Lixia Xia

Tc17 cells are associated with cigarette smoke-induced lung inflammation and emphysema.

Some types of T lymphocytes, especially cytotoxic T‐cells (Tc1) and T‐helper (Th17) cells, play a pivotal role in cigarette smoke‐induced lung diseases. However, whether Tc17 cells are involved remains largely unknown. We investigated Tc17 involvement using a cigarette smoke‐exposure model.

Rapamycin inhibition of eosinophil differentiation attenuates allergic airway inflammation in mice

The mammalian target of rapamycin (mTOR) signalling pathway regulates immune responses, and promotes cell growth and differentiation. Inhibition of mTOR with rapamycin modulates allergic asthma, while the underlying molecular mechanisms remain elusive. Here, we demonstrate that rapamycin, effectively inhibits eosinophil differentiation, contributing to its overall protective role in allergic airway inflammation.

Exogenous Interleukin-17A Inhibits Eosinophil Differentiation and Alleviates Allergic Airway Inflammation

IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5-transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.

Bcl-2 inhibitors reduce steroid-insensitive airway inflammation

Background Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid‐resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies. Objective We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid‐insensitive neutrophilic asthma. Methods Mouse models of either eosinophil‐dominated or neutrophil‐dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro. We also used vav–Bcl‐2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl‐2 inhibitors ABT‐737 or ABT‐199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness. Results Overexpression of Bcl‐2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen‐induced airway inflammation aggravated and persisted in vav–Bcl‐2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl‐2 and resistant to apoptosis. The Bcl‐2 inhibitors ABT‐737 or ABT‐199 play efficient roles in alleviation of either eosinophilic or corticosteroid‐resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, TH2 cells, TH17 cells, and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroids to induce granulocyte apoptosis ex vivo from patients with severe asthma. Conclusion Apoptosis of inflammatory cells is essential for clearance of allergen‐induced airway inflammation. The Bcl‐2 inhibitors ABT‐737 or ABT‐199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid‐insensitive neutrophilic airway inflammation.

Prevention of allergic airway hyperresponsiveness and remodeling in mice by Astragaliradix Antiasthmatic decoction

BackgroundAstragali radix Antiasthmatic Decoction (AAD), a traditional Chinese medication, is found effective in treating allergic diseases and chronic cough. The purpose of this study is to determine whether this medication could suppress allergen-induced airway hyperresponsiveness (AHR) and remodeling in mice, and its possible mechanisms.MethodsA mouse model of chronic asthma was used to investigate the effects of AAD on the airway lesions. Mice were sensitized and challenged with ovalbumin (OVA), and the extent of AHR and airway remodeling were characterized. Cells and cytokines in the bronchoalveolar lavage fluid (BALF) were examined.ResultsAAD treatment effectively decreased OVA-induced AHR, eosinophilic airway inflammation, and collagen deposition around the airway. It significantly reduced the levels of IL-13 and TGF-β1, but exerted inconsiderable effect on INF-γ and IL-10.ConclusionsAAD greatly improves the symptoms of allergic airway remodeling probably through inhibition of Th2 cytokines and TGF-β1.

Ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade

Ozone is a common environmental air pollutant leading to respiratory illness. The mechanisms regulating ozone-induced airway inflammation remain poorly understood. We hypothesize that ozone-triggered inflammasome activation and interleukin (IL)-1 production regulate neutrophilic airway inflammation through IL-17A. Pulmonary neutrophilic inflammation was induced by extended (72 h) low-dose (0.7 ppm) exposure to ozone. IL-1 receptor 1 (Il1r1)−/−, Il17a−/− mice and the caspase-1 inhibitor acetyl-YVAD-chloromethylketone (Ac-YVAD-cmk) were used for in vivo studies. Cellular inflammation and protein levels in bronchial alveolar lavage fluid (BALF), cytokines, and IL-17A-producing γδT-cells, as well as mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) release, and inflammasome activation in lung macrophages were analyzed. Ozone-induced neutrophilic airway inflammation, accompanied an increased production of IL-1β, IL-18, IL-17A, Granulocyte-colony stimulating factor (G-CSF), Interferon-γ inducible protein 10 (IP-10) and BALF protein in the lung. Ozone-induced IL-17A production was predominantly in γδT-cells, and Il17a-knockout mice exhibited reduced airway inflammation. Lung macrophages from ozone-exposed mice exhibited higher levels of mitochondrial ROS, enhanced cytosolic mtDNA, increased caspase-1 activation, and higher production of IL-1β. Il1r1-knockout mice or treatment with Ac-YVAD-cmk decreased the IL-17A production and subsequent airway inflammation. Taken together, we demonstrate that ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade.

Balance of apoptotic cell death and survival in allergic diseases

Allergic diseases result from over-reaction of the immune system in response to exogenous allergens, where inflammatory cells have constantly extended longevity and contribute to an on-going immune response in allergic tissues. Here, we review disequilibrium in the death and survival of epithelial cells and inflammatory cells in the pathological processes of asthma, atopic dermatitis, and other allergic diseases.

mTOR complexes differentially orchestrates eosinophil development in allergy

Eosinophil infiltration is considered a hallmark in allergic airway inflammation, and the blockade of eosinophil differentiation may be an effective approach for treating eosinophil-related disorders. Mammalian target of rapamycin (mTOR) is a vital modulator in cell growth control and related diseases, and we have recently demonstrated that rapamycin can suppress eosinophil differentiation in allergic airway inflammation. Considering its critical role in haematopoiesis, we further investigated the role of mTOR in eosinophil differentiation in the context of asthmatic pathogenesis. Intriguingly, the inhibition of mTOR, either by genetic deletion or by another pharmacological inhibitor torin-1, accelerated the eosinophil development in the presence of IL-5. However, this was not observed to have any considerable effect on eosinophil apoptosis. The effect of mTOR in eosinophil differentiation was mediated by Erk signalling. Moreover, myeloid specific knockout of mTOR or Rheb further augmented allergic airway inflammation in mice after allergen exposure. Ablation of mTOR in myeloid cells also resulted in an increased number of eosinophil lineage-committed progenitors (Eops) in allergic mice. Collectively, our data uncovered the differential effects of mTOR in the regulation of eosinophil development, likely due to the distinct functions of mTOR complex 1 or 2, which thus exerts a pivotal implication in eosinophil-associated diseases.

Nuclear erythroid 2 p45-related factor–2 Nrf2 ameliorates cigarette smoking-induced mucus overproduction in airway epithelium and mouse lungs

BACKGROUND AND OBJECTIVE Nuclear erythroid 2 p45-related factor-2 (Nrf2) is known to play important roles in airway disorders, whereas little has been investigated about its direct role in airway mucus hypersecretion. The aim of this study is to determine whether this factor could protect pulmonary epithelium and mouse airway from cigarette-induced mucus overproduction. METHODS Using genetic approaches, the role of Nrf2 on cigarette smoking extracts (CSE) induced MUC5AC expression was investigated in lung A549 cells. Nrf2 deficiency mice were smoked for various periods, and the airway inflammation and mucus production was characterized. RESULTS Acute smoking exposure induced expression of MUC5AC and Nrf2 in both A549 cells and mouse lungs. Genetic ablation of Nrf2 augmented, whereas overexpression of this molecule ameliorated CSE-induced expression of MUC5AC. Nrf2 knockout mice, after exposure to cigarette smoking, displayed enhanced airway inflammation and mucus production. CONCLUSION Nrf2 negatively regulated smoking-induced mucus production in vitro and in vivo, suggesting therapeutic potentials of this factor in airway diseases with hypersecreted mucus.