Association of Dietary Polyunsaturated Fatty Acid Intake with Allergic Rhinitis in Adults: A Cross-Sectional Study of NHANES 2005-2006.

INTRODUCTION: The incidence of allergic rhinitis (AR) is increasing year by year, and the pathogenesis is complex, in which diet may play an important role. The role of polyunsaturated fatty acids (PUFAs) in AR is still controversial. Previous studies have looked at the effects of PUFA during pregnancy, childhood, and adolescence. In this study, we aimed to determine the association between dietary intake of PUFA and AR in adults. METHODS: We used the NHANES database from 2005 to 2006 to include a total of 4,211 adult subjects. We collected dietary PUFA intake data and information on AR. Logistic regression and restricted cubic spline models were constructed to examine the association between PUFA intake and AR in adults. The t test was used to compare daily PUFA intakes in patients with and without AR. RESULTS: In the fully adjusted model (OR: 1.016; 95% CI: 1.003; 1.028), PUFA intake was positively correlated with allergic symptoms, hay fever, and AR in adults (p < 0.05). In addition, daily PUFA intake was significantly higher in people with allergic symptoms, hay fever, and AR than in people without the disease (p < 0.01). CONCLUSIONS: Our results suggest a positive association between dietary PUFA intake and AR in adults to a certain extent. Future studies on dietary PUFA dose will provide new strategies for the prevention and treatment of allergic diseases such as AR related to non-pharmaceutical interventions.

Association between 19 Allergens and Chronic Constipation in Adults: NHANES 2005-2006.

INTRODUCTION: There are increasing reports of a link between chronic constipation and allergies in children. However, similar epidemiological evidence is limited in the general adult population. Therefore, in this study, we attempted to assess the association between chronic constipation and allergy in adults aged ≥20 years in the USA. METHODS: We established a logistic regression model to test the relationship between chronic constipation and 19 specific immunoglobulin E (sIgE) types in adults aged ≥20 years using large-sample data from the National Health and Nutrition Examination Survey database (2005-2006). The weekly defecation times of the allergic and non-allergic groups were compared using the t test. RESULTS: We found that sIgE-sensitized participants had a 0.723 lower risk of chronic constipation than the general population (95% confidence interval (CI) = 0.566-0.923). There was a negative association between chronic constipation and sensitizations to peanut (odds ratio (OR) = 0.579, 95% CI = 0.381-0.935), egg (OR = 0.335, 95% CI = 0.134-0.838), dog (OR = 0.723, 95% CI = 0.522-0.965), and cockroach (OR = 0.540, 95% CI = 0.373-0.784). In addition, the frequency of defecation per week increased significantly in people allergic to peanuts and cockroaches (p < 0.05). DISCUSSION/CONCLUSION: The results of this study demonstrate an inverse relationship between sIgE sensitization and chronic constipation in adults. However, the specific association mechanism needs to be further studied.

Allergen-induced CD11c + dendritic cell pyroptosis aggravates allergic rhinitis.

BACKGROUND: Pyroptosis is crucial for controlling various immune cells. However, the role of allergen-induced CD11c + dendritic cell (DC) pyroptosis in allergic rhinitis (AR) remains unclear. METHODS: Mice were grouped into the control group, AR group and necrosulfonamide-treated AR group (AR + NSA group). The allergic symptom scores, OVA-sIgE titres, serum IL-1ß/IL-18 levels, histopathological characteristics and T-helper cell-related cytokines were evaluated. CD11c/GSDMD-N-positive cells were examined by immunofluorescence analysis. Murine CD11c + bone marrow-derived DCs (BMDCs) were induced in vitro, stimulated with OVA/HDM, treated with necrosulfonamide (NSA), and further cocultured with lymphocytes to assess BMDC function. An adoptive transfer murine model was used to study the role of BMDC pyroptosis in allergic rhinitis. RESULTS: Inhibiting GSDMD-N-mediated pyroptosis markedly protected against Th1/Th2/Th17 imbalance and alleviated inflammatory responses in the AR model. GSDMD-N was mainly coexpressed with CD11c (a DC marker) in AR mice. In vitro, OVA/HDM stimulation increased pyroptotic morphological abnormalities and increased the expression of pyroptosis-related proteins in a dose-dependent manner; moreover, inhibiting pyroptosis significantly decreased pyroptotic morphology and NLRP3, C-Caspase1 and GSDMD-N expression. In addition, OVA-induced BMDC pyroptosis affected CD4 + T-cell differentiation and related cytokine levels, leading to Th1/Th2/Th17 cell imbalance. However, the Th1/Th2/Th17 cell immune imbalance was significantly reversed by NSA. Adoptive transfer of OVA-loaded BMDCs promoted allergic inflammation, while the administration of NSA to OVA-loaded BMDCs significantly reduced AR inflammation. CONCLUSION: Allergen-induced dendritic cell pyroptosis promotes the development of allergic rhinitis through GSDMD-N-mediated pyroptosis, which provides a clue to allergic disease interventions. Video Abstract.

Notch Signaling Promotes Development of Allergic Rhinitis by Suppressing Foxp3 Expression and Treg Cell Differentiation.

BACKGROUND: The Notch signaling pathway plays an important role in regulating human immune function, but the relationship between allergic rhinitis (AR) and Notch signaling remains unclear. OBJECTIVE: To investigate the role of Notch signaling in the pathogenesis of AR and its regulation on Foxp3-Treg cells. METHOD: The sera of 100 patients with AR and 50 controls were collected to assess the differences in Notch1, Jagged1, and DLL1 (Delta-like 1) expression. Experimental mice were divided into normal control, AR, Notch inhibitor, and dexamethasone groups. Allergic symptoms, total IgE levels, and the proportion of Treg cells in the peripheral blood were detected. Notch1, Jagged1, NICD (Notch intracellular domain, also known as ICN), and Foxp3 expression and Th1/Th2/Th17-related cytokines in the spleen were detected and compared between each group of mice. RESULTS: Compared with the control group, the expression of Notch1 and Jagged1 in patients with AR was significantly elevated (p < 0.05). The expression of Notch1 and Jagged1 in patients with severe AR was higher than that observed in the mild to moderate AR patients and positively correlated with the levels of allergen sIgE (p < 0.05). The animal experiments revealed that compared with the normal control group, the expression of Notch1, Jagged1, and NICD in the AR group was increased, Foxp3 expression was decreased, and the proportion of Treg cells was decreased (p < 0.05). Compared with the AR group, allergic symptoms and total serum IgE levels and the expression of Notch1, Jagged1, and NICD were significantly decreased in the Notch inhibited group, whereas the expression of Foxp3 and the proportion of Treg cells were increased significantly (p < 0.05). The Th2-type immune responses were also enhanced and Th1-type immune responses decreased in the AR group, but the Th1/Th2 imbalance was reversed in the Notch inhibited group. CONCLUSION: Notch signaling downregulates Foxp3 expression and inhibits the differentiation of Treg cells to promote the development of AR. Blocking Notch signaling may be a potential treatment for AR.

Long-term consequences of regulatory T-cell-specific knockout of Notch2 in immune homeostasis.

AIMS: To investigate the long-term alterations in immune function and spontaneous inflammation in mice following specific knockout of Notch2 (Notch2KO) in Treg cells. MAIN METHODS: A Treg cell-specific Notch2 knockout mouse model was constructed, and the mice were named Notch2KO mice. The pathological changes and inflammatory cell infiltration in the lungs, skin, and liver of the mice at 2, 6, 9, and 12 months of age were evaluated by HE staining. The expression of Th1/Th2/Th17/Treg transcription factors was detected by Western blotting. The proportion of CD4 + T-cell subsets was determined by flow cytometry. The levels of Th1/Th2/Th17/Treg cytokines were measured by enzyme-linked immunosorbent assays (ELISAs). KEY FINDINGS: The expression level of Notch2 in Treg cells from the Notch2KO mice was significantly decreased compared with that in Treg cells from the control mice (P < 0.05). HE staining showed that compared with the control mice, the Notch2KO mice displayed spontaneous inflammation and had a large amount of inflammatory cell infiltration in the lungs and skin (P < 0.05). The number of Treg cells, the expression level of Foxp3, and the level of IL-10 were reduced in the Notch2KO mice compared with the control mice (P < 0.05), and these metrics further decreased with increasing age (P < 0.05). In contrast, the number of Th1/Th2 cells, the expression level of T-bet/GATA3, and the levels of Th1 cytokines (IFN-γ)/Th2 cytokines (IL-4, IL-5, and IL-13) were significantly increased in the Notch2KO mice (P < 0.05), and these metrics further increased with increasing age (P < 0.05). There was no significant change in the number of Th17 cells, the expression of RORγt, or the level of IL-17. Further analysis showed that the balance of Th1/Th2 and Treg/Th17 cells in the Notch2KO mice was shifted, and the ratio showed a downward trend over time (P < 0.05). SIGNIFICANCE: The number and function of Treg cells can be severely inhibited by a specific knockout of Notch2 in Treg cells, leading to immune disorders that gradually worsen over time.

Calpeptin may reverse glucocorticoid-resistance of allergic rhinitis associated with cigarette smoke exposure by down-regulating interferon regulatory factor 1.

Cigarette smoke exposure is an important factor in chronic inflammation in patients with allergic rhinitis (AR); however, the relationship between cigarette smoke and AR-related glucocorticoid resistance requires further study. In mice, calpeptin significantly reduces inflammation of the lower respiratory tract caused by cigarette smoke, but whether it can treat glucocorticoid-resistant AR caused by cigarette smoke requires further research. In this study, we confirmed that cigarette smoke exposure can aggravate the Th2 inflammatory response in AR leading to glucocorticoid resistance. The underlying mechanism may be related to decreased expression of DNA methyltransferase 3a (Dnmt3a), and increased expression of interferon regulatory factor 1 (IRF1). In addition, we found that calpeptin can inhibit the expression of IRF1 and thus treat AR-associated glucocorticoid resistance in rats exposed to cigarette smoke. These data suggest that calpeptin may downregulate IRF1 and therefore treat glucocorticoid resistance in AR-associated with cigarette smoke exposure.

Specific knockout of Notch2 in Treg cells significantly inhibits the growth and proliferation of head and neck squamous cell carcinoma in mice.

OBJECTIVE: To investigate the effect of Notch2 gene knockout in Treg cells on head and neck squamous cell carcinoma (HNSCC) in mice. METHODS: A mouse model of HNSCC was constructed. Flow cytometry and immunofluorescence were used to examine the numbers of related immune cells and programmed cell death in tumor cells in the spleen and tumor microenvironment of mice. Western blotting was used to measure the expression of related proteins in tumor tissues. RESULTS: The tumor volume of regulatory T (Treg) cell-specific Notch2-knockout mice (experimental group) was significantly smaller than that of control mice (control group) (P < 0.05). Compared with those in the control group, the number of Treg cells and the expression of Ki67 in Treg cells in the spleen and tumor tissue were significantly decreased in the experimental group, while the numbers of CD45+ hematopoietic cells, CD4+ T cells, CD8+ T cells, T helper 1 (Th1) cells, CD11b+ cells (macrophages), and CD11b+CD11c+ cells (dendritic cells) and the expression of Ki67 in CD4+ T cells and CD8+ T cells were significantly increased (P < 0.05). There was no significant difference in the number of Th2 cells between the two groups (P > 0.05). Immunofluorescence analysis showed that the numbers of CD4+ T cells and CD8+ T cells in the tumor tissue in the experimental group were significantly higher than those in the control group (P < 0.05). Compared with that in the control group, programmed cell death in the experimental group was significantly increased (P < 0.05). Moreover, the expression levels of NLRP3, Caspase-1 and GSDMD in the tumor tissues of the experimental group were higher than those in the control group (P < 0.01), while the expression levels of BCL2, Bax, ATG5, LC3 and p62 were not significantly different (P > 0.05). CONCLUSIONS: Specific knockout of the Notch2 gene in Treg cells significantly decreases the function of Treg cells, inhibits the growth of HNSCC and improves the immune microenvironment in mice, thus effectively treating HNSCC.

Associations between social support and anxiety during the COVID-19 lockdown in young and middle-aged Israelis: A cross-sectional study.

BACKGROUND: This study examined the associations between social support and anxiety during the coronavirus disease 2019 (COVID-19) in an Israeli sample. AIM: To examine the associations between social support and anxiety during the COVID-19 in an Israeli sample. METHODS: Data for this cross-sectional study were retrieved from an online survey. Linear regression, logistic regression and restricted cubic spline models were conducted to test for associations between social support and anxiety. RESULTS: A total of 655 individuals took part in the present study. In the univariate linear regression model, there is a negative correlation between the Generalized Anxiety Disorder-7 score (GAD-7) and the Multidimensional Perceived Social Support Scale (MSPSS) score. For MSPSS score, the multivariable adjusted regression coefficient and 95% confidence interval (CI) of GAD-7 score were -0.779 (-1.063 to -0.496). In the univariate logistic regression model, there was a negative correlation between anxiety (GAD-7 ≥ 9) and MSPSS score, and there was still a negative correlation in multivariate logical regression analysis. The odds ratios and 95%CI were 0.709 (0.563-0.894). CONCLUSION: Social support was inversely correlated with anxiety during COVID-19 in an Israeli sample.

Allergen induces CD11c+ dendritic cell autophagy to aggravate allergic rhinitis through promoting immune imbalance.

The level of autophagy in CD11c+ dendritic cell (DC) and its contribution to the subsequent immune imbalance are still unclear. The aim of this study was to investigate the role and mechanism of them in promoting the allergic inflammatory response. Nasal mucosa tissues were collected from allergic rhinitis (AR) mice and their control group to detect the expression of LC3II, P62 and ATG5 and CD11c+DC autophagy. Different concentration of OVA or the combination of OVA and autophagy inhibitor (3-MA) were used to induce the differentiation of mouse bone marrow-derived DCs (CD11c+BMDCs). Differences in LC3II, P62 and ATG5 expression and autophagosome formation were detected. BMDCs in the above groups were cocultured with spleen lymphocytes to detect the proportions of effector T cells and changes in cytokines. OVA-loaded BMDCs were injected intravenously into C57BL/6 mice to develop allergic model. The nasal mucosa of mice in the AR group showed significantly increased LC3II and ATG5 protein expression, whereas showed significantly decreased P62 protein expression. Moreover, LC3II was mainly co-expressed with CD11c+ DC markers. In vitro, OVA stimulation induced the increase of autophagosomes and the expression of autophagy-related proteins in BMDCs in a dose-dependent manner, and inhibition of autophagy showed significantly decreased LC3II and ATG5 expression and autophagosome abundance. In addition, OVA-induced BMDC autophagy can affect CD4+T cell differentiation and related cytokine levels, however, the Th1/Th2/Th9/Th17/Treg/Tfh cell immune imbalances were significantly reversed after the addition of 3-MA. Adoptive transfer of OVA-loaded BMDCs could promote the allergic inflammation, while the administration of 3-MA on OVA-loaded BMDCs could significantly reduce the AR inflammation. Overall, our findings demonstrate that allergen can induce CD11c+DC autophagy in a dose-dependent manner and promote the immune imbalance of downstream T cells towards a proinflammatory phenotype.

Allergy-related outcomes and sleep-related disorders in adults: a cross-sectional study based on NHANES 2005-2006.

BACKGROUND: Epidemiological evidence between the sleep disorders and allergy-related outcomes is limited. OBJECTIVES: The purpose of the present study was to estimate the relationship between sleep disorders and allergy-related outcomes in adults. METHODS: We built logistic regression models to examine the associations between sleep disorders and allergy-related outcomes in adult participants using the 2005-2006 NHANES database. Allergy-related outcomes included sIgE levels, asthma, hay fever, sneezing, wheezing, and eczema. Sleep disorders included sleep latency, sleep length, sleep problems, OSA symptoms, and daytime sleepiness. A t-test was used for between-group comparisons. RESULTS: Participants with OSA symptoms had 2.72 × higher odds of experiencing hay fever and 1.54 × higher odds of having eczema compared to Non-OSA symptoms participants. Participants with insufficient sleep (≤ 6 h/night) had 1.27 × higher odds of developing allergic sensitisation compared to participants with adequate sleep (7-8 h/night). Sneezing was positively associated with sleep problems (OR: 1.706; 95% CI 1.386, 2.099), OSA symptoms (OR: 1.297; 95% CI 1.049, 1.605), and daytime sleepiness (OR: 1.569; 95% CI 1.205, 2.04). CONCLUSION: Our findings suggest a positive association between allergy-related outcomes and sleep disorders. In particular, OSA symptoms, daytime sleepiness, and sleep problems are strongly associated with allergic conditions.

Diagnostic Value of a Novel Eosinophil Cationic Protein-Myeloperoxidase Test Paper Before and After Treatment for Allergic Rhinitis.

Purpose: To develop and evaluate the effectiveness/clinical application of an eosinophil cationic protein-myeloperoxidase (ECP-MPO) test paper before and after treatment in patients with allergic rhinitis (AR). Patients and Methods: We included 40 controls and 106 AR patients who were enrolled in the Allergy Clinic of Renmin Hospital of Wuhan University. Total IgE, specific IgE and skin prick test (SPT) were detected in all participants. AR patients were treated with oral cetirizine hydrochloride for 14 days. The ECP-MPO test paper results, nasal secretion smear and eosinophil counts, rhinoconjunctivitis total nasal symptom score (TNSS), quality of life questionnaire (RQLQ), visual analogue scale (VAS), serum Th1/Th2/Th17 cytokine, and chemokine data were collected pre- and post-treatment. ECP concentrations in nasal secretions were assessed by ELISA. Pearson correlation test and Kappa consistency test were used for statistical analysis. Results: The post-treatment colour grade of the ECP-MPO test paper was lower in AR patients than the pre-treatment grade. The chromogenic grade correlated positively with the ECP concentration and the eosinophil count in nasal secretions both before and after treatment. Positive ECP-MPO test paper results were consistent with positive SPT, Der p-IgE and Der f-IgE result (Kappa values, 0.843, 0.810, 0.795, respectively). The pre- and post-treatment chromogenic grades correlated positively with the TNSS (r1=0·691; r2=0·539), RQLQ (r1=0·783; r2=0·625), and VAS (r1=0·703; r2=0·682) scores in AR patients. Conclusion: The ECP-MPO test paper can effectively detect ECP in nasal secretions, and its results are consistent with those from the SPT, Der p-IgE and Der f-IgE result. Its chromogenic grade can reflect the symptom severity and specific cytokine and chemokine levels in AR patients.

Allergen immunotherapy enhances the immunosuppressive effects of Treg cells to alleviate allergic rhinitis by decreasing PU-1+ Treg cell numbers.

OBJECTIVE: To investigate the role of Tregs and their subtypes in the treatment of allergic rhinitis with allergen immunotherapy (AIT) as well as the underlying mechanism. METHODS: 1. Thirty-one healthy controls, 29 Allergic rhinitis (AR) patients and 16 AR patients treated with AIT were recruited. The total nasal symptom scores (TNSSs) were calculated. The serum levels of IgE, IL-2, TNF-α, IFN-γ, IL-4, IL-5, IL-6, IL-10 and IL-17 were measured. 2. Changes in the proportions of CD4+ T cells, Treg cells, Treg subtypes and Th1/Th2/Th9/Th17/Tfh cells in the peripheral blood of the subjects in the three groups were measured. 3. The correlations of Treg cells, Treg subtypes and TNSS with the levels of various cytokines in the AR group and AIT group were analysed. RESULTS: 1. Compared with the control group, the TNSS and IgE, IL-5 and IL-6 levels in the AR group were significantly increased, while the IL-2, IFN-γ and IL-10 levels were significantly decreased (P < 0.05). Compared with the AR group, the TNSS and IgE, IL-5 and IL-6 levels in the AIT group were significantly decreased, while the IL-2, IFN-γ and IL-10 levels were significantly increased (P < 0.05). 2. Compared with the control group, the proportions of Tregs, GATA3+ Tregs and Th1 cells in the AR group were significantly reduced, while the proportions of PU-1+ Tregs, T-bet+ Tregs and Th2 cells were significantly increased (P < 0.05). Compared with the AR group, the proportions of Tregs and Th1 cells in the AIT group were significantly increased, while the proportions of PU-1+ Tregs and Th2 cells were decreased (P < 0.05). 3. Correlation analysis showed that Treg cell proportions were negatively correlated with the TNSS, sIgE levels, IL-5 levels and IL-6 levels but positively correlated with the IL-2 and IL-10 levels (P < 0.05). PU-1+ Treg cell proportions were positively correlated with the TNSS, sIgE levels, IL-5 levels and IL-6 levels but negatively correlated with the Treg cell proportions, IL-2 levels and IL-10 levels (P < 0.05). CONCLUSIONS: AIT can reduce the proportions of PU-1+ Treg subtypes in AR patients. PU-1+ Treg cell numbers can potentially be used as an indicator to monitor the therapeutic effect of AIT on AR.

Notch2-dependent GATA3+ Treg cells alleviate allergic rhinitis by suppressing the Th2 cell response.

The aim of this study was to investigate the role and mechanism of Notch2-dependent GATA3+ Treg cells in allergic rhinitis (AR). Samples were collected from patients in the control and AR groups to detect differences in the numbers of GATA3+ Treg cells and their intracellular Notch2 levels. The effects of Notch2 on GATA3+ Treg cell differentiation and function in vitro were detected. AR mice were subjected to adoptive transfer of GATA3+ Treg cells to detect changes in the allergic inflammatory response and Th2 cells. Mice with Treg cell-specific knockout of Notch2 were constructed, and an AR model was established to detect the changes. The number of GATA3+ Treg cells and intracellular Notch2 expression in peripheral blood of the AR group were decreased compared with the controls (P < 0.05), and the number of GATA3+ Treg cells was significantly negatively correlated with the level of allergen-specific IgE (sIgE; P < 0.01). In vitro experiments showed that Notch2 promoted the differentiation and immunosuppressive function of GATA3+ Treg cells, and Notch2 directly promoted GATA3 transcription in Treg cells (P < 0.05). Animal experiments indicated that adoptive transfer of GATA3+ Treg cells reduced the allergic inflammatory response in AR mice (P < 0.05). The number of GATA3+ Treg cells was decreased in gene knockout mice (P < 0.05), and autoimmune inflammation was observed. After modeling, the allergic inflammatory response was further aggravated (P < 0.05). Overall, our findings indicate that Notch2 alleviates AR by specifically increasing GATA3+ Treg cell differentiation. Notch2 expressed in Treg cells is expected to be a new therapeutic target for AR.

Maggot extracts promote regulatory T cell differentiation by upregulating Foxp3 in allergic rhinitis.

BACKGROUND AND OBJECTIVE: Maggots are the larval stage of Lucilia sericata and have strong antibacterial activity and immunomodulatory effects. The objective of our study was to investigate whether maggot extracts can modulate regulatory T cells (Tregs) and treat allergic rhinitis (AR). METHODS: Mice were randomly assigned to five groups (n=6/group): normal, AR, Maggot, AR+ Maggot, and AR+ dexamethasone (DXM). The Total Nasal Symptom Score (TNSS), ovalbumin (OVA)-sIgE titers, histopathological characteristics and Th1-/Th2-/Th17-related cytokine levels were evaluated. The expression of T-bet, GATA3, RORγt and Foxp3 in the spleen and nasal mucosa of mice was detected, and the proportion of differentiated Tregs in the spleen of mice was determined. In addition, the effects of maggot extracts on the expression level of Foxp3 and the differentiation of Tregs in vitro were studied. Histological evaluation of the potential toxicity was also performed. RESULTS: Compared with the AR group, the AR+ Maggot group showed reduction in histopathological inflammation, downregulated OVA-sIgE titers, and restoration of the imbalance in cytokine profiles (P<0.05). After treatment with maggot extracts, the proportions of Tregs and Foxp3 expression in the spleen were significantly increased, the expression of GATA3 and RORγt was decreased (P<0.05), and the expression of T-bet showed no significant change (P>0.05). In vitro, maggot extracts promoted the expression of Foxp3 and differentiation of Tregs in a dose- and time-dependent manner (P<0.05). In addition, no obvious organ damage was observed in mice treated with maggot extracts. CONCLUSION: Maggot extracts can inhibit the progression of AR by upregulating the level of Foxp3 and promoting the differentiation of Tregs, thus serving as an alternate treatment for AR.

Notch2 suppresses the development of allergic rhinitis by promoting FOXP3 expression and Treg cell differentiation.

AIMS: Notch signaling is closely related to a variety of diseases, but the role of Notch2 in allergic rhinitis (AR) remain unclear. This study was performed to investigate the effects of Notch2 on the differentiation of Treg cells and on the inflammatory response of AR. MATERIALS AND METHODS: Peripheral blood (including 101 AR patients and 66 Controls) and nasal mucosa (including 19 AR patients and 17 Controls) were collected to detect the expression levels of Notch2, NICD2 and FOXP3. CD4+ T cells of human origin were selected to detect the effects of Notch2 on the differentiation of Treg cells and FOXP3. An AR mouse model was established, and lentiviruses overexpressing Notch2 were administered. Then, allergic symptoms, OVA-sIgE titers, nasal mucosal inflammation, Th1/Th2/Th17 cytokines and splenic Treg cells were assessed. KEY FINDINGS: Compared with that in the Control group, the expression of Notch2 in the AR group was decreased, and Notch2 expression was negatively correlated with the degree of allergy (P < 0.01). The expression levels of Notch2, NICD2 and FOXP3 were decreased in the nasal mucosa of AR patients. Notch2 can promote the differentiation of human Treg cells in vitro (P < 0.05), and Notch2 can directly promote FOXP3 transcription. Animal experiments showed after the upregulation of Notch2 expression, the allergic inflammatory of mice with AR was reduced, the differentiation of Treg cells was increased, and the imbalance of T cells was reversed (P < 0.05). SIGNIFICANCE: Notch2 promotes the differentiation of Treg cells by upregulating FOXP3 expression, thus significantly inhibiting the inflammatory response of AR.

Tangeretin promotes regulatory T cell differentiation by inhibiting Notch1/Jagged1 signaling in allergic rhinitis.

BACKGROUND AND OBJECTIVE: Tangeretin demonstrates broad anti-inflammatory effects. The present study aimed to assess whether tangeretin functions in regulating T-regulatory cells (Tregs) and alleviating allergic rhinitis (AR). METHODS: An ovalbumin (OVA)-induced AR animal model was constructed to monitor the changes in the allergic symptom score, OVA-specific IgE titers, histopathological characteristics and T-helper cell (Th1, Th2, and Th17)-related cytokine levels under tangeretin or dexamethasone (DXM) administration. The expression levels of Notch1/Jagged1 and FOXP3, and the proportion of Tregs in the spleens of these animals, were also detected. Furthermore, purified naive CD4 + T cells were utilized to assess the effects of tangeretin on Notch1 expression and their differentiation in vitro. RESULTS: Both tangeretin and DXM administration alleviated airway inflammation, decreased the production of serum OVA-induced IgE, but only tangeretin administration restored the balance of cytokine profiles compared with those in the AR group. The abundance of splenic CD4 + CD25 + FOXP3 + Treg cells and the transcription factor FOXP3 were significantly increased under tangeretin treatment, either in AR mice or in naïve CD4 + T-cell differentiation, followed by a concomitant reduction in Notch1/Jagged1 expression. However, as a positive control, the treatment of allergic rhinitis with dexamethasone was not related to the expression of Notch1/Jagged1 or the differentiation of Treg cells. CONCLUSION: Tangeretin could promote regulatory T cell responses by inhibiting Notch1/Jagged1 expression, followed by promoting FOXP3/Treg cell differentiation and thus could serve as a novel curative therapeutic for AR.