House dust mite allergens induce Ca2+ signalling and alarmin responses in asthma airway epithelial cells.

Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the formation of pro-secretory ion transport characterised by elevated basal Cl- current. Studies using human sinonasal epithelial cells treated with HDM extract report a higher protease activated receptor-2 (PAR-2) agonist-induced calcium mobilisation that may be related to airway sensitisation by allergen-associated proteases. Herein, this study aimed to investigate the effect of HDM on Ca2+ signalling and inflammatory responses in asthmatic airway epithelial cells. Primary bronchial epithelial cells (hPBECs) from asthma donors cultured at air-liquid interface were used to assess electrophysiological, Ca2+ signalling and inflammatory responses. Differences were observed regarding Ca2+ signalling in response to PAR-2 agonist 2-Furoyl-LIGRLO-amide (2-FLI), and equivalent short-circuit current (Ieq) in response to trypsin and 2-FLI, in ALI-asthma and healthy hPBECs. HDM treatment led to increased levels of intracellular cations (Ca2+, Na+) and significantly reduced the 2-FLI-induced change of Ieq in asthma cells. Apical HDM-induced Ca2+ mobilisation was found to mainly involve the activation of PAR-2 and PAR-4-associated store-operated Ca2+ influx and TRPV1. In contrast, PAR-2, PAR-4 antagonists and TRPV1 antagonist only showed slight impact on basolateral HDM-induced Ca2+ mobilisation. HDM trypsin-like serine proteases were the main components leading to non-amiloride sensitive Ieq and also increased interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) from asthma hPBECs. These studies add further insight into the complex mechanisms associated with HDM-induced alterations in cell signalling and their relevance to pathological changes within asthma.

Screening Allergenic Potencies of Skin-Contact Products Using the Human-Derived THP-1 Cell Activation Test.

With the prevalence of allergic contact dermatitis (ACD) from the usage of skin-contact products, like wearable, skin care, and hair care products, screening their skin sensitizing potential is necessary, for the sake of alleviating the consequent public health impact. In the present study, a total of 77 skin-contact products classified by four categories, watch bands (WBs), skin care products (SCPs), hair care products (HCPs), and rubber gloves (RGs), were investigated, using an optimized in vitro assay of human cell line activation test (h-CLAT). Extracting the products using neutral artificial sweat simulated well the practical usage scenarios, and testing the extracts showed that 26 of them were allergy test positive, including nine WBs, six SCPs, two HCPs, and nine RGs. The allergenic response was mainly characterized by the induction of CD54 expression, and diverse paradigms of CD54 and CD86 levels were observed by analyzing dose-response curves, which could also be influenced by the compromised viability of the THP-1 cells. The data implicated the intricate regulation by different contributors to suspicious ingredients in the test samples. Altogether, a promising methodology for testing skin allergy potential was well established for commonly used commodities by neutral artificial sweat extraction coupled with h-CLAT screening. The findings would be of great help in tracing the potential allergens in practical products and improving their qualities.

Effect of mesenchymal stem cell therapy in animal models of allergic rhinitis: A systematic review and meta-analysis.

BACKGROUND: Allergic rhinitis (AR) is a worldwide problem that affects people of all ages, impairing patients' physical and mental health and causing great social expenditure. Animal studies have suggested the potential efficacy of mesenchymal stem cell (MSC) therapy in treating AR. Our meta-analysis was performed to evaluate the effect of MSC therapy in animal models of AR by pooling animal studies. METHODS: The search was executed in PubMed, Embase, Web of Science, OVID, and the Cochrane Library for relevant studies up to February 2023. The applicable data were extracted from the eligible studies, and the risk of bias was assessed for each study. The meta-analysis was conducted using Review Manager (version 5.4.1) and Stata (version 15.1). RESULTS: A total of 12 studies were included in the final analysis. Compared to the model control group, the MSC therapy group presented lower frequency of sneezing [(Standardized mean difference (SMD) -1.87, 95% CI -2.30 to -1.43)], nasal scratching (SMD -1.41, 95% CI -1.83 to -0.99), and overall nasal symptoms (SMD -1.88, 95% CI -3.22 to -0.54). There were also remarkable reductions after transplantation with MSCs in the levels of total immunoglobulin E (IgE) (SMD -1.25, 95% CI -1.72 to -0.79), allergen-specific IgE (SMD -1.79, 95% CI -2.25 to -1.32), and allergen-specific immunoglobulin G1 (SMD -1.29, 95% CI -2.03) in serum, as well as the count of eosinophils (EOS) in nasal mucosa (SMD -3.48, 95% CI -4.48 to -2.49). In terms of cytokines, MSC therapy significantly decreased both protein and mRNA levels of T helper cell 2 (Th2)-related cytokines, including interleukin (IL)-4, IL-5, IL-10, and IL-13. CONCLUSION: MSC therapy has the potential to be an effective clinical treatment for AR patients by attenuating Th2 immune responses, reducing secretion of IgE and nasal infiltration of EOS, and consequently alleviating nasal symptoms.

Adeno-Associated Viral Vector-Delivered Pannexin-1 Mimetic Peptide Alleviates Airway Inflammation in an Allergen-Sensitized Mouse Model.

Asthma is a chronic inflammatory disease around the world. Extracellular adenosine triphosphate works as a dangerous signal in responding to cellular stress, irritation, or inflammation. It has also been reported its association with the pathogenicity in asthma, with increased level in lungs of asthmatics. Pannexin-1 is one of the routes that contributes to the release of adenosine triphosphate form intracellular to extracellular. The aim of this study was to apply pannexin-1 peptide antagonist 10Panx1 into adeno-associated viral (AAV) vectors on ovalbumin (OVA)-induced asthmatic mouse model. The results demonstrated that this treatment was able to reduce the adenosine triphosphate level in bronchoalveolar lavage fluid and downregulate the major relevant to the symptom of asthma attack, airway hyperresponsiveness to methacholine. The histological data also gave a positive support with decreased tissue remodeling and mucus deposition. Other asthmatic related features, including eosinophilic inflammation and OVA-specific T helper type 2 responses, were also decreased by the treatment. Beyond the index of inflammation, the proportion of effector and regulatory T cells was examined to survey the potential mechanism behind. The data provided a slightly downregulated pattern in lung GATA3+ CD4 T cells. However, an upregulated population of CD25+FoxP3+ CD4 T cells was seen in spleens. These data suggested that exogeneous expression of 10Panx1 peptide was potential to alleviated asthmatic airway inflammation, and this therapeutic effect might be from 10Panx1-mediated disruption of T cell activation or differentiation. Collectively, AAV vector-mediated 10Panx1 expression could be a naval therapy option to develop.

Effect of gamma-irradiated honey bee venom on gene expression of inflammatory and anti-inflammatory cytokines in mice.

In this study, the effect of gamma-irradiated honey bee venom (doses of 0, 2, 4, 6, and 8 kGy, volume of 0.1 ml and concentration of 0.2 mg/ml) was evaluated on the reduction of allergen compounds and the gene expression of inflammatory and anti-inflammatory cytokines in mice. Hence, edema activity induced by the bee venom irradiated at 4, 6, and 8 kGy was reduced, compared with the control group and that irradiated at 2 kGy. In contrast, the paw edema induced by the bee venom irradiated at 8 kGy increased, compared with 4 and 6 kGy. At all the time periods, there was a significant decrease in the gene expression of interferon gamma (IFN-γ), interleukin 6 (IL-6), and interleukin 10 (IL-10) in the bee venoms irradiated at 4, 6, and 8 kGy, compared with the control group and that irradiated at 2 kGy. In contrast, there was an increase in the gene expression of IFN-γ and IL-6 in the bee venom irradiated at 8 kGy, compared with those irradiated at 4 and 6 kGy. Therefore, gamma irradiation at 4 and 6 kGy reduced the gene expression of cytokines at each time period by decreasing the allergen compounds of honey bee venom.

Triple-tyrosine kinase inhibition by BIBF1000 attenuates airway and pulmonary arterial remodeling following chronic allergen challenges in mice.

BACKGROUND: Airway remodeling is an important pathological feature of chronic airway diseases, which leads to a progressive decline in lung function. The present study examined the anti-remodeling and anti- inflammatory effect of BIBF1000, a triple-tyrosine kinase inhibitor that targets VEGF, PDGF, and FGF receptor signaling in a mouse model of repeated ovalbumin (OVA) challenges. METHODS: Female Balb-c mice were immunized intraperitoneally on days 0 and 12 with 50 µg ovalbumin plus 1 mg of Al(OH)3 in 200 µl saline. Intranasal OVA challenges (20 µg/50 µl in PBS) were administered on days 26, 29, and 31, and were repeated twice a week for 3 months. Animals received vehicle or BIBF1000 (25 mg/kg, b.i.d.) through gavage from day 26 to the end of fourth month. On day 120, bronchoalveolar lavage (BAL) and lung tissue were collected for biochemical and immunohistological analysis. RESULTS: Compared to vehicle controls, treatment with BIBF1000 reduced the numbers of BAL eosinophils, macrophages, neutrophils, and lymphocytes by 70.0%, 57.9%, 47.5%, and 63.0%, respectively, and reduced IL-5 and IL-13 in BAL. Treatment with BIBF1000 reduced airway mucus secretion, peribronchial fibrosis, small airway, and pulmonary arterial wall thickness, compared to vehicle controls. Furthermore, treatment with BIBF1000 also reduced the expression of inflammatory mediators (TNF-α, IL-1ß, IL-5, IL-13, MMP-2, MMP-9, COX-2, and iNOS) and inhibited ERK and AKT phosphorylation. CONCLUSIONS: The protective effect afforded by triple-tyrosine kinase inhibition with BIBF1000 in reducing allergen-induced airway and arterial remodeling was associated with down-regulation of inflammatory mediators, as well as inhibition of ERK and AKT signaling pathways.

Triptonide, a Diterpenoid Displayed Anti-Inflammation, Antinociceptive, and Anti-Asthmatic Efficacy in Ovalbumin-Induced Mouse Model.

The present study was intended to explore the valuable effects of triptonide on inflammation, asthmatic, and nociceptive. Triptonide possesses numerous beneficial effects extensively managed in the treatment of inflammation disease condition. Initially, triptonide showed anti-inflammation properties over lipopolysaccharide-induced RAW 264.7 cells. Hence, the present study was directed to explore the protecting efficacy of triptonide in ovalbumin (OVA)-induced asthma in mice. Asthma was induced intraperitoneally administration (200µL) in female BALB/c mice with suspension which has ovalbumin (100 µg/mL) and aluminum hydroxide (10 mg/mL). Triptonide (30 mg/kg) over OVA-induced experimental animals altered lung mass, nitric oxide, myeloperoxidase, immunoglobulin E status, interleukins (4, 5, and 13) inflammatory cytokines status, and histological modifications. Animals were also managed with the standard drug dexamethasone (50 mg/kg) followed by the asthma induction, which is also efficient over OVA-induced experimental animals. The nociception was provoked in male Swiss mice by various chemicals (acetic acid, capsaicin, and glutamate). The animals were administered with triptonide (5, 10, and 15 mg/kg) and separate standard drugs like diclofenac sodium (10 mg/kg) and morphine (5 mg/kg) over chemical-induced nociceptive animals. The present outcome evidently established that the triptonide considerably reduced the various chemical-induced nociception in mice (Fig. 7A, B, and C). Ultimately, the present work explored the evident powerful anti-inflammation, antinociceptive, and anti-asthma properties of a diterpenoid, triptonide experimental animal models. And it is recommended that triptonide is an excellent compound in the management of asthma and its related diseases.

Novel Approaches for Inhibiting the Indoor Allergen Der f 2 Excreted from House Dust Mites by Todomatsu Oil Produced from Woodland Residues.

House dust mite (HDM) is a globally ubiquitous domestic cause of allergic diseases. There is a pressing demand to discover efficient, harmless, and eco-friendly natural extracts to inhibit HDM allergens that are more likely to trigger allergies and challenging to be prevented entirely. This study, therefore, is aimed at assessing the inhibition of the allergenicity of major HDM allergen Der f 2 by todomatsu oil extracted from residues of Abies Sachalinensis. The inhibition was investigated experimentally (using enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)) and in silico using molecular docking. The results showed that todomatsu oil inhibits the allergenicity of Der f 2 by reducing its amount instead of the IgG binding capacity of a single protein. Moreover, the compounds in todomatsu oil bind to Der f 2 via alkyl hydrophobic interactions. Notably, most compounds interact with the hydrophobic amino acids of Der f 2, and seven substances interact with CYS27. Contrarily, the principal compounds fail to attach to the amino acids forming the IgG epitope in Der f 2. Interestingly, chemical components with the lowest relative percentages in todomatsu oil show high-affinity values on Der f 2, especially ß-maaliene (-8.0 kcal/mol). In conclusion, todomatsu oil has been proven in vitro as a potential effective public health strategy to inhibit the allergenicity of Der f 2.

Suppression of airway allergic eosinophilia by Hp-TGM, a helminth mimic of TGF-ß.

Type 2-high asthma is a chronic inflammatory disease of the airways which is increasingly prevalent in countries where helminth parasite infections are rare, and characterized by T helper 2 (Th2)-dependent accumulation of eosinophils in the lungs. Regulatory cytokines such as TGF-ß can restrain inflammatory reactions, dampen allergic Th2 responses, and control eosinophil activation. The murine helminth parasite Heligmosomoides polygyrus releases a TGF-ß mimic (Hp-TGM) that replicates the biological and functional properties of TGF-ß despite bearing no structural similarity to the mammalian protein. Here, we investigated if Hp-TGM could alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen, house dust mite (HDM) extract or alum-adjuvanted ovalbumin protein (OVA). Intranasal administration of Hp-TGM during Alternaria exposure sharply reduced airway and lung tissue eosinophilia along with bronchoalveolar lavage fluid IL-5 and lung IL-33 cytokine levels at 24 h. The protective effect of Hp-TGM on airway eosinophilia was also obtained in the longer T-cell mediated models of HDM or OVA sensitisation with significant inhibition of eotaxin-1, IL-4 and IL-13 responses depending on the model and time-point. Hp-TGM was also protective when administered parenterally either when given at the time of allergic sensitisation or during airway allergen challenge. This project has taken the first steps in identifying the role of Hp-TGM in allergic asthma and highlighted its ability to control lung inflammation and allergic pathology. Future research will investigate the mode of action of Hp-TGM against airway allergic eosinophilia, and further explore its potential to be developed as a biotherapeutic in allergic asthma.

An immune-shift induced by lycopene; from an eosinophil-dominant type towards an eosinophil/neutrophil-co-dominant type of airway inflammation.

Lycopene as the main carotenoid from tomatoes is known to have beneficial effects on various inflammatory diseases. In mice, lycopene ameliorates asthma symptoms and in human asthmatic patients serum lycopene levels are reduced. To further investigate the immunomodulatory effect of lycopene, first, we used a ragweed pollen extract (RWE)-induced asthma model in mice. In a second approach, we established a RWE-induced asthma model in gerbils, because of a more human-like carotenoid absorption in these animals. In RWE-sensitized/RWE-challenged gerbils (C+) following a basal diet, mainly the number of eosinophils in the broncho-alveolar lavage (BAL) significantly increased, comparable to RWE-sensitized/PBS-challenged gerbils (C-). In RWE-sensitized/PBS-challenged gerbils with lycopene-supplementation (L-), an elevated number of mainly neutrophils, in addition to eosinophils, was detected compared to C-, whereas in RWE-sensitized/RWE-challenged animals with lycopene-supplementation (L+), mainly increased neutrophil numbers in BAL were detected compared to C+. Furthermore, using LC-MS, we determined an array of eicosanoids/docosanoids in the lungs and observed that 5-, 8-lipoxygenase (LOX) and cyclooxygenase (COX) pathways were significantly increased after intranasal RWE-challenge in sensitized mice and just by tendency in gerbils. In PBS- and RWE-challenged animals, lycopene-supplementation significantly raised COX-pathway metabolites. In conclusion, we found that lycopene-supplementation resulted in an increased inflammatory influx of neutrophils in combination with increased COX-pathways metabolites. This pro-inflammatory, pro-neutrophil activity induced by lycopene might be an important shift from allergic asthma towards an inflammatory symptomatic asthma type, though with the potential for resolution.

Circulating SSEA-1+ stem cell-mediated tissue repair in allergic airway inflammation.

Structural changes known as airway remodeling characterize chronic/severe asthma and contribute to lung dysfunction. We previously reported that neonatal SSEA-1+ pulmonary stem/progenitor cells (PSCs) ameliorated airway inflammation in asthmatic mice. However, the molecular mechanisms by which endogenous SSEA-1+ PSC of adult mice afford beneficial effects in alveolar homeostasis and lung repair after allergen challenge remain incompletely understood. To analyze the expression profile and clarify the biological significance of endogenous adult lung SSEA-1+ cells in asthmatic mice. Lung SSEA-1+ cells and circulating SSEA-1+ cells in peripheral blood were determined by confocal microscopy and cytometric analysis. GFP chimeric mice were used to trace cell lineage in vivo. The roles of circulating SSEA-1+ cells were verified in ovalbumin-induced and house dust mite-induced allergic asthmatic models. In asthmatic mice, endogenous lung SSEA-1+ cells almost disappeared; however, a unique population of circulating SSEA-1+ cells was enriched after the challenge phase. In asthmatic mice, adoptive transfer of circulating SSEA-1+ cells had a specific homing preference for the lung in response to inhaled antigen through upregulating CXCR7-CXCL11 chemokine axis. Circulating SSEA-1+ cells can transdifferentiate in the alveolar space and ameliorate lung inflammation and structural damage through inhibiting the infiltration of inflammatory cells into peribronchovascular and goblet cell hyperplasia areas, reducing the thickened smooth muscle layers and PAS-positive mucus-containing goblet cells. Reinforcing bone marrow-derived circulating SSEA-1+ cells from peripheral blood into lung tissue which create a rescue mechanism in maintaining alveolar homeostasis and tissue repair to mediate lung protection for emergency responses after allergen challenge in asthmatic conditions.

Immunomodulatory and Allergenic Properties of Antimicrobial Peptides.

With the growing problem of the emergence of antibiotic-resistant bacteria, the search for alternative ways to combat bacterial infections is extremely urgent. While analyzing the effect of antimicrobial peptides (AMPs) on immunocompetent cells, their effect on all parts of the immune system, and on humoral and cellular immunity, is revealed. AMPs have direct effects on neutrophils, monocytes, dendritic cells, T-lymphocytes, and mast cells, participating in innate immunity. They act on B-lymphocytes indirectly, enhancing the induction of antigen-specific immunity, which ultimately leads to the activation of adaptive immunity. The adjuvant activity of AMPs in relation to bacterial and viral antigens was the reason for their inclusion in vaccines and made it possible to formulate the concept of a "defensin vaccine" as an innovative basis for constructing vaccines. The immunomodulatory function of AMPs involves their influence on cells in the nearest microenvironment, recruitment and activation of other cells, supporting the response to pathogenic microorganisms and completing the inflammatory process, thus exhibiting a systemic effect. For the successful use of AMPs in medical practice, it is necessary to study their immunomodulatory activity in detail, taking into account their pleiotropy. The degree of maturity of the immune system and microenvironment can contribute to the prevention of complications and increase the effectiveness of therapy, since AMPs can suppress inflammation in some circumstances, but aggravate the response and damage of organism in others. It should also be taken into account that the real functions of one or another AMP depend on the types of total regulatory effects on the target cell, and not only on properties of an individual peptide. A wide spectrum of biological activity, including direct effects on pathogens, inactivation of bacterial toxins and influence on immunocompetent cells, has attracted the attention of researchers, however, the cytostatic activity of AMPs against normal cells, as well as their allergenic properties and low stability to host proteases, are serious limitations for the medical use of AMPs. In this connection, the tasks of searching for compounds that selectively affect the target and development of an appropriate method of application become critically important. The scope of this review is to summarize the current concepts and newest advances in research of the immunomodulatory activity of natural and synthetic AMPs, and to examine the prospects and limitations of their medical use.

Transcriptional changes in dendritic cells underlying allergen specific induced tolerance in a mouse model.

To investigate food allergy-tolerance mechanisms induced through allergen-specific immunotherapy we used RNA-Sequencing to measure gene expression in lymph-node-derived dendritic cells from Pru p 3-anaphylactic mice after immunotherapy with glycodendropeptides at 2 nM and 5 nM, leading to permanent tolerance and short-term desensitization, respectively. Gene expression was also measured in mice receiving no immunotherapy (anaphylaxis); and in which anaphylaxis could never occur (antigen-only). Compared to anaphylaxis, the antigen-only group showed the greatest number of expression-changes (411), followed by tolerant (186) and desensitized (119). Only 29 genes changed in all groups, including Il12b, Cebpb and Ifngr1. The desensitized group showed enrichment for genes related to chronic inflammatory response, secretory granule, and regulation of interleukin-12 production; the tolerant group showed genes related to cytokine receptor activity and glucocorticoid receptor binding, suggesting distinct pathways for similar outcomes. We identified genes and processes potentially involved in the restoration of long-term tolerance via allergen-specific immunotherapy, representing potential prognostic biomarkers.

Anxiety-like behavior induced by allergen is associated with decreased irregularity of breathing pattern in rats.

Allergic rhinitis (AR) is a chronic inflammatory disorder associated with a high prevalence of anxiety symptoms and respiratory disorders that adversely affect the quality of life. Studies have shown that allergen exposure induces anxiety-like behaviors. On the other hand, stress impairs the breathing pattern. However, the effect of stress on respiration and the relationship between anxiety-like behavior and stress-induced changes in breathing pattern has not been evaluated in AR. We assessed the impact of ovalbumin (OVA)-induced anxiety-like behaviors on stress-induced breathing pattern changes. Our findings showed that the allergic rhinitis induced by OVA challenge in sensitized rats induces anxiety-like behavior. Also, we found that stress decreases respiratory irregularity and increases respiratory variability, as well as the synchronization between IBI and RV time-series in AR animals. Moreover, in AR animals, we found a significant positive correlation between anxiety-like behavior and respiratory irregularity under non-stress conditions. Besides, a significant negative correlation was observed under stress conditions. The findings showed that anxiety-related behaviors may contribute to respiratory impairments under stress conditions in AR.

The bile acid-activated retinoic acid response in dendritic cells is involved in food allergen sensitization.

BACKGROUND: Alteration of commensal microbiota is highly correlated with the prevalence of allergic reactions to food in the gastrointestinal tract. The mechanisms by which microbiota modulate food allergen sensitization in the mucosal site are not fully understood. METHODS: We generate DCs specific knockout of retinoic acid receptor α (Rara) gene mice (DC KO Rara) to evaluate food sensitization. The bile acid-activated retinoic acid response was evaluated by flow cytometry, real-time RT-PCR and Illumina transcriptome sequencing. The global effect of Abx treatment on BA profiles in the mucosal lymph tissue mLN in mice was examined by UPLC-MS analysis. RESULTS: In this study, we demonstrate that depletion of commensal gut bacteria leads to enhanced retinoic acid (RA) signaling in mucosal dendritic cells (DCs). RA signaling in DCs is required for the production of food allergen-specific IgE and IgG1. Antibiotics induced an enlarged bile acid (BA) pool, and dysregulated BA profiles contributed to enhanced RA signaling in mucosal DCs. BA-activated RA signaling promoted DC upregulation of interferon I signature, RA signature, OX40L, and PDL2, which may lead to T helper 2 differentiation of CD4+ T cells. BA-activated RA signaling involved the farnesoid X receptor and RA receptor α (RARa) interaction. Depletion of bile acid reduces food allergen specific IgE and IgG1 levels in mice. CONCLUSION: Our research unveils a mechanism of food sensitization modulated by BA-RA signaling in DCs, which suggests a potential new approach for the intervention of food allergic reactions.

Allergen disrupts amygdala-respiration coupling.

Allergic asthma affects both the respiratory function and central nervous system. Communication between the amygdala and respiratory control system is critical for regulating breathing function. To date, no study provides the effect of allergic inflammation on amygdala-respiration coupling. Here, we simultaneously recorded respiration and local field potentials of the amygdala during awake immobility in a rat model of allergic asthma. A decreased synchrony was found between amygdala and respiration in asthmatic rats. Allergen also reduced the modulatory effect of the respiration phase on amygdala power at delta, theta and gamma2 (80-120 Hz) frequencies. Moreover, in the animal model of allergic asthma, delta and theta oscillations strongly coordinate local gamma2 activity in the amygdala. These findings suggest that allergen can induce brain alterations and therefore shed light on future works to address how disruption of amygdala-respiration coupling contributes to respiratory dysfunction in allergic asthma.

Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization.

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen.

Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

Detoxification of Bee Venom Increases Its Anti-inflammatory Activity and Decreases Its Cytotoxicity and Allergenic Activity.

Bee venom is a medicinal product that is widely used in traditional therapies owing to its excellent anti-inflammatory activity. However, the use of bee venom has shown adverse effects. Therefore, there is a need for research that can remove the cytotoxicity of bee venom and enhance its efficacy. In this study, we hydrolyzed melittin, the main component of bee venom, and removed the other components to eliminate the toxicity of bee venom. To compare the efficacy of bee venom and detoxified bee venom, we examined their antioxidant effects using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. In addition, cytotoxicity was confirmed in MCF 10A and RAW 264.7 cells, using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Detoxified bee venom showed a strong antioxidant activity and decreased a cytotoxicity in MCF 10A and RAW 264.7 cells. The anti-inflammatory activity of detoxified bee venom and bee venom were assessed by comparison of the expression of inflammatory cytokine mRNA and phosphorylation of IκBα in RAW 264.7 cells. Degranulation in RBL-2H3 cells was analyzed through ß-hexosaminidase release assay to confirm the allergenic activity of bee venom and detoxified bee venom. Treatment of the detoxified bee venom inhibited inflammatory cytokine mRNA expression, IκBα phosphorylation, and ß-hexosaminidase release. Taken together, the results indicated that compared to bee venom, detoxified bee venom exhibited decreased cytotoxicity and allergenicity and increased anti-inflammatory activity. In conclusion, detoxification of bee venom efficiently decreases the adverse effects, making it suitable for medicinal applications.

Semi-correlations as a tool to model for skin sensitization.

Semi-correlation specifically assesses the correlation between a binary variable and a continuous variable. Semi-correlations were applied to develop binary models for various endpoints. We applied the semi-correlation to develop models of two kinds of skin sensitization one related to animals (local lymph node assay LLNA) and one to human beings (direct peptide reactivity assay DPRA and/or human cell line activation test h-CLAT). The models refer to binary classification for a two-level strategy: the first level (analysis of all compounds) is used in the format "sensitizer or non-sensitizer", and the second level (only sensitizers) is a further classification in the format "strong or weak sensitizer". The ranges of statistical characteristics of the models depend on the endpoint, LLNA or DPRA/h-CLAT: for the first level, sensitivity: 0.69-0.88, specificity: 0.75-0.89, accuracy: 0.77-0.87, Matthew's correlation coefficient (MCC): 0.54-0.57 and for the second level, sensitivity: 0.70-1.0, specificity: 0.78-0.83, accuracy: 0.77-0.87, MCC: 0.54-0.76. Thus, the described approach can be applied to building up models of the skin sensitization potency.