Th2 Cell-mediated Airway Inflammation Research Articles

S14G-Humanin ameliorates ovalbumin-induced airway inflammation in asthma mediated by inhibition of toll-like receptor 4 (TLR4) expression and the nuclear factor κ-B (NF-κB)/early growth response protein-1 (Egr-1) pathway.

Asthma is a chronic inflammatory disease with a high morbidity rate in children and significantly impacts their healthy growth. It is reported that Th2 cell-mediated airway inflammation and activated oxidative stress are involved in the pathogenesis of asthma. S14G-humanin (HNG) is a derivative of Humanin with higher activity. The present study proposes to explore the potential treating property of HNG on asthma. An asthma model was constructed in mice using ovalbumin (OVA), the mice were treated with 2.5 mg/kg and 5 mg/kg HNG for 16 days. Dramatically increased lung weight index, elevated number of monocytes, eosinophils, and neutrophils, promoted production of Th2 cytokines including interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), and severe histological pathology were observed in OVA-challenged mice, all of which were extremely alleviated by 2.5 mg/kg and 5 mg/kg HNG. Furthermore, the increased malondialdehyde (MDA) level and declined superoxide dismutase (SOD) activity in OVA-challenged mice were abolished by 2.5 mg/kg and 5 mg/kg HNG. Lastly, the upregulated TLR4, p-NF-κB p65, and early growth response 1 (Egr-1) in lung tissues of OVA-challenged mice were pronouncedly downregulated by 2.5 mg/kg and 5 mg/kg HNG. Collectively, our data suggested that HNG ameliorated airway inflammation in asthma partially due to NF-κB and Egr-1-mediated responses.

Critical Involvement of CD44 in T Helper Type 2 Cell-Mediated Eosinophilic Airway Inflammation in a Mouse Model of Acute Asthma.

Interactions between CD44 and hyaluronan (HA) are crucial for recruiting leukocytes to inflamed tissues. This review summarizes findings from our studies of the roles of CD44-HA interactions in leukocyte trafficking, with a particular focus on airway T helper type 2 (Th2) cells in mouse models of acute asthma. In a mite allergen-induced model of acute asthma, intraperitoneal injection of anti-CD44 monoclonal antibodies blocked lymphocytes and eosinophils from accumulating in the lung, and suppressed both the antigen-induced increase in Th2 cytokines in the bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR). CD44 deficiency was associated with decreased mite allergen-induced Th2 cell-mediated airway inflammation and AHR in sensitized mice. Asthmatic responses to antigen-sensitized splenic CD4+ T cells transferred from CD44-deficient mice were weaker than in wild-type mice. Administration of anti-CD44 monoclonal antibodies preferentially suppressed the airway accumulation of antigen-specific Th2 cells induced by antigen challenge, without affecting Th1 and Th17 cells. Increased HA-binding ability of CD44 and expression of Neu1 sialidase were observed on antigen-specific Th2 cells compared with antigen-specific Th1 and Th17 cells. Finally, in a mouse model of acute asthma, neuraminidase 1-deficient SM/J mice exhibited a lower Th2 cytokine concentration and a lower absolute Th2 cell number in the BALF, as well as an attenuated AHR. Our findings indicate that CD44 critically contributes to the antigen challenge-induced airway accumulation of antigen-specific Th2 cells, without affecting Th1 and Th17 cells, in mice. Furthermore, neuraminidase 1 activity is necessary for the interaction between HA and CD44, and Th2 cell-mediated airway inflammation.

L-type amino acid transporter 1 inhibitor suppresses murine Th2 cell-mediated bronchial hyperresponsiveness independently of eosinophil accumulation.

BackgroundThe activation of Th2 cells that play a pivotal role in the development of allergic eosinophilic inflammation is regulated by an L-type amino acid transporter (LAT) 1. However, the contribution of LAT1 to the pathogenesis of Th2 cell-mediated airway inflammation has not been investigated.ObjectiveIn this study, we investigated the effect of a LAT1 inhibitor, JPH203, on Th2 cell-mediated airway eosinophilic inflammation.MethodsBALB/c mice were transferred with ovalbumin (OVA)-specific Th2 cell and challenged by corresponding allergen with or without administration of JPH203. Then, the infiltration of inflammatory cells including eosinophils and allergen-specific Th2 cells in the lungs and bronchial hyperresponsiveness (BHR) was assessed.ResultsInflammatory responses in the lungs with massive accumulation of eosinophils and BHR were induced in Th2 cell-transferred mice upon challenge with OVA. The treatment with JPH203 significantly suppressed the allergen-induced BHR but not eosinophil infiltration. The infused Th2 cells were also accumulated in the lungs upon allergen challenge, though the response was not affected by JPH203 treatment.ConclusionJPH203 suppressed Th2 cell-mediated BHR through the mechanisms independently of the lung accumulation of eosinophils and Th2 cells.

Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation

Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.

Effect of inhibiting the phosphorylation of signal transducer and activator of transcription-3 on Th2 cell-mediated airway inflammation and airway remodeling in a mouse model of asthma

Objective To study the effect of inhibiting the phosphorylation of signal transducer and activator of transcription-3 (STAT3) on Th2 cell-mediated airway inflammation and airway remodeling, and to explore the role of STAT3 in the pathophysiology of bronchial asthma. Methods Forty Balb/c mice were randomly divided into control group(n=10), asthma group(n=10), AG490 by intraperitoneal group (n=10), and AG490 by inhalation group (n=10). The mice were sensitized with ovalbumin to establish the asthmatic model.The histological changes were evaluated by means of HE staining, while total broalchial wall thickness(Wat)and smooth muscle thickness(Wam) were mea-sured by using image analysis system.The percentages of collagen deposition were detected by way of Masson's trichrome staining; the bronchoalveolar lavage fluid (BALF) were collected, the total cell and the cell differentials were counted, the levels of IL-4, IL-5 in BALF were measured by enzyme-linked immunosorbent assay; the lung tissue extracts were analyzed for phosphorylation of STAT3(p-STAT3)by Western blot.The SPSS 13.0 software was used to analyze the data. Results 1.The histological changes by HE staining showed that less inflammatory cells infiltration in airway and around the pulmonary vascular in AG490 administration groups compared with asthmatic group.Wat, Wam and the percentages of collagen deposition in AG490 administration groups was significantly lower than that in asthmatic group(F=49.5, 41.7, 58.2, all P< 0.05).2.The level of p-STAT3 in the lung of AG490 administration groups were significantly lower than those in asthmatic group(F=34.17, P< 0.05).3. The total cells and eosinophils amounts in BALF of AG490 administration groups were significantly lower than those in asthmatic group(F=42.5, 64.7, all P< 0.05). The levels of IL-4, IL-5 in BALF of AG490 administration groups were significantly lower than those in asthmatic group, respectively (F=39.2, 75.1, all P<0.05). Conclusions STAT3 signaling pathway is pivotal in Th2 cell-mediated airway inflammation and airway remodeling in asthmatic models, and AG490 can ameliorate airway inflammation and airway remodeling efficiently by inhibiting the phosphorylation of STAT3, and targeting this signaling pathway may be a novel therapy for asthma. Key words: Asthma; Th2 type cell; Airway inflammation; Airways remodeling; Signal transducer and activator of transcription-3

House Dust Mite Allergy and Associated Allergen-Specific Immunotherapy in Allergic Asthma

Allergic asthma, an important subtype of asthma endotypes, is characterized by allergen-specific and Th2 cellmediated airway inflammation. Except for pharmacologic treatment, Allergen-specific immunotherapy (ASIT) has also been considered as a potential therapy for allergic asthma. House dust mite (HDM) is a common airborne allergen among patients with allergic asthma. This review is focused on the relationship between HDM allergy and allergic asthma, underlying mechanism of ASIT, and current evidence of HDM-specific immunotherapy for allergic asthma. It was demonstrated that HDM allergy is a risk factor associated with disease development of allergic asthma. The induction of immune tolerance by regulatory T cells was proved to play a pivotal role in the immunological mechanisms of ASIT. Experimental studies in murine models of allergic asthma reveal that HDM-specific immunotherapy has not only therapeutic efficacy but also preventive potential for disease development. The clinical trials also demonstrated the efficacy of HDM-specific immunotherapy in reducing asthma symptoms and medication use. Today, the clinical application of ASIT in allergic asthma has limitation when considering the extent of benefit and systemic adverse reactions. Although sublingual immunotherapy with HDM extract was demonstrated to have better safety profile when comparing with subcutaneous immunotherapy. To make HDM-specific immunotherapy more practicable in clinical application, further advances in the development of immunotherapy and clinical trials are needed.

Airway Inflammation and IgE Production Induced by Dust Mite Allergen-Specific Memory/Effector Th2 Cell Line Can Be Effectively Attenuated by IL-35

CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-α, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Rα(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC-motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation.

The distinct effects of a butanol fraction of Bidens pilosa plant extract on the development of Th1-mediated diabetes and Th2-mediated airway inflammation in mice

Bidens pilosa is claimed to be useful for immune or anti-inflammatory disorders; however, little scientific evidence has been published concerning its function. In this paper, immune disease mouse models were used to study the function of a butanol fraction of B.pilosa. We demonstrated treatment with the butanol fraction of B.pilosa ameliorated Th1 cell-mediated autoimmune diabetes in nonobese diabetic (NOD) mice but caused deterioration of Th2 cell-mediated airway inflammation induced by ovalbumin (OVA) in BALB/c mice. We next showed that Th2 cytokines (IL-4 and/or IL-5) increased but Th1 cytokine (IFN-gamma) decreased following injections with the butanol fraction of B.pilosa in both mouse strains. Accordingly, Th2 cytokine-regulated IgE production in mouse serum increased following treatment with this fraction. Finally, we found that the butanol fraction of B.pilosa inhibited Th1 cell differentiation but promoted Th2 cell differentiation. Taken together, the butanol fraction of B.pilosa has a dichotomous effect on helper T cell-mediated immune disorders, plausibly via modulation of T cell differentiation.