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Immunity, Inflammation and Disease Jun 2024The hygiene hypothesis suggests that early life exposure to helminth infections can reduce hypersensitivity in the immune system.
BACKGROUND
The hygiene hypothesis suggests that early life exposure to helminth infections can reduce hypersensitivity in the immune system.
OBJECTIVE
The present study aims to evaluate the effects of Toxocara cati (T. cati) somatic products on allergic airway inflammation.
METHODS
Between 2018 and 2020, T. cati adult worms were collected from stray cats in Mashhad, Iran (31 out of 186 cats), and their somatic extract was collected. Thirty BALB/c mice were equally divided into three groups, including the OVA group (sensitized and challenged with ovalbumin), the somatic administered group (received somatic extract along with ovalbumin sensitization), and the PBS group (sensitized and challenged with phosphate buffer saline). Bronchoalveolar lavage (BAL) fluid was collected to assess the number of cells, and lung homogenates were prepared for cytokine analysis. Histopathological analysis of the lungs was performed, and inflammatory cells and mucus were detected. Cytokine levels (IL-4, IL-5, IL-10) were measured using enzyme-linked immunosorbent assay (ELISA), and ovalbumin-specific immunoglobulin E (IgE) levels were determined using a capture ELISA.
RESULTS
The somatic group significantly decreased regarding the lung pathological changes, including peribronchiolitis, perivasculitis, and eosinophil influx, compared to the group treated with ovalbumin alone. These changes were accompanied by a decrease in proinflammatory cytokines IL-4 and IL-5 and an increase in the anti-inflammatory cytokine IL-10, indicating a shift toward a more balanced immune response. The number of inflammatory cells in the BAL fluid was also significantly reduced in the somatic group, indicating a decrease in inflammation.
CONCLUSION
These preclinical findings suggest that in experimental models, T. cati somatic extract exhibits promising potential as a therapeutic agent for mitigating allergic airway inflammation. Its observed effects on immune response modulation and reduction of inflammatory cell infiltration warrant further investigation in clinical studies to assess its efficacy and safety in human patients.
Topics: Animals; Mice; Toxocara; Mice, Inbred BALB C; Cytokines; Immunoglobulin E; Ovalbumin; Lung; Bronchoalveolar Lavage Fluid; Asthma; Disease Models, Animal; Cats; Female; Toxocariasis
PubMed: 38860753
DOI: 10.1002/iid3.1307 -
Cell Death & Disease Jun 2024Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of...
Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1β, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1β were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1β was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1β production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.
Topics: Animals; Asthma; Phosphate-Binding Proteins; Mice; Disease Models, Animal; Intracellular Signaling Peptides and Proteins; Ovalbumin; Humans; Mice, Knockout; Airway Remodeling; Female; Inflammation; Mice, Inbred C57BL; Male; Cytokines; Pyroptosis; Lung; Gasdermins
PubMed: 38849380
DOI: 10.1038/s41419-024-06777-5 -
Biomolecules & Therapeutics Jul 2024Apoptosis signal-regulating kinase 1 (ASK1) is an upstream signaling molecule in oxidative stress-induced responses. Because oxidative stress is involved in asthma...
Apoptosis signal-regulating kinase 1 (ASK1) is an upstream signaling molecule in oxidative stress-induced responses. Because oxidative stress is involved in asthma pathogenesis, ASK1 gene deficiency was investigated in animal models of allergic asthma. However, there is no study to investigate whether ASK1 inhibitors could be applied for asthma to date. Selonsertib, a potent and selective ASK1 inhibitor, was applied to BALB/c mice of an ovalbumin (OVA)-induced allergic asthma model. Selonsertib suppressed antigen-induced degranulation of RBL-2H3 mast cells in a concentration-dependent manner. The administration of selonsertib both before OVA sensitization and OVA challenge significantly reduced airway hyperresponsiveness, and suppressed eosinophil numbers and inflammatory cytokine levels in the bronchoalveolar lavage fluid. Histopathologic examination elucidated less inflammatory responses and reduced mucin-producing cells around the peribronchial regions of the lungs. Selonsertib also suppressed the IgE levels in serum and the protein levels of IL-13 in the bronchoalveolar lavage fluid. These results suggest that selonsertib may ameliorate allergic asthma by suppressing immune responses and be applicable to allergic asthma.
PubMed: 38844790
DOI: 10.4062/biomolther.2023.203 -
Biomedical Research (Tokyo, Japan) 2024Mixed lymphocyte culture under the blockade of CD80/CD86-CD28 co-stimulation induces anergic (completely hyporesponsive) T cells with immune suppressive function...
Mixed lymphocyte culture under the blockade of CD80/CD86-CD28 co-stimulation induces anergic (completely hyporesponsive) T cells with immune suppressive function (inducible suppressing T cells: iTS cells). Previously, iTS cell therapy has demonstrated outstanding benefits in clinical trials for organ transplantation. Here, we examined whether peptide antigen-specific iTS cells are inducible. DO 11.10 iTS cells were obtained from splenocytes of BALB/c DO 11.10 mice by stimulation with OVA peptide and antagonistic anti-CD80/CD86 mAbs. When DO 11.10 iTS or Foxp3- DO 11.10 iTS cells were stimulated with OVA, these cells produced IL-13, but not IL-4. DO 11.10 iTS cells decreased IL-4 and increased IL-13 production from OVA-stimulated naïve DO 11.10 splenocytes. When Foxp3+ DO 11.10 iTS cells were prepared, these cells significantly inhibited the production of IL-4 and IL-13 compared with freshly isolated Foxp3+ DO 11.10 T cells. Moreover, an increase in the population expressing OX40, ICOS, and 4-1BB suggested activation of Foxp3+ DO 11.10 iTS cells. Thus, blockade of CD80/CD86-CD28 co-stimulation during peptide antigen stimulation augments the inhibitory function of Foxp3+ regulatory T cells, and does not induce anergic Foxp3- conventional T cells. Peptide-specific Foxp3+ regulatory iTS cells could be useful for the treatment of allergic and autoimmune diseases without adverse effects.
Topics: Animals; T-Lymphocytes, Regulatory; CD28 Antigens; Mice; B7-1 Antigen; B7-2 Antigen; Mice, Inbred BALB C; Forkhead Transcription Factors; Peptides; Lymphocyte Activation; Interleukin-4; Interleukin-13; Ovalbumin; Spleen; Antibodies, Monoclonal
PubMed: 38839354
DOI: 10.2220/biomedres.45.115 -
The Journal of Veterinary Medical... Jun 2024The expression of nicotinic acetylcholine receptor (nAChR) subunits on various immune cells suggests their involvement in allergic rhinitis. However, how exactly they...
The expression of nicotinic acetylcholine receptor (nAChR) subunits on various immune cells suggests their involvement in allergic rhinitis. However, how exactly they contribute to this pathogenesis is not yet confirmed. Our present study examined the therapeutic potential of GTS-21, an α7 nAChR agonist, for treating allergic rhinitis by employing its mouse models. GTS-21 treatment reduced allergen-induced immediate nasal response in ovalbumin (OVA)-sensitized model. However, nasal hyperresponsiveness or eosinophil infiltration elicited in either the OVA-sensitized or T helper 2 cell-transplanted model was not affected by GTS-21. GTS-21 did not alter allergen-induced passive cutaneous anaphylaxis response in anti-dinitrophenyl IgE-sensitized mice. This evidence implies GTS-21's potential to alleviate allergic rhinitis without perturbing T cells or mast cells.
PubMed: 38839347
DOI: 10.1292/jvms.24-0033 -
Drug Discoveries & Therapeutics Jun 2024This study aims to investigate the antiallergic effects of Shiikuwasha (Citrus depressa Hayata) leaf and peel extracts by examining the regulation of degranulation and...
Shiikuwasha leaf and peel extracts inhibit allergic reactions by suppressing degranulation in RBL-2H3 rat basophilic leukemia cells and immunoglobulin production in mouse spleen lymphocytes.
This study aims to investigate the antiallergic effects of Shiikuwasha (Citrus depressa Hayata) leaf and peel extracts by examining the regulation of degranulation and inflammatory cytokine production from rat basophilic leukemia (RBL-2H3) cells and antigen-specific antibody production in sensitized mouse spleen lymphocytes. In vivo antiallergic activity was evaluated using the passive cutaneous anaphylaxis (PCA) reaction model. Extracts of Shiikuwasha leaves and peel were prepared using 80% methanol and dissolved in dimethylsulfoxide. The dinitrophenyl-human serum albumin-induced β-hexosaminidase levels in immunoglobulin (Ig) E-sensitized RBL-2H3 cells were assessed using enzymatic assays. Cytokine production was measured by enzyme-linked immunosorbent assay. Antibody production capacity was evaluated using lymphocytes isolated from spleens of type I allergy model mice. Lymphocytes were cultured for 72 h with Shiikuwasha extracts, and ovalbumin-specific IgE, IgG1, and IgG2a levels were measured. Shiikuwasha leaf and peel extract significantly reduced β-hexosaminidase release and suppressed interleukin-4 and tumor necrosis factor-α production from RBL-2H3 cells. Ovalbumin-specific IgE and IgG1 production decreased in Shiikuwasha extract-treated lymphocytes. These extracts also significantly suppressed the PCA reaction. Shiikuwasha leaf and peel extract reduce degranulation in RBL-2H3 cells and antibody production in spleen-derived lymphocytes and therefore exhibit antiallergic effects.
PubMed: 38839286
DOI: 10.5582/ddt.2024.01016 -
Frontiers in Pharmacology 2024We previously revealed that Cang-ai volatile oil (CAVO) regulates T-cell activity, enhancing the immune response in people with chronic respiratory diseases. However,...
We previously revealed that Cang-ai volatile oil (CAVO) regulates T-cell activity, enhancing the immune response in people with chronic respiratory diseases. However, the effects of CAVO on allergic rhinitis (AR) have not been investigated. Herein, we established an ovalbumin (OVA)-induced AR rat model to determine these effects. Sprague-Dawley (SD) rats were exposed to OVA for 3 weeks. CAVO or loratadine (positive control) was given orally once daily for 2 weeks to OVA-exposed rats. Behavior modeling nasal allergies was observed. Nasal mucosa, serum, and spleen samples of AR rats were analyzed. CAVO treatment significantly reduced the number of nose rubs and sneezes, and ameliorated several hallmarks of nasal mucosa tissue remodeling: inflammation, eosinophilic infiltration, goblet cell metaplasia, and mast cell hyperplasia. CAVO administration markedly upregulated expressions of interferon-γ, interleukin (IL)-2, and IL-12, and downregulated expressions of serum tumor necrosis factor-α, IL-4, IL-5, IL-6, IL-13, immunoglobulin-E, and histamine. CAVO therapy also increased production of IFN-γ and T-helper type 1 (Th1)-specific T-box transcription factor (T-bet) of the cluster of differentiation-4+ T-cells in splenic lymphocytes, and protein and mRNA expressions of T-bet in nasal mucosa. In contrast, levels of the Th2 cytokine IL-4 and Th2-specific transcription factor GATA binding protein-3 were suppressed by CAVO. These cumulative findings demonstrate that CAVO therapy can alleviate AR by regulating the balance between Th1 and Th2 cells.
PubMed: 38835658
DOI: 10.3389/fphar.2024.1332036 -
Biomolecules & Therapeutics Jul 2024Asthma is characterized by chronic inflammation and respiratory tract remodeling. Peroxisome proliferator-activated receptors (PPARs) play important roles in the...
Asthma is characterized by chronic inflammation and respiratory tract remodeling. Peroxisome proliferator-activated receptors (PPARs) play important roles in the pathogenesis and regulation of chronic inflammatory processes in asthma. The role of PPARγ has been studied using synthetic PPARγ agonists in patients with asthma. However, involvement of PPARα/δ has not been studied in asthma. In the present study, we investigated if elafibranor, a PPARα/δ dual agonist, can modulate ovalbumin (OVA)-induced allergic asthma, which is a potential drug candidate for non-alcoholic fatty liver in obese patients. Elafibranor suppresses antigen-induced degranulation in RBL-2H3 mast cells without inducing cytotoxicity . In mice with OVA-induced allergic asthma, the administration of elafibranor suppressed OVA-induced airway hyper-responsiveness at a dose of 10 mg/kg. Elafibranor also suppressed the OVA-induced increase in immune cells and pro-inflammatory cytokine production in the bronchoalveolar lavage fluid (BALF). Histological studies suggested that elafibranor suppressed OVA-induced lung inflammation and mucin hyper-production in the bronchial airways. In addition, elafibranor suppressed OVA-induced increases in serum immunoglobulin E and IL-13 levels in BALF. Conversely, the present study suggests that elafibranor has the potential for use in patients with allergic asthma.
PubMed: 38835138
DOI: 10.4062/biomolther.2023.194 -
Allergy, Asthma, and Clinical... Jun 2024Recombinant human Interleukin receptor antagonist (rhIL-Ra) can bind to the IL-1 receptor on the cell membrane and reversibly blocks the proinflammatory signaling...
BACKGROUND
Recombinant human Interleukin receptor antagonist (rhIL-Ra) can bind to the IL-1 receptor on the cell membrane and reversibly blocks the proinflammatory signaling pathway. However, its effect on allergic rhinitis (AR) and the underlying mechanism remains unknown. This study aims to investigate the efficacy of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on AR guinea pigs.
METHODS
Guinea pigs were systemically sensitized by intraperitoneal injection and topical intranasal instillation with ovalbumin within 21 days. Animals administrated with saline served as the normal control. The AR animals were randomly divided into the model group and distinct concentrations of rhIL-1Ra and budesonide treatment groups. IL-1β and ovalbumin specific IgE levels were detected by ELISA kits. Nasal mucosa tissues were stained with hematoxylin & eosin (HE) for histological examination.
RESULTS
It was found that the numbers of sneezing and nose rubbing were remarkably reduced in rhIL-1Ra and budesonide-treated guinea pigs. Besides, rhIL-1Ra distinctly alleviated IgE levels in serum and IL-1β levels in nasal mucus, together with decreased exfoliation of epithelial cells, eosinophilic infiltration, tissue edema and vascular dilatation.
CONCLUSIONS
rhIL-1Ra is effective in AR guinea pigs and may provide a novel potential choice for AR treatments.
PubMed: 38835041
DOI: 10.1186/s13223-024-00893-9 -
Respiratory Research Jun 2024Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as...
BACKGROUND
Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma.
METHODS
The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor.
RESULTS
Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-β1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression.
CONCLUSIONS
Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.
Topics: Animals; Amino Acid Oxidoreductases; Ovalbumin; Airway Remodeling; Proto-Oncogene Proteins c-akt; Mice; Humans; Asthma; Signal Transduction; Female; Mice, Inbred BALB C; Male; Epithelial-Mesenchymal Transition
PubMed: 38824593
DOI: 10.1186/s12931-024-02811-4