Maintenance of airway hyperresponsiveness in chronic asthma may be mediated by Th2-independent mechanisms*1 (original) (raw)
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Open Allergy J, 2008
CD4+, Th2-mediated inflammation is an important component of airway hyperresponsiveness (AHR) in allergic airway disease. IL-4 specifically interacts with the Type 1 IL-4 receptor comprised of IL-4R and the common chain, whereas IL-4 and IL-13 mediate their effects through a common receptor complex made up of IL-4R and IL-13R 1 (i.e. the Type II IL-4 receptor). In this study, we examined the effects of impaired Th2 signaling on AHR using IL4R -/mice in a murine model of allergic asthma. IL-4R -/mice and control BALB/c (IL-4R +/+ ) mice were sensitized to and challenged with Aspergillus fumigatus. Airway disease was assessed at days 14, 28, 51, and 57 after intratracheal conidia challenge. AHR was evaluated by plethysmography after intravenous methacholine. Whole lung levels of cytokines and chemokines, and serum immunoglobulins were measured by specific ELISA. Paraffin-embedded lung sections were stained for histology. Bronchoalveolar lavage (BAL) fluid was cytospun for differential cell counts. While AHR was significantly reduced in IL-4R -/mice (p<0.01) at days 14 and 28 after conidia challenge, it was increased when compared to controls at later time points (days 51 and 57) even though Th2 cytokines were significantly decreased at day 57, and total IgE and IgG1 levels were markedly decreased throughout the study (p<0.0001). Goblet cell metaplasia was also evident at days 51 and 57 in the knockout groups. These results demonstrate that airway hyperresponsiveness and mucus cell metaplasia in a model of allergic asthma can develop in the absence of a predominant Th2 signaling pathway, suggesting that Th2-independent mechanisms may arbitrate chronic stages of airway disease due to A. fumigatus.
American Journal of Respiratory Cell and Molecular Biology, 2002
Airway inflammation and airway hyperresponsiveness (AHR) are hallmarks of asthma. Cytokines produced by T helper type 2 (Th2) lymphocytes have been implicated in both processes. There is strong support for the idea that Th2 cytokines can produce AHR indirectly by promoting the recruitment of inflammatory cells. Less attention has been given to the possibility that Th2 cytokines might induce AHR by acting directly on resident airway cells. To investigate this, we polarized and activated CD4 ؉ T cells in vitro and analyzed airway function after administration of lymphocyte-conditioned media to the airways of naive mice. Th2-lymphocyte-conditioned medium induced AHR within 6 h. This finding was reproduced in mastcell-deficient and in T-and B-lymphocyte-deficient mice. AHR did not occur when Th2-lymphocyte-conditioned medium was administered to mice lacking the IL-4 receptor ␣ subunit or Stat6, suggesting a critical role for interleukin (IL)-4 and/or IL-13. This was confirmed by the finding that recombinant IL-4 and IL-13 both induced AHR within 6 h. The induction of AHR occurred in the absence of inflammatory cell recruitment or mucus production. These results strongly suggest that products of activated Th2 lymphocytes can rapidly perturb airway function through direct effects on resident airway cells.
Clinical & Experimental Allergy, 2007
T-helper type 2 (Th2)-derived cytokines such as IL-4, IL-5, IL-9 and IL-13 play an important role in the synthesis of IgE and in the promotion of allergic eosinophilic inflammation and airway wall remodelling. We determined the importance of IL-13 alone, and of the four Th2 cytokines together, by studying mice in which either IL-13 alone or the Th2 cytokine cluster was genetically disrupted. The knock-out mice and their BALB/c wild-type (wt) counterparts were sensitized and repeatedly exposed to ovalbumin (OVA) aerosol. Bronchial responsiveness measured as the concentration of acetylcholine aerosol needed to increase baseline lung resistance by 100% (PC100) was decreased in IL-13-/-, but increased in IL-4/5/9/13-/- mice. Chronic allergen exposure resulted in airway hyperresponsiveness (AHR) in wt mice but not in both genetically modified mice. After allergen exposure, eosinophil counts in bronchoalveolar lavage fluid and in airways mucosa, and goblet cell numbers were not increased in IL-4/5/9/13-/- mice, and were only attenuated in IL-13-/- mice. Airway smooth muscle (ASM) hyperplasia after allergen exposure was prevented in both IL-13-/- and IL-4/5/9/13-/- mice to an equal extent. Similarly, the rise in total or OVA-specific serum IgE levels was totally inhibited. IL-13 is mainly responsible for AHR, ASM hyperplasia and increases in IgE, while IL-4, -5 and -9 may contribute to goblet cell hyperplasia and eosinophilic inflammation induced by chronic allergen exposure in a murine model. Both redundancy or complementariness of Th2 cytokines can occur in vivo, according to specific aspects of the allergic response.
Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness
The Journal of allergy and clinical immunology, 2015
TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, ...
Allergen-induced Th2-independent production of IL-4 in the airways of mice
Matters (Zürich), 2016
It is thought that release of cytokines from allergen-damaged epithelial cells induces production of an innate source of IL-4 and IL-13 that are important in initiating adaptive T-helper type II (Th2)-mediated allergic responses. However, detecting innate production of IL-4 or IL-13 in vivo is difficult due to high levels of adaptive production of IL-4 and IL-13 by Th2 cells. The IL-4 receptor (IL-4R) and the IL-4/13 co-receptor (IL-13R) share a common receptor subunit (IL-4Ra). Consequently, both IL-4 and IL-13 signal via the IL-4Ra-associated signaling molecule, signal transducer and activator of transcription factor 6 (STAT6). STAT6 signaling in T-cells, B-cells, and airway epithelial cells is essential for Th2 differentiation, isotype class switching to IgE, and mucus production, respectively. Therefore, Epi-STAT6 mice (STAT6-/-mice with airway epithelial-specific transgenic STAT6 expression) are defective in Th2 immune responses but can produce mucus in response to IL-4 and/or IL-13 in their airways. As compared to wildtype mice, allergen-challenged Epi-STAT6 mice were deficient in IgE production and the levels of IL-13 expressed were not above appropriate controls. However, significant levels of IL-4 and mucin gene expression were detected in their lungs. These observations support the existence of an allergen-responsive, non-Th2-derived source of IL-4 in the airways of mice.
1996
Reversible airway hyperreactivity underlies the pathophysiology of asthma, yet the precise mediators of the response remain unclear. Human studies have correlated aberrant activation of T helper (Th) 2-like effector systems in the airways with disease. A routine model of airway hyperreactivity in response to acetylcholine was established using mice immunized with ovalburain and challenged with aerosolized antigen. No airway hyperreactivity occurred in severe combined immunodeficient mice. Identically immunized BALB/c mice developed an influx of cells, with a predominance of eosinophils and CD4 + T cells, into the lungs and bronchoalveolar lavage fluid at the time that substantial changes in airway pressure and resistance were quantitated. Challenged animals developed marked increases in Th2 cytokine production, eosinophil influx, and serum immunoglobulin E levels. Neutralization of interleukin (IL) 4 using monoclonal antibodies administered during the period of systemic immunization...
Airway Remodeling Is Absent in CCR1-/- Mice During Chronic Fungal Allergic Airway Disease
The Journal of Immunology, 2000
Asthmatic-like reactions characterized by elevated IgE, Th2 cytokines, C-C chemokines, eosinophilic inflammation, and persistent airway hyperresponsiveness follow pulmonary exposure to the spores or conidia from Aspergillus fumigatus fungus in sensitized individuals. In addition to these features, subepithelial fibrosis and goblet cell hyperplasia characterizes fungal-induced allergic airway disease in mice. Because lung concentrations of macrophage inflammatory protein-1␣ and RANTES were significantly elevated after A. fumigatus-sensitized mice received an intrapulmonary challenge with A. fumigatus spores or conidia, the present study addressed the role of their receptor, C-C chemokine receptor 1 (CCR1), in this model. A. fumigatus-sensitized CCR1 wild-type (؉/؉) and CCR1 knockout (؊/؊) mice exhibited similar increases in serum IgE and polymorphonuclear leukocyte numbers in the bronchoalveolar lavage. Airway hyperresponsiveness was prominent in both groups of mice at 30 days after an intrapulmonary challenge with A. fumigatus spores or conidia. However, whole lung levels of IFN-␥ were significantly higher whereas IL-4, IL-13, and Th2-inducible chemokines such as C10, eotaxin, and macrophage-derived chemokine were significantly lower in whole lung samples from CCR1 ؊/؊ mice compared with CCR1 ؉/؉ mice at 30 days after the conidia challenge. Likewise, significantly fewer goblet cells and less subepithelial fibrosis were observed around large airways in CCR1 ؊/؊ mice at the same time after the conidia challenge. Thus, these findings demonstrate that CCR1 is a major contributor to the airway remodeling responses that arise from A. fumigatus-induced allergic airway disease.
Journal of Infectious Diseases, 2008
Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection with Cryptococcus neoformans. Both cytokines use the IL-4 receptor alpha-chain (IL-4Ralpha). In this study, we investigated the role played by IL-4Ralpha expression in susceptibility to pulmonary C. neoformans infection. IL-4Ralpha(-/-) mice were extremely resistant. To characterize the effect of IL-4Ralpha expression level on disease outcome, we generated IL-4Ralpha(+/-) first-generation (F1) mice. IL-4Ralpha(+/-) mice showed intermediate levels of IL-4Ralpha expression, in contrast to higher levels in wild-type mice and no expression in IL-4Ralpha(-/-) mice, indicating biallelic expression of the gene for IL-4Ralpha (Il4ra). Concomitant with intermediate IL-4Ralpha expression, F1 mice showed intermediate susceptibility associated with altered Th2/Th17 cytokine production, decreased immunoglobulin E levels, and reduced allergic inflammation. This indicates a gen...