An eosinophil-Sos1-RAS axis licenses corticosteroid resistance in patients with allergic rhinitis.

BACKGROUND: Corticosteroid resistance (CR) is a serious disadvantage in treating many chronic inflammatory conditions. Eosinophils are the main inflammation cells in allergic reactions. Environmental pollution, such as PM2.5, is associated with the pathogenesis of allergic disorders. The objective of this study is to elucidate the mechanism by which the exposure to PM2.5 confers eosinophil CR status. METHODS: Patients with allergic rhinitis were recruited and assigned to corticosteroid sensitive (CS) and CR groups. Eosinophils were purified from nasal lavage fluids collected from patients with allergic rhinitis. A murine AR mouse model was developed with dust mite allergens and PM2.5 as the sensitization reagents. RESULTS: CR status was detected in about 60% eosinophil collected in patients with AR. Upon exposure to eosinophil activators, CS eosinophils released a large quantity of mediators, which was suppressed by the presence of steroids in the culture. CR eosinophils demonstrated resistance to steroidal therapy. RAS activation levels in eosinophils were higher in CR eosinophils than in CS eosinophils. Higher expression of the Son of sevenless-1 (Sos1) was detected in CR eosinophils, which formed a complex with RAS and glucocorticoidreceptor-α in CR eosinophils to prevent the binding between steroids and glucocorticoidreceptor-α. The presence of an Sos1 inhibitor dissociated glucocorticoid receptor-α from RAS/Sos1 complex, that restored the sensitivity to steroids in eosinophils. Administering the Sos1 inhibitor effectively attenuated the experimental allergic rhinitis. CONCLUSIONS: CR status was detected in approximately 1/3 eosinophils sampled from patients with allergic rhinitis. Sos1 was instrumental in the development and perseverance of CR in eosinophils. Sos1 inhibition restored sensitivity to steroids in CR eosinophils, which effectively reduced experimental allergic rhinitis.

Livin in synergy with Ras induces and sustains corticosteroid resistance in the airway mucosa.

Rationale: Corticosteroid resistance (CR) seriously affects the therapeutic effects of steroids on many chronic inflammatory disorders, including airway allergy. The mechanism of CR development is unclear. Recent research indicates that livin, an apoptosis inhibitor, is associated with the regulation in cell activities. This study investigates the role of livin in the inducing and sustaining CR in the airway mucosa. Methods: Nasal epithelial cells (NECs) were isolated from surgically removed nasal mucosal tissues of patients with allergic rhinitis (AR) and nasal polyps with or without CR. Differentially expressed genes in NECs were analyzed by the RNA sequencing. A CR mouse model was developed to test the role of livin in CR development. Results: The results showed that NECs of AR patients with CR expressed high levels of livin, that was positively correlated with the thymic stromal lymphopoietin (TSLP) expression and the high Ras activation status in NECs. Livin and Ras activation mutually potentiating each other in the inducing and sustaining the TSLP expression in NECs. TSLP induced eosinophils and neutrophils to express glucocorticoid receptor-ß (GRß). Eosinophils and neutrophils with high CRß expression were resistant to corticosteroids. Depletion of livin or inhibition of TSLP markedly attenuated CR and airway allergy. Conclusions: Livin facilitates CR development in the airways by promoting TSLP expression in epithelial cells and the GRß expression in eosinophils and neutrophils. Depletion of livin or inhibiting TSLP attenuates CR development and inhibits airway allergy, this has the translational potential to be used in the treatment of airway allergy.

Role of FcγRI in Antigen-Dependent Eosinophil Activation in Patients With Allergic Rhinitis.

BACKGROUND: The eosinophil (Eo) activation is a crucial factor evoking allergic rhinitis (AR) attacks; factors; the mechanism of triggering Eo activation remains to be further investigated. The interaction of antigen (Ag) and antibody plays a critical role in evoking allergy attacks. This study aims to elucidate the role of FcγRI, the high affinity receptor of IgG, in the Ag-mediated Eo activation. METHODS: Nasal lavage fluids (NLF) were collected from AR patients and healthy control (HC) subjects. Eos were isolated by flow cytometry cell sorting and analyzed by pertinent immunological approaches. RESULTS: Eos composed more than 60% of the cellular components in AR NLF. Exposure to specific Ags (sAgs) in the culture triggered Eos to release inflammatory mediators. High levels of FcγRI were detected on the surface of AR NLF Eos. Exposure to lipopolysaccharide markedly increased the FcγRI expression in naive Eos, which could be bound by Ag-specific IgG (sIgG) to form complexes on the surface of Eos; this made Eos at the sensitized status. Eos bore with the sIgG/FcγRI complexes could be activated upon exposure to sIgG in the culture; these Eos can be designated as Ag-specific Eos. Passive transfer of Ag-specific Eos resulted in profound AR response in mice upon sAg challenge. Depletion of FcγRI on Eos efficiently abolished AR response in mice. CONCLUSIONS: AR Eos express high levels FcγRI, that can be bound by sIgG to make Eos sensitized. Re-exposure to specific Ags can activate the sensitized Eos.

Probiotic extracts ameliorate nasal allergy by inducing interleukin-35-producing dendritic cells in mice.

BACKGROUND: The therapeutic efficacy of allergic rhinitis (AR) needs to be improved. Probiotics have immunoregulatory functions. In this study we evaluated the effects of protein extracts of probiotics in the amelioration of AR. METHODS: Extracts of Bifidobacterium infantis (EBI) were prepared by lysing the live probiotics. AR mice were developed to be used to evaluate the therapeutic efficacy of EBI. RESULTS: The results show that EBI induced interleukin (IL)-10-producing dendritic cells (DCs) via increasing IL-35 and signal transducer and activator of transcription 3 (STAT3) phosphorylation. IL-10-expressing DCs induced IL-10-producing B cells (B10 cells), with the latter showing immunosuppressive functions. After challenge with specific antigens, AR mice showed sneezing, nasal itch, and increases in serum-specific immunoglobulin E (IgE) and mouse mast cell protease-1; higher levels of T helper 2 (Th2) cytokines (IL-4, 67.17 ± 10.66; IL-5, 62.83 ± 9.70; IL-13, 51.00 ± 6.69, before treatment) in nasal mucosal protein extracts, which were significantly suppressed (IL-4, 27.00 ± 6.66; IL-5, 23.86 ± 4.53; IL-13, 25.67 ± 4.93, after treatment (p < 0.001) by administration with EBI nasal drops. CONCLUSION: EBI can suppress AR via inducing B10 cells. Thus, after carrying out required preclinical experiments and tests, EBI has the translational potential to be used in the treatment of AR and other allergic diseases.

[Effects of cool restrain stress on eosinophils and interleukin 2 and 6 in nasal mucosa of rats with allergic rhinitis.].

OBJECTIVE: To study the effects of cool restrain stress on the accumulation of eosinophils and expression of Th cytokines in rat nasal mucosa with allergic rhinitis model. METHODS: Fifty healthy female rats were randomly divided into 5 groups: control group, allergic rhinitis (AR) group, AR plus stress group, stress plus AR group and simultaneous stress-AR group. Cool restrain stress, AR model and simultaneous stress-AR were made. Nasal mucosa of septum from rats of five groups were stained routinely by haematoxylin eosin (HE) and immunohistochemistry respectively. The density of eosinophils and expression of interleukin (IL)2, IL-6 were observed by using software of image analysis systems under microscope. RESULTS: The density of eosinophiles and IL-6 in the nasal mucosa of stress-AR group were significantly higher than those in AR [(14.1 +/- 3.2) for eosinophiles, and (15.3 +/- 4.8) for IL-6 ] and were also significantly higher than those in control groups [(2.3 +/- 1.4) for eosinophiles, and (4.9 +/- 2.4) for IL-6)], and the differences reached statistical significance. (F were respectively 7.06, 7.14, 8.54, 8.20, P were respectively < 0.05 or < 0.01), but no significant differences of the three groups (AR plus stress, stress plus AR and simultaneous stress-AR groups) were found (F were respectively 2.90 and 3.20, P > 0.05). The expression of IL-2 in nasal mucosa of stress-AR group was significantly reduced compared with AR and control groups (F were respectively 7.27, 7.32, P were respectively < 0.05 or < 0.01). But there were also no significant differences of the three groups (AR plus stress, stress plus AR and simultaneous stress-AR groups, F = 3.12, P > 0.05). CONCLUSIONS: The abnormal infiltration and accumulation of eosinophiles and the differences in expression of IL-2 and IL-6 which represented Th1 and Th2 cytokines in rats nasal mucosa varied in different groups. The eosinophiles and IL-6 were rarely expressed in control group and moderately expressed in AR group, but significantly expressed in cool restrain groups. The IL-2 representing Th1 cytokines were reduced in cool restrain stress gruops. All these results indicated that cool restrain stress might play a role in inducing rat allergic rhinitis.