analysis of bulk RNA-seq and single cell RNA-seq (scRNA-seq) data were used to identify core genes and determine the internal gene network associated with IL33. The expression of EGR1 was subsequently analyzed in vitro in the BEAS-2B cell line and in vivo in a house dust mite (HDM)-induced mouse asthma model. The functional experiments of EGR1 were investigated in vitro via siRNA knockdown and over-expressed plasmid. Chromatin immunoprecipitation (ChIP)-PCR and dual-luciferase reporter assay validation were subsequently performed to investigate the mechanisms by which EGR1 regulates IL33 secretion., Results: Bulk RNA-seq and scRNA-seq data identified EGR1 as an epithelial cell-derived gene implicated in IL33 expressions in asthma. The comprehensive analysis of multiple datasets indicated that the high EGR1 expression in epithelial cells may suggest a mechanistic basis of T2-endotype childhood asthma. Moreover, we verified that the expressions of EGR1 in airway epithelial cells were elevated both in vitro and in vivo asthma models. EGR1 regulated the production of IL33. Ultimately, ChIP and luciferase reporter assays confirmed that transcription factor EGR1 directly regulate the transcription of IL33 mRNA., Conclusions: Our integrated bioinformatic analysis elucidated that EGR1 directly regulates the production of IL33 in T2-asthma and provide insights underlying the progression of asthma., Competing Interests: Declarations. Ethics approval and consent to participate: Institutional Review Board of Children’s Hospital of Chongqing Medical University; No. CHCMU-IACUC20230804005. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2025. The Author(s).)

The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to investigate whether REDD1 (Regulated in Development and DNA Damage Responses 1) mediates the nuclear-to-cytoplasmic translocation and release of IL-33 in airway epithelial cells induced by house dust mites (HDM)., Methods: REDD1 expression levels in bronchial asthma patients were validated using public databases, followed by immunohistochemical analysis of REDD1 protein in airway epithelial cells from these patients. An asthma model was then established using HDM-induced 16HBE cell lines, with REDD1 gene knockout performed. The relationship between varying levels of REDD1 expression, Nrf2, and related inflammatory factors was assessed using Western blot and qPCR. To further investigate the role of the REDD1-Nrf2-IL-33 axis in the development of asthma, we employed Nrf2 activators and inhibitors to reassess the impact of REDD1 on IL-33., Results: At both mRNA and protein levels, we found that REDD1 was significantly overexpressed in samples from asthma patients (P < 0.05). In vitro, 24-hour exposure to HDM induced a notable nuclear-to-cytoplasmic translocation of IL-33 and increased its levels in the culture medium of 16HBE cells. In addition, HDM treatment significantly upregulated the expression of both REDD1 and Nrf2. Knockdown of REDD1 markedly suppressed HDM-induced IL-33 release and the expression of TNF-α, IL-6, and IL-1β, while enhancing Nrf2 expression. Moreover, treatment with the Nrf2 agonist curcumin inhibited HDM-induced nuclear-to-cytoplasmic translocation and extracellular secretion of IL-33, whereas the opposite effect was observed when using the Nrf2 antagonist ML385., Conclusion: This study reveals the crucial regulatory role of the REDD1-Nrf2-IL-33 axis in the pathological process of bronchial asthma. REDD1 modulates the expression of IL-33 and other inflammatory factors through the Nrf2 signaling pathway, thereby influencing the onset and progression of asthma., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethical approval: was obtained from the Ethics Committee of Zhongshan People’s Hospital (approval number: K2020-14). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Silibinin, a major compound of silymarin, has been reported to alleviate respiratory diseases including acute lung injury, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis through its antifibrotic, anti-inflammatory, and antioxidant properties. However, the specific mechanisms underlying its therapeutic effects, particularly in allergic asthma, are not fully understood. With the increasing prevalence and impact of allergic asthma, there is a need to elucidate the exact underlying mechanisms of its potential treatment effects. Herein, we investigated the therapeutic effects of silibinin on allergic asthma using house dust mite (HDM)-exposed mice and an HDM-stimulated human bronchial epithelium cell line, focusing on the roles of the NLR family CARD domain containing 4 (NLRC4) inflammasome and matrix metalloproteinase-9 (MMP-9). To induce airway inflammation, HDM extracts were instilled intranasally on days 0, 4, 8, and 12 to mice. Silibinin (20 and 40 mg/kg) was orally administered daily from days 0-12. The results showed that silibinin treatment attenuated allergic immune responses induced by HDM exposure, as evidenced by decreased airway hyperresponsiveness, reduced inflammatory cells and cytokines, lower immunoglobulin E levls, and decreased mucus production. Furthermore, silibinin treatment suppressed NLRC4 inflammasome activation and downregulated MMP-9 expression in the lungs. In HDM-stimulated cells, silibinin treatment decreased inflammatory cytokine levels and the expression of NLRC4 and interleukin-1β, indicating inhibition of NLRC4 inflammasome activation. Overall, our data demonstrated that silibinin alleviated allergic responses in HDM-induced asthmatic mice by inhibiting NLRC4 inflammasome activation and MMP-9 expression, underscoring its therapeutic potential in the treatment of asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To assess the effect of allergen immunotherapy (AIT) on patients with central compartment atopic disease (CCAD) and house dust mite (HDM) sensitization post-surgery., Methods: A retrospective cohort of surgically treated, HDM-sensitized CRSwNP patients phenotyped as CCAD was assessed. Patients were divided into two groups based on whether they had AIT commenced as part of their surgical care. All AIT patients started immunotherapy prior to their surgery. The primary endpoint was reformation of middle turbinate (MT) edema 12 months postsurgery. Secondary endpoints were corticosteroid irrigation use (<4 times/week vs. ≥4 times/week, %) and the rhinologic domain of the 22-item sino-nasal outcome test (SNOT-22). Demographic characteristics, concomitant asthma, smoking status, history of aspirin-exacerbated respiratory disease, conjunctival symptoms, polysensitization, serum eosinophils (cell × 10 9 /L), tissue eosinophilia (% > 100/HPF), and serum IgE (kU/L) were also recorded., Results: Eighty-six CCAD patients were assessed (41 ± 14 yrs, 64% female). AIT was applied in 37% (n = 32). Baseline features were similar apart from greater conjunctival symptoms (72 vs. 45%, p = 0.02) in the AIT group. At 12 months post-surgery, the AIT group has less MT edema (% ≥ diffuse 15.6 vs. 52.9, p < 0.01). Patients on AIT also had less pharmacotherapy requirements at 12 months (% ≥ 4/week, 37.5 vs. 79.6%, p < 0.01). The rhinologic symptoms were similar (21.1 ± 17.1 vs. 20.1 ± 21.6, p = 0.83)., Conclusions: Surgery and pharmacotherapy are effective in managing CCAD, but the addition of AIT improved allergic phenomenon and allowed de-escalation of topical therapy. Longer term studies are required to demonstrate further immunomodulation., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Environmental pollutants have been found to contribute to the development and acute exacerbation of asthma. Microplastics (MPs) have received widespread attention as an emerging global pollutant. Airborne MPs can cause various adverse health effects. Due to their hydrophobicity, MPs can act as a carrier for other pollutants, pathogens, and allergens. This carrier effect of MPs may adsorb allergens and thus make the body exposed to MPs and a large number of allergens simultaneously. We hypothesized that co-exposure to inhaled MPs and aeroallergens may promote the development of airway inflammation of asthma by disrupting the airway epithelial barrier., Methods: The effects of co-exposure to Polyethylene microplastics (PE-MPs) and allergens on allergic airway inflammation and airway epithelial barrier were examined in a mouse model of asthma. The mice were divided into four groups: (i) Control group, treated only with PBS; (ii) MP group, exposed to PE-MPs and PBS; (iii) HDM group, mice were sensitized and challenged with HDM, and intranasally treated with PBS; (iv) HDM + MP group, mice were sensitized and challenged with HDM, and intranasally treated with PE-MPs. Histology and ELISA assays were used to evaluate the severity of airway inflammation. FITC-dextran permeability assay, immunofluorescence assay, and RT-PCR were used to evaluate the airway epithelial barrier function and the expression of relevant molecules. Transcriptomics analysis with lung tissue sequencing was conducted to identify possible pathways responsible for the effects of PE-MPs., Results: Co-exposure of mice to PE-MPs and HDM induced a higher degree of inflammatory cell infiltration, bronchial goblet cell hyperplasia, collagen deposition, allergen sensitization, and Th2 immune bias than exposure to HDM alone. Co-exposure to PE-MPs and HDM aggravated oxidative stress injury in the lung and the production of cytokine IL-33 in the BALF. In addition, co-exposure of mice to PE-MPs and HDM resulted in a more pronounced decrease in the expression of relevant molecules of the airway epithelial barrier and more significant increase in the permeability of airway epithelia. Lung tissue transcriptomics analysis revealed that PE-MPs exposure was associated with CXCL1 signaling and neutrophil activation., Conclusion: Co-exposure to MPs and HDM may promote airway inflammation and airway epithelial barrier disruption and induce immune responses characterized by CXCL1 signaling and neutrophilic inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: It is well-documented that house dust mite (HDM) exposure can cause tissue damage and activate innate immune responses. However, its role in promoting gastrointestinal sensitization and allergenicity to food proteins has been relatively unexplored., Methods: This study investigates the immunostimulatory effects of HDM in a murine model of oral sensitization to egg white (EW) in the absence of exogenous adjuvants. Additionally, we examined a proteolytically inactivated form of HDM (iHDM) to assess the contribution of HDM protease activity to its adjuvant potential., Results: Both HDM and iHDM enhanced allergic responses to EW proteins via the oral route, evidenced by mast cell degranulation in the intestinal tract upon EW challenge. Notably, only iHDM induced detectable concentrations of serum EW-specific IgE and IgG1 antibodies. Whereas HDM increased intestinal expression of genes encoding tight junction proteins and Th2-inducing alarmins to a greater extent than iHDM, active proteinases were not required for its adjuvant activity, as iHDM preferentially promoted Th2 responses in intestinal lymphoid tissues., Conclusions: These findings suggest that ingestion of environmental dust may contribute to food allergy development and highlight the complex and context-dependent nature of the adjuvant activity of HDM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Benedé, Pérez-Rodríguez, Menchén-Martínez, Molina and López-Fandiño.)

BRCA1/BRCA2-containing complex subunit 3 (BRCC3) serves as a deubiquitinating enzyme contributing to multiple inflammation-related disorders. However, the role of BRCC3 in modulating airway inflammation in asthma has not been investigated. This study aimed to examine the role of BRCC3 in airway inflammation using a mouse model of asthma induced by ovalbumin (OVA). BRCC3 levels were found to be elevated in mice with asthma. BRCC3 knockout (KO) mice demonstrated a notable improvement in pathological changes, accompanied by reduced levels of inflammatory cell infiltration and inflammatory cytokines, compared to wild-type (WT) mice following OVA challenge. The NLRP3 inflammasome was high activated in asthmatic mice, which was restrained by BRCC3 KO, as companied by a decrease in NLRP3, ASC, cleaved Caspase-1, cleaved Gasdermin D (GSDMD), IL-1β, and IL-18. In vitro studies demonstrated BRCC3 levels increased in airway epithelial cells in response to house dust mite (HDM) stimulation, depending on the dose and duration of exposure. Silencing BRCC3 in airway epithelial cells protected against HDM-induced cell injury and inflammation, along with inhibiting the NLRP3 inflammasome and pyroptosis. Conversely, the overexpression of BRCC3 in airway epithelial cells worsened DM-induced cell injury and inflammation while also enhancing the NLRP3 inflammasome and pyroptosis. Further investigations revealed that silencing BRCC3 increased the ubiquitination of NLRP3, whereas overexpressing BRCC3 decreased it. Pharmacological inhibition of the NLRP3 inflammasome diminished the effects of BRCC3 overexpression on the inflammation and pyroptosis induced by HDM in airway epithelial cells. Overall, these findings underscore the importance of BRCC3 in the pathogenesis of asthma. Deletion of BRCC3 alleviates airway inflammation in asthma by impeding the activation of the NLRP3 inflammasome, thus indicating that BRCC3 could serve as a potential target for asthma therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The pathophysiologic processes of asthma are characterized not only by significant changes in miRNA expression but also by the modulation of HMGB1 and its downstream effectors. However, the specific roles of miR-15b-5p and HMGB1 in asthma remain poorly understood. This study explores the regulatory role of miR-15b-5p in asthma by targeting HMGB1. We utilized HMGB1-conditioned knockout mice (Sftpc-cre; HMGB1 flox/flox ) in type II alveolar epithelial cells (AT2), induced with house dust mite (HDM), to establish a mouse model of asthma. Results demonstrated that AT2 cell-specific deletion of HMGB1 attenuated allergen-induced airway hyperresponsiveness and reduced airway inflammation. Concurrently, miR-15b-5p levels were significantly reduced in wild-type (WT) asthmatic mice, while HMGB1, TLR4, and IL-33 levels were elevated. Administration of miR-15b-5p agomir mirrored the effects of HMGB1 knockdown, reducing peribronchiolar inflammatory cells and ameliorating airway inflammation and remodeling. A luciferase reporter gene assay system was employed to predict and verify HMGB1 as a direct target of miR-15b-5p. Overexpression of miR-15b-5p significantly inhibited apoptosis and activation of HMGB1, TLR4, and IL-33, and decreased NLRP3, Caspase-1, and IL-1β expression. In vitro, miR-15b-5p overexpression and HMGB1 knockdown attenuated HDM-induced cellular inflammation and production of Cleaved-caspase-9, Cleaved-caspase-3, and Bax, while enhancing mitochondrial membrane potential. This study suggests that miR-15b-5p acts as a protective mechanism against allergic airway inflammation by inhibiting the HMGB1/TLR4/IL-33 signaling pathway in AT2 cells. Targeting the HMGB1/TLR4/IL-33 signaling by miR-15b-5p may offer a potential therapeutic strategy for asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Asthma affects approximately 300 million individuals worldwide and the onset predominantly arises in childhood. Children are exposed to multiple environmental irritants, such as viruses and allergens, that are common triggers for asthma onset, whilst their immune systems are developing in early life. Understanding the impact of allergen exposures on the developing immune system and resulting alterations in lung function in early life will help prevent the onset and progression of allergic asthma in children. In this study, we developed an in silico model describing the pulmonary immune response to a common allergen, house dust mite, to investigate its downstream impact on the pathophysiology of asthma, including airway eosinophilic inflammation, remodelling, and lung function. We hypothesised that altered epithelial function following allergen exposure determines the onset of airway remodelling and abnormal lung function, which are irreversible with current asthma therapies. We calibrated the in silico model using age appropriate in vivo data from neonatal and adult mice. We validated the in silico model using in vivo data from mice on the effects of current treatment strategies. The in silico model recapitulates experimental observations and provides an interpretable in silico tool to assess airway pathology and the underlying immune responses upon allergen exposure. The in silico model simulations predict the extent of bronchial epithelial barrier damage observed when allergen sensitisation occurs and demonstrate that epithelial barrier damage and impaired immune maturation are critical determinants of reduced lung function and asthma development. The in silico model demonstrates that both epithelial barrier repair and immune maturation are potential targets for therapeutic intervention to achieve successful asthma prevention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The purpose of this study was to investigate the effectiveness of allergen-specific immunotherapy (AIT) on small airway dysfunction (SAD) and the underlying mechanism with a special focus on basophils., Methods: Sixty-five children with mild to moderate asthma who were under regular inhaled corticosteroid (ICS) treatment for more than 1 year but whose FEF 75 remained below 65% of the predicted value and had positive results for serum Der p or Der f were enrolled. Children with asthma underwent house dust mite (HDM) subcutaneous immunotherapy (SCIT) treatment for 1 year. Clinical symptoms and lung function were evaluated every 3 months during HDM SCIT treatment. Basophil activation test (BAT) was carried out before and after HDM SCIT treatment. RNA sequencing was performed in isolated basophils from peripheral blood after 6 months of HDM SCIT treatment, followed by GO term and KEGG pathway enrichment analysis between patients with and without HDM SCIT treatment., Results: HDM AIT treatment ameliorated clinical symptoms while concurrently improved lung function parameters, such as FEV 1 /FVC, FEF 75 , FEF 50 and MMEF (p < .05). It is worth noting that FEF 75 values showed a highly significant, gradual and persistent increase (from 49.55 ± 1.27% at baseline to 71.89 ± 2.64% after 1 year of therapy) and 22 of 35 patients no longer had SAD after 1 year of treatment. BAT results revealed that AIT treatment significantly reduced basophil activity to the inhalant allergen mixtures containing HDM in vitro challenge from baseline. GO term and KEGG pathway enrichment analysis of basophils revealed that downregulated genes were mainly involved in immune cell activation, antigen presentation, and Th2 cell differentiation., Conclusions: Our study demonstrated that HDM AIT not only improved SAD related lung function parameters, but also reduced basophil activity. RNA sequencing revealed the inhibition of phagocytosis and the phagosome pathway in basophils which may affect the polarization of Th2 cell differentiation after HDM AIT., (© 2024 Wiley Periodicals LLC.)

Introduction: MicroRNAs (miRNAs) have been linked to allergic diseases but their effects on sensitisation to allergens in individuals with asthma are unknown. We aimed to identify miRNAs associated with house dust mite (HDM) sensitisation in childhood asthma., Methods: Serum samples from 1126 children with asthma who participated in the Genetics of Asthma in Costa Rica Study (GACRS) were profiled for 304 miRNAs. We first divided according to HDM sensitisation and then tested whether miRNAs were differentially expressed (DE) between the two groups. Gene enrichment analysis for target genes of the DE miRNAs was then performed to identify potential causal pathways. Replication analysis was performed in the Childhood Asthma Management Program (CAMP), in which expression data of 258 miRNAs in 491 children were available. A mediation analysis was conducted to discern relationships between miRNA and phenotype differences according to HDM sensitisation in GACRS cohort., Results: There were 906 (80.5%) and 220 (19.5%) subjects in the GACRS HDM+ and HDM- groups. Compared with HDM- participants, those in the HDM+ group were more likely to be severe in variables including pulmonary function, oral corticosteroid use and blood tests. A total of 17 miRNAs were DE (p < 0.05) between the two groups, with miR-642a-3p, let-7c-5p and miR-107 most significantly associated with HDM sensitisation. In CAMP, there were 39 DE miRNAs, and increased expression of miR-107 in HDM+ children was replicated in this cohort. In both GACRS and CAMP, the cadherin-binding pathway was enriched in an analysis of target genes for DE miRNA. In a mediation analysis, miR-107 showed significant indirect effects on eosinophil count and total IgE that were mediated by HDM sensitisation., Conclusion: In children with asthma, miR-107 is associated with HDM sensitisation. Furthermore, miR-107 was indirectly associated with total IgE and eosinophil count through HDM sensitisation., (© 2024 John Wiley & Sons Ltd.)

This study aimed to investigate how maternal asthma during pregnancy disrupts fetal lung development by altering lipid metabolism in the amniotic fluid, which is crucial for fetal development. A pregnancy-induced asthma model was established in female rats using house dust mite (HDM) as a common allergen. The fetuses were divided into four groups based on whether the mother and fetus were exposed to the allergen: PBS+PBS, PBS+HDM, HDM+PBS, and HDM+HDM. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze changes in the lipid profile of the amniotic fluid and bronchoalveolar lavage fluid (BALF). Principal component analysis (PCA) and ChemRICH methods were used to explore the potential relationship between lipid metabolism abnormalities and impaired fetal lung development. The results indicate that maternal asthma exacerbates asthma-related inflammatory markers in fetuses, leading to pathological changes in the lungs and elevated levels of cytokines IL-5, IL-13, and IgE. Additionally, 18 differential lipids, primarily oxygenated lipids, were identified in the amniotic fluid after modeling, suggesting an enhanced oxidative stress environment for the fetus. This environment causes metabolic disturbances in various lipid groups in fetal lungs, with the HDM+HDM group showing significant abnormalities in lipids critical for lung development, including phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and fatty acids (FA). In conclusion, gestational asthma can reshape the lipid profile in the amniotic fluid and BALF, significantly disrupting fetal growth and lung development. Restoring normal lipid metabolism in the amniotic fluid and fetal lungs may offer a potential therapeutic approach to managing aberrant fetal lung development in asthmatic mothers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Indoor allergen exposure and senitization is expected to increase significantly during the COVID-19 pandemic. The aim of this study was to assess the impact of this altered allergen exposure on allergen sensitivity patterns in children with asthma., Methods: Demographic data, clinical characteristics, and laboratory findings of asthmatic children aged 5 years and younger were assessed May 2019 to May 2020, 1 year after the start of lockdown measures. Those asthmatic children were compared with age- and sex-matched asthmatic peers assessed before the pandemic. Group I included asthmatic children who underwent skin testing within 12 months of the start of the lockdown (n = 112), while Group II included asthmatic children whose skin testing was done before the lockdown (n = 224)., Results: A total of 336 preschool children diagnosed with asthma were evaluated. House dust mite (HDM) and animal dander (cat, dog) senitization rates were significantly higher in Group I than in Group II (66.1% vs. 42.9%; OR: 2.5, 95% CI: 1.6-4.1, p < 0.001 and 8.0% vs. 1.3%; OR: 6.4, CI: 1.7-24.2, p = 0.006, respectively). However, the number of asthma attacks requiring systemic corticosteroid treatment was higher in Group I than in Group II (p = 0.001). The duration of lockdown emerged as a significant risk factor for HDM senitization (p < 0.001, OR: 2.6, 95% CI: 1.6-4.1) and animal allergen senitization (p = 0.006, OR: 6.4, 95% CI: 1.7-27.3)., Conclusion: During the pandemic, senitization to indoor allergens, including HDM and animal dander, increased significantly in asthmatic children. This may be attributed to changes in lifestyle, increased time spent indoors and increased pet ownership., (© 2024 Wiley Periodicals LLC.)

Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT 7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT 7 -MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT 7 -MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

DNA damage underlies the progression of asthma toward a severe, steroid hyporesponsive phenotype. The accumulation of double-stranded DNA within the cytosol triggers the activation of cytosolic DNA-sensing pathways, notably the Stimulator of Interferon Genes (STING) pathway. However, the precise role of STING in driving steroid hyporesponsiveness remains elusive and warrants further investigation. This study evaluates STING levels in human bronchial fibroblasts from severe asthmatic patients and in lung homogenates from a steroid hyporesponsive lung inflammation mouse model. STING level is assessed at baseline, post house dust mites (HDM) stimulation, and following treatment with dexamethasone and STING inhibitor. The effect of STING inhibitors on regulating steroid hyporesponsiveness particularly glucocorticoid receptor (GR)-α/GR-β ratio is also examined. Severe asthmatic fibroblasts exhibit elevated STING/IFN-I pathway activation, further heightened by HDM and a similar pattern is seen in lung homogenates from steroid hyporesponsive mice. Dexamethasone combined with an STING inhibitor reduces STING activity, while dexamethasone alone is ineffective. Interestingly, the STING inhibitor restores steroid sensitivity by increasing the GRα/GRβ ratio. Furthermore, nanoparticle-encapsulated STING inhibitor more effectively reduces airway hyperresponsiveness and restores steroid sensitivity than the free inhibitor. These findings emphasize STING's role in severe asthma pathogenesis, proposing nanoparticle delivery of STING inhibitors as a promising therapeutic strategy., (© 2024 Wiley‐VCH GmbH.)

Background: House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although allergic sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, the molecular mechanisms driving this process remain incompletely elucidated., Objective: This study aimed to elucidate the molecular mechanisms underlying HDM-induced AR., Methods: We examined the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and the NLRP3 inflammasome in both AR patients and mice. Additionally, we investigated the role of CMPK2 and STING in the activation of the NLRP3 inflammasome in AR., Results: The expression of CMPK2, STING and the NLRP3 inflammasome was significantly increased in the nasal mucosa of AR patients compared to non-AR controls. A positive correlation was found between CMPK2 expression and the levels of STING, NLRP3, ASC, CASP1 and IL-1β. HDM treatment up-regulated the expression of CMPK2, and CMPK2 overexpression enhanced NLRP3 inflammasome activation in human nasal epithelial cells (HNEPCs). Additionally, mitochondrial reactive oxygen species (mtROS) production following HDM exposure contributed to mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA), which activated the cyclic GMP-AMP synthase (cGAS)-STING pathway. Remarkably, depletion of mtDNA or inhibition of STING signalling reduced HDM-induced NLRP3 inflammasome activation in HNEPCs. In vivo, genetic knockout of CMPK2 or STING alleviated NLRP3 inflammasome activation and ameliorated clinical symptoms of AR in mice., Conclusions: Our results suggest that HDM promotes the activation of NLRP3 inflammasome through the up-regulation of CMPK2 and ensuing mtDNA-STING signalling pathway, hence revealing additional therapeutic target for AR., Key Points: Cytidine/uridine monophosphate kinase 2 (CMPK2) expression is up-regulated in the nasal mucosa of patients and mice with allergic rhinitis (AR). CMPK2 caused NLRP3 inflammasome activation via mitochondrial DNA (mtDNA)-STING pathway. Blocking CMPK2 or STING signalling significantly reduced the activation of NLRP3 in house dust mite (HDM)-challenged mice and human nasal epithelial cells (HNEPCs)., (© 2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Introduction: In Japan, telemedicine has gradually expanded due to deregulation in response to the COVID-19 pandemic. However, its current status remains unclear, as it is primarily provided by general practitioners. This study aims to examine the use of telemedicine in sublingual immunotherapy (SLIT) for patients with Japanese cedar pollen allergy and/or house dust mite allergic rhinitis. Methods: We conducted a retrospective analysis of medical record data from seven otorhinolaryngology clinics and performed an exploratory evaluation between a group that combined telemedicine and in-person visits during the initial 6 months of SLIT and another group with only in-person visits. Results: Following propensity score matching, 51 and 82 patients were eligible for the telemedicine and in-person groups, respectively, with 33 cases in both groups. Both groups had similar characteristics after matching. No significant difference was found in the withdrawal rate at 6 months from the start of SLIT (6.1% and 9.1% in each group; p = 1.00), side effects, or treatment efficacy between the two groups. The average copayment for patients tended to be significantly higher in the telemedicine group after one, three, and 6 months following SLIT initiation. Discussion: The situation of patients who receive an appropriate combination of telemedicine and in-person visits is not significantly different from patients who receive in-person visits alone. This study may help indicate the actual status of telemedicine in Japan. Further investigation at more facilities is necessary in the future to dispel concerns in the practice setting.

Introduction: Multiple antigen environmental sources have been identified as possible causes of allergies, but few studies have evaluated changes in the sensitization profiles over time. The aim of this study was to evaluate the changes in IgE sensitization and exposure to dust mites, cats, dogs, and cockroaches over a 10-year period., Methods: During a period of 10 years among patients with asthma, rhinitis and/or atopic dermatitis, we evaluated the annual frequency of atopy to Dermatophagoides farinae, Dermatophagoides pteronyssinus, Blomia tropicalis, Canis familiaris, Felis domesticus and cockroaches (Periplaneta americana and Blatella germanica). Exposure to sources was also assessed using questionnaires (Pets) or direct counts (House dust mites and cockroaches). The association between some risk factors and the prevalence of atopy was explored., Results: A total of 6,000 records were included. Among the patients, 82% had IgE sensitization to at least one of the six allergenic sources. Sensitization to Dermatophagoides spp. was the most frequent (>78%). Exposure and sensitization in the first decade of life to Dermatophagoides spp. seem to determine the molecular spreading to other allergenic sources. Exposure to Blomia tropical increases significantly over time (year 2015; 38% vs. year 2022; 51%, p 0.03). Exposure to dogs was higher than with cats but association between atopy and exposure was stronger with cats (OR 27.4, 95% CI: 22.3-33.6, p < 0.01)., Conclusion: Exposure and sensitization in the first decade of life to Dermatophagoides spp. determine the molecular spreading of IgE antibodies to other allergenic sources. Household exposure to dogs and cats seems to be important for the subsequent development of atopy. Sensitization to B. tropicalis and cockroach appears to be mostly from cross-reactivity rather than direct exposure., (© 2024 S. Karger AG, Basel.)

Background: Standardized quality (SQ) house-dust mite (HDM) sublingual immunotherapy tablets (10,000 Japanese allergy units [JAU], equivalent to 6 SQ-HDM in Europe and the United States) are licensed for the treatment of HDM-induced allergic rhinitis (AR) without age restriction, based on 52-week administration clinical trials. There are no large-scale data on the administration of 10,000 JAU for > 1 year in actual clinical practice. Objective: To examine the safety and effectiveness of 10,000 JAU during use for up to 3 years at real-world clinical sites in Japan. Methods: This survey was a multicenter, observational, prospective study. We assessed the safety and effectiveness of the long-term administration of 10,000 JAU as well as effectiveness after its discontinuation in patients with HDM AR with an observation period of 3 years. Results: The safety analysis included 815 patients, and the effectiveness analysis included 768 patients. Adverse reactions that occurred in 144 patients (17.67%) were mainly site-related events that occurred early in the dosing period. Serious adverse reactions were dyspnea and anaphylactic reaction in one patient each, and both patients recovered. With regard to effectiveness, compared with scores before the administration of SQ-HDM, nasal symptom scores decreased, depending on the administration period, from 6 months to 3 years. Overall, 67.34% of the patients had improved quality of life after 6 months, and this improvement continued after 12 months. The proportion of patients with "improved and slightly improved" of overall improvement exceeded 90% after 2 years. Treatment discontinuation because "symptoms disappeared" occurred in 24.42% of the patients at 3 years. Patients who discontinued 10,000 JAU ( n = 39) had a sustained improvement in nasal symptom scores compared with baseline, even 1 year after discontinuing treatment. Conclusion: The real-world safety and effectiveness of 10,000 JAU SQ-HDM sublingual immunotherapy tablets were confirmed in Japanese patients with HDM AR. No new safety and effectiveness precautions were required.