IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation

IL-23/IL-17 axis is an important regulator in various inflammatory diseases. However, the role of IL-23 in allergic airway inflammation is not well understood. In this study, we show that in an allergen-induced asthma model, mice with transgenic overexpression of IL-23R exhibited increased airway infiltration of eosinophils and Th2 cytokine production, whereas those deficient in IL-23 displayed reduced airway inflammation. In vitro, IL-23-IL-23R signaling promoted GATA-3 expression and enhanced Th2 cytokine expression. Conversely, in the absence of this signal, Th2 cell differentiation was partially inhibited. Therefore, IL-23 signaling may regulate allergic asthma through modulation of Th2 cell differentiation.

Maternal Disononyl Phthalate Exposure Activates Allergic Airway Inflammation via Stimulating the Phosphoinositide 3-kinase/Akt Pathway in Rat Pups

Objective To evaluate the effect of diisononyl phthalate（DINP） exposure during gestation and lactation on allergic response in pups and to explore the role of phosphoinositide 3-kinase/Akt pathway on it. Methods Female Wistar rats were treated with DINP at different dosages（0, 5, 50, and 500 mg/kg of body weight per day）. The pups were sensitized and challenged by ovalbumin（OVA）. The airway response was assessed; the airway histological studies were performed by hematoxylin and eosin（HE） staining; and the relative cytokines in phosphoinositide 3-kinase（PI3K）/Akt pathway were measured by enzyme-linked immunosorbent assay（ELISA） and western blot analysis. Results There was no significant difference in DINP＇s effect on airway hyperresponsiveness（AHR） between male pups and female pups. In the 50 mg/（kg·d） DINP-treated group, airway response to OVA significantly increased and pups showed dramatically enhanced pulmonary resistance（RI） compared with those from controls（P〈0.05）. Enhanced Akt phosphorylation and NF-κB translocation, and Th2 cytokines expression were observed in pups of 50 mg/（kg·d） DINP-treated group. However, in the 5 and 500 mg/（kg·d） DINP-treated pups, no significant effects were observed. Conclusion There was an adjuvant effect of DINP on allergic airway inflammation in pups. Maternal DINP exposure could promote OVA-induced allergic airway response in pups in part by upregulation of PI3K/Akt pathway.

Establishment of Allergic Airway Inflammation Model in Late-phase Response of Sprague-Dawley Rats

Objective To establish allergic airway inflammation model in late-phase airway reaction of Sprague-Dawley (SD) rats. Methods Thirty-six SD rats were randomly divided into three groups-, control group (Group Ⅰ) ,single challenge group (Group Ⅱ ),consecutive challenge group (Group Ⅲ). The rats in Group Ⅱ and Group Ⅲ were sensitized twice by injection of ovalbumin (OA) together with aluminum hydroxide and Bordetella pertussis as adjuvants, followed by challenge with aerosolized OA for 20 min once in Group Ⅱ or one time on each day for one week in, Group Ⅲ. The rats in Group Ⅰ received 0. 9% saline by injection and inhalation. Results Compared with group Ⅰ , there were positive symptoms observed in the group Ⅱ and group Ⅲ; the amount of total leucocytes and eosinophil percentage in brochoalveolar lavage fluid (BALF) significantly increased (P<0.05 or P<0. 01 respectively) in Group Ⅱ or Ⅲ ; histopathologic changes of lung showed acute allergic inflammation changes in Group Ⅱ: Disrupted epithelium damaged subepithelial structure and eosinophil infiltration in the airway wall. As for the Group Ⅲ, there were allergen- induced characteristic features of chronic allergic airways inflammation: hypertrophy and hyperplasia of bronchial smooth muscle, goblet cell hyperplasia, basement membrane thickening, eosinophil in filtration, edema. Conclusion The model of allergic airway inflammation in late-phase response of SD rats was successfully established by OA sensitization (twice) and consecutive challenge.

Therapeutic Effects of DNA Vaccine on Allergen-Induced Allergic Airway Inflammation in Mouse Model

Vaccination with DNA encoding Dermatophagoides pteronyssinus group 2 （Der p 2） allergen previously showed its effects of immunologic protection on Der p 2 allergen-induced allergic airway inflammation in mice. In present study, we investigated whether DNA vaccine encoding Der p 2 could exert therapeutic role on allergen-induced allergic airway inflammation in mouse model and explored the mechanism of DNA vaccination in asthma specific-allergen immunotherapy. After sensitized and challenged by Der p 2, the BALB/c mice were immunized with DNA vaccine. The degrees of cellular infiltration were scored. IgE levels in serum and IL-4/IL-13 levels in BALF were determined by ELISA. The lung tissues were assessed by histological examinations. Expressions of STAT6 and NF-kB in lung were determined by immunohistochemistry staining. Vaccination of mice with DNA vaccine inhibited the development of airway inflammation and the production of mucin induced by allergen, and reduced the level of Der p 2-specific IgE level. Significant reductions of eosinophil infiltration and levels of IL-4 and IL-13 in BALF were observed after vaccination. Further more, DNA vaccination inhibited STAT6 and NF-kB expression in lung tissue in Der p 2-immunized mice. These results indicated that DNA vaccine encoding Der p 2 allergen could be used for therapy of allergen-induced allergic airway inflammation in our mouse model. Cellular ＆ Molecular Immunology.

DNA vaccine encoding Der p2 allergen down-regulates STAT6 expression in mouse model of allergen-induced allergic airway inflammation

Background Activation of signal transducer and activator of transcription 6 （STAT6） plays a critical role in the late phase of Th2-dependent allergy induction. STAT6 is essential to Th2 cell differentiation, recruitment, and effector function. Our previous study confirmed that DNA vaccination inhibited STAT6 expression of spleen cells induced by allergen. In the present study, we determined whether DNA vaccine encoding Dermatophagoides pteronyssinus group 2 （Der p2 ） could down-regulate the expression and activation of STAT6 in lung tissue from asthmatic mice. Methods After DNA vaccine immunization, BALB/c mice were sensitized by intmperitoneal injection and challenged by intranasal instillation of rDer p2. The levels of the cytokines IL-4 and IL-13 in BAL fluid were measured by enzyme-linked immunosorbent assay. The lung tissue was assessed by immunohistochemical staining with anti-STAT6. The protein expression of STAT6 was determined by Western blot. The activation of STAT6 binding ability was analyzed with electrophoretic mobility shift assay. Results DNA vaccine encoding Der p2 allergen effectively decreased the levels of IL-4 and IL-13 in the asthmatic mice. Histological evidence and Western blot showed that the expression of STAT6 in the DNA treated mice was markedly attenuated. STAT6 binding to specific DNA motif in lung tissue from the gene vaccinated mice was inhibited. Condusion DNA vaccine encoding Der p2 prevents allergic pulmonary inflammation probably by inhibiting the STAT6 signaling pathway in mice with Der p2 allergen-induced allergic airway infammafion.

Plasmacytoid dendritic cell deficiency in neonates enhances allergic airway inflammation via reduced production of IFN-α

Allergic asthma,a chronic inflammatory airway disease associated with type 2 cytokines,often originates in early life.Immune responses at an early age exhibit a Th2 cell bias,but the precise mechanisms remain elusive.Plasmacytoid dendritic cells(pDCs),which play a regulatory role in allergic asthma,were shown to be deficient in neonatal mice.We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model.Adoptive transfer of pDCs or administration of IFN-αto neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1−/−mice.Similarly,adult mice developed more severe allergic inflammation when pDCs were depleted.The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20,GM-CSF,and IL-33,which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway.In asthmatic patients,the percentage of pDCs and the level of IFN-αwere lower in children than in adults.These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergeninduced allergic airway inflammation.

How Much Do We Know about Atopic Asthma: Where Are We Now?

Asthma is a common disease in the worldwide and it affects over 3.5 million adults and children in the UK. Asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation, airway remodelling and reversible airway obstruction. Inflammatory cells, cytokines, chemokines, adhesion molecules, and mediators are involved in pathogenesis of asthma. Chronic airway inflammation and remodelling are the major characters in asthma, which result in decreased pulmonary function. The precise processes are far understood at moment. Although corticosteroid therapy plus other exiting drugs （bronchodilators and oral leukotriene receptor antagonists） influences many different inflammatory and structural cell types and continues to be as the ＂gold standard＂ of therapy in asthma, many thousands have chronic, severe diseases and suffer daily symptoms which make their lives a misery. There remains a clear need for novel approaches to therapy, which will be informed by a clearer understanding of disease pathogenesis, particularly in the target organ where airway inflammation and remodelling, the hallmarks of asthma occur. Cellular ＆ Molecular Immunology.

The transcription factor RelB restrains group 2 innate lymphoid cells and type 2 immune pathology in vivo

The exact relationships between group 2 innate lymphoid cells(ILC2s)and Th2 cells in type 2 pathology,as well as the mechanisms that restrain the responses of these cells,remain poorly defined.Here we examined the roles of ILC2s and Th2 cells in type 2 lung pathology in vivo using germline and conditional fie/b-deficient mice.We found that mice with germline deletion of Relb^(-/-)spontaneously developed prominent type 2 pathology in the lung,which contrasted sharply with mice with T-cell-specific Relb deletion(Relb^(f/f)Cd4-Cre),which were healthy with no observed autoimmune pathology.We also found that in contrast to wild-type B6 mice,Rel6-defident mice showed markedly expanded ILC2s but not ILC1s or ILC3s.Moreover,adoptive transfer of naive CD4^(+)T cells into Rag1^(-/-)Relb^(-/-)hosts induced prominent type 2 lung pathology,which was inhibited by depletion of ILC2s.Mechanistically,we showed that Relb deletion led to enhanced expression of Bcl11b,a key transcription factor for ILC2s.We concluded that RelB plays a critical role in restraining ILC2s,primarily by suppressing Bcl11b activity,and consequently inhibits type 2 lung pathology in vivo.

RhoA and Cdc42 in T cells:Are they targetable for T cell-mediated inflammatory diseases?

Many inflammatory diseases are not curable,necessitating a better understanding of their pathobiology that may help identify novel biological targets.RhoA and Cdc42 of Rho family small GTPases regulate a variety of cellular functions such as actin cytoskeletal organization,cell adhesion,migration,proliferation,and survival.Recent characterization of mouse models of conditional gene knockout of RhoA and Cdc42 has revealed their physiological and cell type-specific roles in a number of cell types.In T lymphocytes,which play an important role in the pathogenesis of most,if not all,of the inflammatory diseases,we and others have investigated the effects of T cell-specific knockout of RhoA and Cdc42 on T cell development in the thymus,peripheral T cell homeostasis,activation,and differentiation to effector and regulatory T cells,and on T cell-mediated allergic airway inflammation and colitis.Here we highlight the phenotypes resulting from RhoA and Cdc42 deletion in T cells and discuss whether pharmacological targeting of RhoA and Cdc42 is feasible in treating asthma that is driven by allergic airway inflammation and colitis.