Role of IgE in Th2 cell-mediated allergic airway inflammation

Recent studies with gene knockout mice have demonstrated that T helper 2 (Th2) cell-derived cytokines, including IL-4, IL-5, and IL-13, play important roles in causing allergic airway inflammation. In addition to Th2 cytokines, IgE-dependent activation of mast cells has been suggested to play a role in allergic airway inflammation. In this review, we will discuss the role of IgE in Th2 cell-mediated allergic airway inflammation. We used IgE transgenic mice, which enabled us to investigate the role of IgE without the influence of activated T cells and other immunoglobulins. Whereas IgE cross-linking by antigens did not induce eosinophil recruitment into the airways or airway hyperreactivity, IgE cross-linking induced CD4+ T cell recruitment into the airways. In addition, when antigen-specific Th2 cells were transferred to IgE transgenic mice, IgE cross-linking significantly enhanced antigen-induced eosinophil recruitment into the airways. These findings suggest that IgE-dependent mast cell activation plays an important role in allergic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.     

DC-derived TSLP promotes Th2 polarization in LPS-primed allergic airway inflammation

Thymic stromal lymphopoietin (TSLP) plays important roles in the pathogenesis of allergic diseases. Whether and how TSLP is involved in the initial priming of T helper type‐2 (Th2) differentiation against harmless antigen remains unclear. Using an intranasal sensitization protocol with OVA and LPS, we showed that TSLP signaling is required for low‐dose LPS‐induced Th2 inflammation, but not for high‐dose LPS‐induced Th1 immunity. We further demonstrated that low‐dose LPS‐activated bone marrow‐derived dendritic cells expressed relatively high Tslp but low Il12a, and were able to prime naïve DO11.10 T cells to differentiate into Th2 cells in a TSLP‐dependent manner. After transfer into wild‐type recipient mice, the low‐dose LPS‐activated OVA‐loaded dendritic cells (DCs) induced airway eosinophilia, but primed neutrophil‐dominated airway inflammation when TSLP‐deficient DCs were used. These studies demonstrate that TSLP released by DCs in response to a low concentration of LPS plays a role in priming Th2 differentiation and thus may serve as a polarizing third signal, in addition to antigen/MHC class II and co‐stimulatory factors, from antigen‐presenting DCs to direct effector T‐cell differentiation.     

Th1/Th2细胞因子处理的树突状细胞在过敏性气道炎症中作用

目的 探讨Th1/Th2细胞因子IL-4或IFN7对树突状细胞生物学性状的影响以及经IL-4或IFNγ处理后的树突状细胞在过敏性气道炎症中的作用.方法 体外扩增小鼠骨髓来源的树突状细胞,采用流式细胞术检测IL-4或IFNγ对树突状细胞表型的影响以及观察IL-4或IFNγ处理的树突状细胞对T细胞的作用;观察IL-4或IFNγ处理的树突状细胞过继卵蛋白致敏小鼠肺组织病理特点和支气管肺泡灌洗液细胞类型.结果 IL-4或IFNγ处理的树突状细胞表达CD80和MHC Ⅱ均明显增加并呈剂量依赖性;IL-4处理的树突状细胞显著增加T细胞分泌IL-4,而IFNγ处理的树突状细胞显著增加T细胞分泌IL-4和IFNγ;IL-4或IFNγ处理的树突状细胞过继小鼠肺组织可见典型的过敏性气道炎症改变,支气管肺泡灌洗液细胞类型与哮喘组无显著差异.结论 IL-4活化的树突状细胞诱导Th2免疫反应,IFNγ活化的树突状细胞诱导Th1和Th2免疫反应,而且IFNγ并未改善过敏性气道炎症.     

Food allergy promotes a Th2/Th17 response that drives house dust mite-induced allergic airway inflammation in humanized mice

Food allergy is related to increasing risk of the development of allergic asthma, but the precise interplay between sensitization to different allergens in different compartments of the body is not fully understood. The aim of this study was to develop a novel humanized murine model of mixed food and respiratory allergy that recapitulates the human anaphylactic response and to more clearly understand the impact of food allergies on asthma. Immunodeficient mice transferred with peripheral blood mononuclear cells (PBMCs) from donors with peanut and house dust mite (HDM) allergy were exposed and challenged to peanut. Between peanut exposure and challenge, mice were intranasally treated to HDM. Allergic parameters were analyzed. Allergen-specific immunoglobulin (Ig)E in sera could only be measured in mice treated with peripheral blood mononuclear cells (PBMCs) plus allergen. A preceding peanut exposure increased IgE levels, histamine release, bronchial hyper-responsiveness and lung inflammation. Recruitment of inflammatory cells to the airways was aggravated associated with an enhanced T helper type 2 (Th2)/Th17 cytokine secretion when the two allergies were present. A preceding peanut exposure amplifies allergic asthma in this humanized model, which may contribute to the understanding of underlying immunological mechanism of polysensitization occurring in allergic individuals and evaluation of therapeutic interventions.     

Murine lung eosinophil activation and chemokine production in allergic airway inflammation

Eosinophils play important roles in asthma and lung infections. Murine models are widely used for assessing the functional significance and mechanistic basis for eosinophil involvements in these diseases. However, little is known about tissue eosinophils in homeostasis. In addition, little data on eosinophil chemokine production during allergic airway inflammation are available. In this study, the properties and functions of homeostatic and activated eosinophils were compared. Eosinophils from normal tissues expressed costimulation and adhesion molecules B7-1, B7-2 and ICAM-1 for Ag presentation but little major histocompatibility complex (MHC) class II, and were found to be poor stimulators of T-cell proliferation. However, these eosinophils expressed high levels of chemokine mRNA including C10, macrophage inflammatory protein (MIP)-1α, MIP-1γ, MIP-2, eotaxin and monocyte chemoattractant protein-5 (MCP-5), and produced chemokine proteins. Eosinophil intracellular chemokines decreased rapidly with concomitant surface marker downregulation upon in vitro culturing consistent with piecemeal degranulation. Lung eosinophils from mice with induced allergic airway inflammation exhibited increased chemokines mRNA expression and chemokines protein production and upregulated MHC class II and CD11c expression. They were also found to be the predominant producers of the CCR1 ligands CCL6/C10 and CCL9/MIP-1γ in inflamed lungs. Eosinophil production of C10 and MIP-1γ correlated with the marked influx of CD11b^high lung dendritic cells during allergic airway inflammation and the high expression of CCR1 on these dendritic cells (DCs). The study provided baseline information on tissue eosinophils, documented the upregulation of activation markers and chemokine production in activated eosinophils, and indicated that eosinophils were a key chemokine-producing cell type in allergic lung inflammation.     

Pristimerin attenuates ovalbumin-induced allergic airway inflammation in mice

Pristimerin has been shown to possess antiinflammatory activity. However, its potential use for asthma induced by airway inflammation has not yet been studied. First, we established a ovalbumin (OVA)-induced allergic asthma mice model. BALB/c mice were immunized and challenged by OVA. Treatment with pristimerin caused a marked reduction in the levels of OVA-specific IgE, immune cells, and IL-4, IL-5, IL-13 secretion. Histological studies using H&E staining were used to study the alterations in lung tissue. These results were similar to those obtained with dexamethasone treatment. We then investigated which signal transduction mechanisms could be implicated in pristimerin activity by Western blot. The data showed that pristimerin could inhibit MAPKs and NF-κB inflammatory pathways.     

Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation

Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4‐mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen‐activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE‐12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE‐12 did not affect CXCL12‐mediated calcium influx, indicating that CXCR7 does not modulate CXCR4‐mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12‐mediated signalling through β‐arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.     

薯蓣皂苷减轻卵清蛋白诱导的过敏性哮喘小鼠的气道炎症

目的探讨薯蓣皂苷对卵清蛋白(ovalbumin,OVA)诱导的过敏性哮喘小鼠中过敏性支气管炎的影响及机制。方法24只小鼠随机分为对照组、OVA组、OVA+30 mg/kg薯蓣皂苷组和OVA+60 mg/kg薯蓣皂苷组,每组纳入6只小鼠。全自动生化仪检测各组支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)中嗜中性粒细胞、嗜酸性粒细胞和单核细胞的数量;ELISA法检测BALF中促炎因子IL-1β、IL-4、IL-5和TNF-α的含量;PAS染色法观察肺组织黏液分泌情况并对黏液分泌程度进行评分;免疫组化法观察肺组织p-NF-κB p65的表达和分布情况;Western blotting法检测肺组织中p-IκB和NF-κB p65的蛋白表达水平。结果薯蓣皂苷可降低过敏性哮喘小鼠BALF中炎性细胞数量,同时降低BALF中促炎因子IL-1β、IL-4、IL-5和TNF-α的水平以及肺部黏液的分泌和NF-κB的活化水平。结论薯蓣皂苷能减轻过敏性哮喘小鼠的气道炎症,且其抗炎作用与抑制NF-κB活化有关。     

Effects of phenanthraquinone on allergic airway inflammation in mice

BACKGROUND: Diesel exhaust particles (DEP) enhance allergic airway inflammation in mice (Takano et al., Am J Respir Crit Care Med 1997; 156: 36-42). DEP consist of carbonaceous nuclei and a vast number of organic chemical compounds. However, it remains to be identified which component(s) from DEP are responsible for the enhancing effects. 9,10-Phenanthraquinone (PQ) is a quinone compound involved in DEP. OBJECTIVE: To investigate the effects of PQ inoculated intratracheally on allergic airway inflammation related to ovalbumin (OVA) challenge. MATERIALS AND METHODS: We evaluated effects of PQ on airway inflammation, local expression of cytokine proteins, and allergen-specific immunoglobulin production in mice in the presence or absence of OVA. Results In the presence of OVA, PQ (2.1 ng/animal) significantly increased the numbers of eosinophils and mononuclear cells in bronchoalveolar lavage fluid as compared with OVA alone. In contrast, the numbers of these cells around the airways were not significantly different between OVA challenge and OVA plus PQ challenge in lung histology. PQ exhibited adjuvant activity for the allergen-specific production of IgG1 and IgE. OVA challenge induced significant increases in the lung expression of IL-4, IL-5, eotaxin, macrophage chemoattractant protein-1, and keratinocyte chemoattractant as compared with vehicle challenge. However, the combination of PQ with OVA did not alter the expression levels of these proteins as compared with OVA alone. CONCLUSION: These results indicate that PQ can enhance the immunoglobulin production and the infiltration of inflammatory cells into alveolar spaces that are related to OVA, whereas PQ seems to be partially responsible for the DEP toxicity on the allergic airway inflammation.     

Schnurri-2 regulates Th2-dependent airway inflammation and airway hyperresponsiveness

Schnurri (Shn)-2 is a large zinc finger-containing protein, which plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient (Shn-2(-/-)) CD4 T cells, the activation of nuclear factor-kappaB is up-regulated and their ability to differentiate into Th2 is enhanced. Here, we extend our investigation and demonstrate that Shn-2 regulates Th2 responses in vivo using an ovalbumin-induced allergic asthma model. Eosinophilic inflammation, mucus hyperproduction and airway hyperresponsiveness (AHR) were all enhanced in Shn-2(-/-) mice. Moreover, eosinophilic infiltration and AHR were enhanced in mice given a transfer of Shn-2(-/-) effector Th2. Shn-2 in Th2 is thus considered to play an important role as a negative regulator in allergic airway inflammation.     

Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice

Bone marrow-derived mesenchymal stromal cells (BMSCs) mitigate inflammation in mouse models of acute lung injury. However, specific mechanisms of BMSC actions on CD4 T lymphocyte-mediated inflammation in vivo remain poorly understood. Limited data suggests promotion of Th2 phenotype in models of Th1-mediated diseases. However, whether this might alleviate or worsen Th2-mediated diseases such as allergic asthma is unknown. To ascertain the effects of systemic administration of BMSCs in a mouse model of Th2-mediated allergic airways inflammation, ovalbumin (OVA)-induced allergic airways inflammation was induced in wild-type C57BL/6 and BALB/c mice as well as in interferon-γ (IFNγ) receptor null mice. Effects of systemic administration during antigen sensitization of either syngeneic or allogeneic BMSC on airways hyperreactivity, lung inflammation, antigen-specific CD4 T lymphocytes, and serum immunoglobulins were assessed. Both syngeneic and allogeneic BMSCs inhibited airways hyperreactivity and lung inflammation through a mechanism partly dependent on IFNγ. However, contrary to existing data, BMSCs did not affect antigen-specific CD4 T lymphocyte proliferation but rather promoted Th1 phenotype in vivo as assessed by both OVA-specific CD4 T lymphocyte cytokine production and OVA-specific circulating immunoglobulins. BMSCs treated to prevent release of soluble mediators and a control cell population of primary dermal skin fibroblasts only partly mimicked the BMSC effects and in some cases worsened inflammation. In conclusion, BMSCs inhibit Th2-mediated allergic airways inflammation by influencing antigen-specific CD4 T lymphocyte differentiation. Promotion of a Th1 phenotype in antigen-specific CD4 T lymphocytes by BMSCs is sufficient to inhibit Th2-mediated allergic airways inflammation through an IFNγ-dependent process.     

Attenuation of allergic airway inflammation in IL-4 deficient mice

To investigate the role of IL-4 in vivo in allergic asthma, we developed a murine model of allergen-induced airway inflammation. Repealed daily exposures of actively immunised C57BL/6 mice to aerosolized ovalbumin (OVA) induced a peribronchial inflammation and an increase in eosinophils and lymphocytes in bronchoalveolar-lavage(BAL) fluid. In IL-4 deficient (IL4^?/?) mice, treated in the same way, there were substantially fewer eosinophils in BAL and much less peribronchial inflammation compared with wild type mice. In this model, mast cell deficient (W/W^v) mice developed a similar degree of BAL eosinophilia and peribronchial inflammation as wild type mice, demonstrating that the mast cell is not required for the induction of chronic airway inflammation. In contrast, BAL eosinophilia and airway inflammation were absent in OVA-treated MHC ClassII deficient (B6.Aa^?/?) mice which lack mature CD4⁺ T lymphocytes. In conclusion, these results indicate that IL-4 is a central mediator of allergic airway inflammation, regulating antigen-induced eosinophil recruitment into the airways by a T cell dependent mechanism.