T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-γ and IL-13 production

131

Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ–producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target.

mentioning

confidence: 72%

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Wang

Baines

et al. 2010

131

“…Thus, we were able to demonstrate that an important second signal, associated with the activation of innate host defense pathways by LPS, contributes to a mechanism whereby Th1 cells induce AHR and enhance the recruitment of pulmonary neutrophils. LPS has been previously shown to cooperate with Th cells of a mixed phenotype, which secrete both IFN-␥ and type 2 cytokines (e.g., IL-13 and IL-9) and induced eosinophilic (similar to Th2-induced responses) and neutrophilic inflammation in response to Ag challenge (27). In this model, IL-18 played a critical role in promoting the mixed Th phenotype and AHR but the role of neutrophils and macrophages and the steroid sensitivity of the response was not determined.…”

Section: Discussionmentioning

confidence: 99%

“…In some settings, Agspecific Th1 cells may induce AHR and features of allergic inflammation by IFN-␥ and IL-13 production (27). To determine the role of the IL-13/STAT6 pathway as a common downstream effector mechanism for AHR induced by Th2 and Th1 cells, we compared airway reactivity and inflammation in WT and STAT6 Ϫ/Ϫ mice treated with Th1/OVA plus LPS or IFN-␥ plus LPS (Fig.…”

Section: Ahr Induced By Th1 Cells and Lps But Not Th2 Cells Is Stermentioning

confidence: 99%

Pathogenesis of Steroid-Resistant Airway Hyperresponsiveness: Interaction between IFN-γ and TLR4/MyD88 Pathways

Yang

Kumar

Foster

2009

110

Chronic inflammation and airway hyperresponsiveness (AHR) in asthmatics are usually managed effectively by treatment with glucocorticoids. However, a subset of patients remains refractory to therapy. The underlying mechanisms are largely unknown, although recruitment of neutrophils (rather than eosinophils) is strongly correlated, suggesting a role for nonallergic host defense responses. Increased levels of IFN-γ and endotoxins are also related to severe asthma and because these activate host defense pathways, we investigated a possible common etiologic link to steroid-resistant disease. To be able to unravel the complexity of asthmatic inflammation, we used two model systems which permitted dissection of the relevant molecular pathways. In the first of these, we transferred transgenic OVA323–339 peptide-specific IFN-γ-producing Th1 cells into mice. These animals were subsequently challenge via the airways with OVA323–339 peptide and/or LPS. Challenge with both components, but not with either one individually, induced AHR. Importantly, AHR was resistant to treatment with dexamethasone. Development of AHR was dependent on IFN-γ, inhibited by depletion of pulmonary macrophages (but not neutrophils) and abrogated in TLR4- or MyD88-deficient mice. In contrast, in the second model in which we transferred OVA323–339 peptide-activated Th2 cells, eosinophilic inflammation and AHR were induced, and both were suppressed by steroid treatment. We conclude that cooperative signaling between IFN-γ and TLR4/MyD88 constitutes a previously unrecognized pathway that regulates macrophage-dependent steroid-resistant AHR.

“…It has been generally accepted that Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13 play critical roles in orchestrating and amplifying allergic inflammation in asthma. Th1 cytokine IFN-␥ was thought to prevent this process (2,3), however, recent studies indicate that IFN-␥ secreted by Th1 cells may cause severe airway inflammation under certain conditions (4,5).…”

mentioning

confidence: 99%

IL-17-Producing Alveolar Macrophages Mediate Allergic Lung Inflammation Related to Asthma

Song¹,

Luo²,

Zhang³

et al. 2008

265

207

IL-17 is a pivotal proinflammatory molecule in asthmatics. However, the cellular source of IL-17 in asthma has not been identified to date. In this study, we report that macrophages rather than Th17 cells are the main producer of IL-17 in allergic inflammation related to asthma. After OVA challenge in a mouse model mimicking allergic asthma, the increased IL-17+ cells in the lung were mainly CD11b+F4/80+ macrophages, instead of T cells or others. Importantly, IL-17+ alveolar macrophages (AMs), but not IL-17+ interstitial macrophages, were significantly increased after allergen challenge. The increase of IL-17+ AMs was not due to the influx of IL-17+ macrophages from circulation or other tissues, but ascribed to the activation of AMs by mediator(s) secreted by IgE/OVA-activated mast cells. Depleting alveolar macrophages or neutralizing IL-17 prevented the initiation of OVA-induced asthma-related inflammation by inhibiting the increase of inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid. Th2 cytokine IL-10 could down-regulate IL-17 expression in alveolar macrophages. The increased IL-17 and the decreased IL-10 in bronchoalveolar lavage fluid were further confirmed in asthmatic patients. These findings suggest that IL-17 is mainly produced by macrophages but not Th17 cells in allergic inflammation related to asthma. Mast cell-released mediators up-regulate the expression of IL-17 by macrophages, whereas IL-10 down-regulates IL-17 expression.