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Chlamydia pneumoniae Infection Induced Allergic Airway Sensitization Is Controlled by Regulatory T-Cells and Plasmacytoid Dendritic Cells  [PDF]
Timothy R. Crother,Nicolas W. J. Schr?der,Justin Karlin,Shuang Chen,Kenichi Shimada,Anatoly Slepenkin,Randa Alsabeh,Ellena Peterson,Moshe Arditi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020784
Abstract: Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2?/?, and TLR4?/? mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2?/? mice, but not in TLR4?/? mice, due to differential Treg responses in these genotypes. TLR2?/? mice had reduced numbers of Tregs in the lung during CP infection while TLR4?/? mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.
Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation
Ian P Lewkowich, Scottie B Day, John R Ledford, Ping Zhou, Krista Dienger, Marsha Wills-Karp, Kristen Page
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-122
Abstract: Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry.Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass-stimulated wild type BMDCs were sufficient to induce AHR and allergic airway inflammation, while GC frass-stimulated PAR-2-deficient BMDC had attenuated responses.Together these data suggest an important role for allergen activation of PAR-2
Escherichia coli Heat-Labile Detoxified Enterotoxin Modulates Dendritic Cell Function and Attenuates Allergic Airway Inflammation  [PDF]
I-Ping Lin, Yu-Shen Hsu, Ssu-Wei Kang, Miao-His Hsieh, Jiu-Yao Wang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090293
Abstract: Various mutant forms of Escherichia coli heat-labile enterotoxin (LT) have been used as a mucosal adjuvant for vaccines, as it enhances immune responses to specific antigens including antigen-specific IgA antibodies when administrated intranasally or orally. We hypothesized that a detoxified mutant form of LT, LTS61K, could modulate dendritic cell (DC) function and alleviate allergen-induced airway inflammation. Two protocols, preventative and therapeutic, were used to evaluate the effects of LTS61K in a Dermatophagoides pteronyssinus (Der p)-sensitized and challenged murine model of asthma. LTS61K or Der p-primed bone marrow-derived dendritic cells (BMDCs) were also adoptively transferred into Der p-sensitized and challenged mice. Intranasal inoculations with LTS61K or LTS61K/Der p decreased allergen-induced airway inflammation and alleviated systemic TH2-type immune responses. Bronchoalveolar lavage fluid (BALF) and sera from LTS61K/Der p-treated mice also had higher concentrations of Der p-specific immunoglobulin (Ig) A than those of other groups. In vitro, BMDCs stimulated with Der p underwent cellular maturation and secreted proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)α In contrast, Der p-stimulated BMDCs that were pretreated with LTS61K showed decreased IL-6 and TNFα production and were less mature. Intratracheal adoptive transfer of LTS61K- or LTS61K/Der p-primed BMDCs into Der p-sensitized mice reduced inflammatory cell infiltration and TH2-type chemokines in BALF and alleviated airway inflammation in treated mice. LTS61K influenced DC maturation and decreased inflammatory cytokine production. Moreover, LTS61K/Der p induced increased Der p-specific IgA production to decrease allergic TH2 cytokine responses and alleviated airway inflammation in Der p-sensitized mice. These results suggest that the immunomodulatory effects of LTS61K may have clinical applications for allergy and asthma treatment.
Antigen-Specific IgG ameliorates allergic airway inflammation via Fcγ receptor IIB on dendritic cells
Yumiko Ishikawa, Kazuyuki Kobayashi, Masatsugu Yamamoto, Kyosuke Nakata, Tetsuya Takagawa, Yasuhiro Funada, Yoshikazu Kotani, Hajime Karasuyama, Masaru Yoshida, Yoshihiro Nishimura
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-42
Abstract: In FcγRIIB deficient (KO) and C57BL/6 (WT) mice, the effects of intratracheal instillation of antigen-specific IgG were analysed using the model with sensitization and airborne challenge with ovalbumin (OVA). Thoracic lymph nodes instilled with fluorescein-conjugated OVA were analysed by fluorescence microscopy. Moreover, we analysed the CD11c+ MHC class II+ cells which intaken fluorescein-conjugated OVA in thoracic lymph nodes by flow cytometry. Also, lung-derived CD11c+ APCs were analysed by flow cytometry. Effects of anti-OVA IgG1 on bone marrow dendritic cells (BMDCs) in vitro were also analysed. Moreover, in FcγRIIB KO mice intravenously transplanted dendritic cells (DCs) differentiated from BMDCs of WT mice, the effects of intratracheal instillation of anti-OVA IgG were evaluated by bronchoalveolar lavage (BAL).In WT mice, total cells and eosinophils in BAL fluid reduced after instillation with anti-OVA IgG1. Anti-OVA IgG1 suppressed airway inflammation in hyperresponsiveness and histology. In addition, the number of the fluorescein-conjugated OVA in CD11c+ MHC class II+ cells of thoracic lymph nodes with anti-OVA IgG1 instillation decreased compared with PBS. Also, MHC class II expression on lung-derived CD11c+ APCs with anti-OVA IgG1 instillation reduced. Moreover, in vitro, we showed that BMDCs with anti-OVA IgG1 significantly decreased the T cell proliferation. Finally, we demonstrated that the lacking effects of anti-OVA IgG1 on airway inflammation on FcγRIIB KO mice were restored with WT-derived BMDCs transplanted intravenously.Antigen-specific IgG ameliorates allergic airway inflammation via FcγRIIB on DCs.It is estimated that as many as 300 million people of all ages suffer from bronchial asthma, and that asthmatic patients are increasing by 50% per decade worldwide [1]. The mucosa of respiratory tracts are replete with organized follicles and scattered antigen reactive or sensitized lymphoid elements, including B cells, T cells, plasma cells, dendriti
Resident CD11b+Ly6C? Lung Dendritic Cells Are Responsible for Allergic Airway Sensitization to House Dust Mite in Mice  [PDF]
Claire Mesnil, Catherine M. Sabatel, Thomas Marichal, Marie Toussaint, Didier Cataldo, Pierre-Vincent Drion, Pierre Lekeux, Fabrice Bureau, Christophe J. Desmet
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0053242
Abstract: Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to na?ve recipients. Transfer of lung CD11c+CD11b+ DCs, but not CD11c+CD11b?CD103+ DCs, was sufficient to prime airway allergy. The CD11c+CD11b+ DC subpopulation was composed of CD11c+CD11b+Ly6C+ inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c+CD11b+Ly6C? DCs, which remain stable. Counterintuitively, only CD11c+CD11b+Ly6C? DCs, and not CD11c+CD11b+Ly6C+ DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c+CD11b+Ly6C? DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice.
Notch Ligand Delta-Like 4-Pretreated Dendritic Cells Alleviate Allergic Airway Responses by Enhancing IL-10 Production  [PDF]
Huei-Mei Huang, George Hsiao, Chia-Kwung Fan, Chu-Lun Lin, Sy-Jye Leu, Bor-Luen Chiang, Yueh-Lun Lee
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063613
Abstract: The Notch pathway plays a role in the processes of cell proliferation, differentiation, and apoptosis, which affect the development and function of various organs. Dendritic cells (DCs), as professional antigen-presenting cells (APCs), induce T cell activation and promote T cell differentiation by antigen stimulation. Research has shown that Notch ligand delta-like 4 (Dll4) in APCs is associated with stimulation of a Th1-type response. However, the regulatory roles of Dll4 in the activation and function of DCs have yet to be clearly elucidated. In this study, we demonstrated that activation of Dll4-pretreated bone marrow-derived DCs by performing ovalbumin (OVA) stimulation expressed a high level of interleukin (IL)-10 without diminishing IL-12 production. By contrast, the proinflammatory cytokines, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, decreased in Dll4-pretreated DCs by performing either lipopolysaccharide (LPS) or OVA stimulation. Compared to fully mature DCs, lower levels of MHC class II CD40 and higher levels of CD80 and CD86 molecules were expressed in these semi-mature like DCs. Dll4 Notch signaling also enhanced Notch ligand mRNA expression of Dll1, Dll4, and Jagged1 in DCs. Dll4-modified DCs exhibited a reduced capacity to stimulate the proliferation of OVA-specific CD4+ T cells, but actively promoted large amounts of IL-10 production in these activated T cells. Furthermore, immunomodulatory effects of Dll4-modified DCs were examined in an established asthmatic animal model. After adoptive transfer of OVA-pulsed plus Dll4-pretreated DCs in OVA-immunized mice, OVA challenge induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, lower eotaxin, keratinocyte-derived chemokine (KC), IL-5, and IL-13 release in bronchial alveolar lavage fluid, attenuated airway hyper-responsiveness, and promoted higher IL-10 and interferon (IFN)-γ production in the spleen. In summary, our findings elucidate the new role of Dll4 in the phenotype and function of DCs and provide a novel approach for manipulating T cell-driven deleterious immune diseases.
Bromelain Inhibits Allergic Sensitization and Murine Asthma via Modulation of Dendritic Cells  [PDF]
Eric R. Secor Jr.,Steven M. Szczepanek,Christine A. Castater,Alexander J. Adami,Adam P. Matson,Ektor T. Rafti,Linda Guernsey,Prabitha Natarajan,Jeffrey T. McNamara,Craig M. Schramm,Roger S. Thrall,Lawrence K. Silbart
Evidence-Based Complementary and Alternative Medicine , 2013, DOI: 10.1155/2013/702196
Abstract: The incidence of atopic conditions has increased in industrialized countries. Persisting symptoms and concern for drug side-effects lead patients toward adjunctive treatments such as phytotherapy. Previously, we have shown that Bromelain (sBr), a mixture of cysteine proteases from pineapple, Ananas comosus, inhibits ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). However, sBr’s effect on development of AAD when treatment is administered throughout OVA-alum sensitization was unknown and is the aim of the present study. C57BL/6J mice were sensitized with OVA/alum and challenged with 7 days OVA aerosol. sBr 6?mg/kg/0.5?ml or PBS vehicle were administered throughout sensitization. Lung, bronchoalveolar lavage (BAL), spleen, and lymph nodes were processed for flow cytometry and OVA-specific IgE was determined via ELISA. sBr treatment throughout OVA-alum sensitization significantly reduced the development of AAD (BAL eosinophils and lymphocytes). OVA-specific IgE and OVA TET+ cells were decreased. sBr reduced CD11c+ dendritic cell subsets, and in vitro treatment of DCs significantly reduced CD44, a key receptor in both cell trafficking and activation. sBr was shown to reduce allergic sensitization and the generation of AAD upon antigen challenge. These results provide additional insight into sBr's anti-inflammatory and antiallergic properties and rationale for translation into the clinical arena. 1. Introduction The incidence of atopic conditions such as asthma, food allergies and atopic dermatitis have increased dramatically in industrialized countries over the last fifty years. Presently, approximately 1 out of 5 Americans suffer from atopic disorders [1], with 1 out of 12 having asthma [2]. Despite major efforts to diagnose and treat these conditions, current conventional medications for allergic disorders are not fully effective. For example, it is estimated that 58% of primary care patients with asthma have poorly controlled asthma [3]. Poor asthma control may result from inadequate assessment or implementation of asthma therapy by healthcare providers or from poor adherence with prescribed therapy by patients [4]. The persistence of symptoms and disease flares, despite medical therapy and the concern for long-term side effects of corticosteroids [5–8] and long-acting beta-2 adrenergic agonists [9], have caused many patients to turn to complementary and alternative medicine (CAM) treatments [10]. A review of 17 articles reported that up to 70–80% of adult asthmatics in the USA use CAM to help control their asthma [11]. Similarly,
树突状细胞Wnt/β-catenin信号通路对哮喘小鼠气道变态反应性炎症的调控作用
Regulation of allergic airway inflammation in asthmatic mice by Wnt/β-catenin pathway of dendritic cells
 [PDF]

,,张进召,,,张秋红,刘艳琴,,,,,,,李雅莉
- , 2017, DOI: 10.7652/jdyxb201703018
Abstract: 摘要:目的 探讨Wnt/β-catenin信号通路对哮喘小鼠气道变态反应性炎症的调控作用。方法 通过小鼠骨髓细胞诱导分化建立树突状细胞(DCs)体系,并用氯化锂(LiCl)和PKF118-310干预细胞,光镜下观察细胞形态;同种异体混合淋巴细胞反应检测DCs刺激淋巴细胞的增殖能力;Western blot方法检测DCs中GSK-3β和β-catenin蛋白的表达水平。选用BALB/c雌性小鼠为研究对象,使用OVA联合氢氧化铝构建哮喘模型,并用LiCl和PKF干预小鼠,干预结束后收集标本,观察支气管肺泡灌洗液(BALF)中细胞总数和嗜酸性粒细胞百分比;HE染色观察小鼠肺部变态反应性炎症情况;ELISA检测BALF、脾细胞培养上清液中干扰素-γ(IFN-γ)和白介素-4(IL-4)的含量及血清总IgE抗体水平;Western blot检测肺脏组织中Wnt/β-catenin信号通路的重要组分GSK-3β和β-catenin蛋白的表达变化。结果 ①LiCl组DCs对同种异体T细胞的刺激和促增殖能力明显弱于PKF组DCs(P<0.05);②LiCl组DCs中GSK-3β的蛋白表达水平明显低于PKF组,而其β-catenin的蛋白表达水平显著高于后者(P<0.05);③动物实验中,与哮喘组相比,LiCl组BALF中白细胞总数和嗜酸性粒细胞百分比均较低,而PKF组与此相反(P<0.05);④肺组织病理表明,LiCl组肺部炎症程度最轻,PKF组最重(P<0.05);⑤LiCl组小鼠BALF及脾脏中IL-4水平最低,IFN-γ水平最高;PKF组与此相反,哮喘组介于两者之间(P<0.05);⑥各组小鼠血清中总IgE含量,与正常对照组比较,实验组IgE显著升高(P<0.05);LiCl组总IgE水平明显低于哮喘组和PKF组(P<0.05);⑦LiCl组肺组织中GSK-3β的蛋白表达水平明显低于各组(P<0.05),而其β-catenin的蛋白表达水平显著高于各组(P<0.05),PKF组β-catenin的蛋白表达水平明显低于各组(P<0.05),哮喘组和PKF组之间GSK-3β的蛋白表达水平未见明显差异(P>0.05)。结论 LiCl和PKF118-310可通过调控哮喘小鼠肺组织中Wnt/β-catenin信号通路重要组分GSK-3β和β-catenin的蛋白表达而改变哮喘严重程度,为哮喘的治疗提供了新方向。
ABSTRACT: Objective To investigate the role of Wnt/β-catenin pathway in regulating allergic airway inflammation in asthmatic mice. Methods We induced dendritic cells (DCs) from bone marrow of BALB/c mice, and then treated the cells with LiCl and PKF118-310, separately. We observed the morphological features of DCs under light microscope. Mixed lymphocyte reaction (MLR) was used to observe the functional changes of DCs. Western blot was used to detect the expressions of GSK-3β and β-catenin at the protein level. We established a mouse asthma model by using ovalbumin (OVA), and then treated these mice with LiCl and PKF118-310. The total number of cells and eosinophil percentage in BALF were determined. The lungs of mice were observed by HE staining to evaluate the degree of allergic inflammation. The cytokines in BALF and spleen cells supernatant were assayed by enzyme-linked immunoassay (ELISA), and the total IgE in the serum was also measured by ELISA. The protein expression levels of GSK-3β and β-catenin in lung tissue were assayed by Western blot. Results ① The DCs treated with LiCl promoted the proliferation of allogeneic T lymphocytes in MLR more weakly than those treated with PKF118-310 (P<0.01). ② The GSK-3β protein expression level of DCs treated with LiCl was significantly lower than DCs treated with PKF118-310. In contrast, the β-catenin protein expression of DCs treated with LiCl was higher than that of DCs treated with PKF118-310 (P<0.01). ③ The total number of cells and eosinophil percentage in BALF
The contribution of L-selectin to airway hyperresponsiveness in chronic allergic airways disease  [cached]
Simon G Royce,Melissa Lee,Mimi L K Tang
Journal of Asthma and Allergy , 2010,
Abstract: Simon G Royce, Melissa Lee, Mimi L K TangDepartment of Allergy and Immunology, Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Victoria 3052, AustraliaAbstract: L-selectin is a cell adhesion molecule, which mediates leukocyte rolling on bronchopulmonary endothelium. Previous studies in a murine model of allergic airways disease have shown that L-selectin plays a role in the regulation of airway hyperresponsiveness in asthma via mechanisms independent of inflammation. Airway remodeling has been shown to modulate airway hyperresponsiveness independently of inflammation.Purpose: Our aim was to determine if L-selectin influenced airway hyperresponsiveness via modulation of structural changes as a result of airway remodeling.Method: A chronic ovalbumin-induced allergic airways disease model was applied to L-selectindeficient mice and wild-type control mice. The development of airway inflammation was assessed by examining leukocyte influx into bronchoalveolar lavage fluid. Airway remodeling changes were determined via histology and morphometric analysis of lung tissue sections, and the development of airway hyperresponsiveness was assessed by invasive plethysmography.Results: Total cell counts, but not individual differential cell counts, were reduced in the ovalbumin-treated L-selectin-deficient mice compared to wildtype ovalbumin-treated mice. L-selectin-deficient mice had significantly reduced epithelial thickness and smooth muscle thickness. Airway hyperresponsiveness was abrogated in ovalbumin treated L-selectin-deficient mice compared to wild-type controls.Conclusion: L-selectin plays an important role in regulating airway remodeling in an animal model of chronic allergic airways disease. Abrogated airway hyperresponsiveness may be related to reduced remodeling changes in L-selectin-deficient mice. L-selectin represents a potential target for novel asthma treatment for airway remodeling and airway hyperresponsiveness.Keywords: asthma, L-selectin, airway hyperresponsiveness, airway remodeling
The contribution of L-selectin to airway hyperresponsiveness in chronic allergic airways disease
Simon G Royce, Melissa Lee, Mimi L K Tang
Journal of Asthma and Allergy , 2010, DOI: http://dx.doi.org/10.2147/JAA.S9775
Abstract: ontribution of L-selectin to airway hyperresponsiveness in chronic allergic airways disease Original Research (2504) Total Article Views Authors: Simon G Royce, Melissa Lee, Mimi L K Tang Published Date June 2010 Volume 2010:3 Pages 9 - 17 DOI: http://dx.doi.org/10.2147/JAA.S9775 Simon G Royce, Melissa Lee, Mimi L K Tang Department of Allergy and Immunology, Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Victoria 3052, Australia Abstract: L-selectin is a cell adhesion molecule, which mediates leukocyte rolling on bronchopulmonary endothelium. Previous studies in a murine model of allergic airways disease have shown that L-selectin plays a role in the regulation of airway hyperresponsiveness in asthma via mechanisms independent of inflammation. Airway remodeling has been shown to modulate airway hyperresponsiveness independently of inflammation. Purpose: Our aim was to determine if L-selectin influenced airway hyperresponsiveness via modulation of structural changes as a result of airway remodeling. Method: A chronic ovalbumin-induced allergic airways disease model was applied to L-selectindeficient mice and wild-type control mice. The development of airway inflammation was assessed by examining leukocyte influx into bronchoalveolar lavage fluid. Airway remodeling changes were determined via histology and morphometric analysis of lung tissue sections, and the development of airway hyperresponsiveness was assessed by invasive plethysmography. Results: Total cell counts, but not individual differential cell counts, were reduced in the ovalbumin-treated L-selectin-deficient mice compared to wildtype ovalbumin-treated mice. L-selectin-deficient mice had significantly reduced epithelial thickness and smooth muscle thickness. Airway hyperresponsiveness was abrogated in ovalbumin treated L-selectin-deficient mice compared to wild-type controls. Conclusion: L-selectin plays an important role in regulating airway remodeling in an animal model of chronic allergic airways disease. Abrogated airway hyperresponsiveness may be related to reduced remodeling changes in L-selectin-deficient mice. L-selectin represents a potential target for novel asthma treatment for airway remodeling and airway hyperresponsiveness.
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