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1.
Respir Res ; 15: 73, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24980659

RESUMO

BACKGROUND: A neuroimmune crosstalk between dendritic cells (DCs) and airway nerves in the lung has recently been reported. However, the presence of DCs in airway sensory ganglia under normal and allergic conditions has not been explored so far. Therefore, this study aims to investigate the localisation, distribution and proliferation of DCs in airway sensory ganglia under allergic airway inflammation. METHODS: Using the house dust mite (HDM) model for allergic airway inflammation BALB/c mice were exposed to HDM extract intranasally (25 µg/50 µl) for 5 consecutive days a week over 7 weeks. With the help of the immunohistochemistry, vagal jugular-nodose ganglia complex (JNC) sections were analysed regarding their expression of DC-markers (MHC II, CD11c, CD103), the neuronal marker PGP 9.5 and the neuropeptide calcitonin gene-related peptide (CGRP) and glutamine synthetase (GS) as a marker for satellite glia cells (SGCs). To address the original source of DCs in sensory ganglia, a proliferation experiment was also carried in this study. RESULTS: Immune cells with characteristic DC-phenotype were found to be closely located to SGCs and vagal sensory neurons under physiological conditions. The percentage of DCs in relation to neurons was significantly increased by allergic airway inflammation in comparison to the controls (HDM 51.38 ± 2.38% vs. control 28.16 ± 2.86%, p < 0.001). The present study also demonstrated that DCs were shown to proliferate in jugular-nodose ganglia, however, the proliferation rate of DCs is not significantly changed in the two treated animal groups (proliferating DCs/ total DCs: HDM 0.89 ± 0.38%, vs. control 1.19 ± 0.54%, p = 0.68). Also, increased number of CGRP-positive neurons was found in JNC after allergic sensitisation and challenge (HDM 31.16 ± 5.41% vs. control 7.16 ± 1.53%, p < 0.001). CONCLUSION: The present findings suggest that DCs may migrate from outside into the ganglia to interact with sensory neurons enhancing or protecting the allergic airway inflammation. The increase of DCs as well as CGRP-positive neurons in airway ganglia by allergic airway inflammation indicate that intraganglionic DCs and neurons expressing CGRP may contribute to the pathogenesis of bronchial asthma. To understand this neuroimmune interaction in allergic airway inflammation further functional experiments should be carried out in future studies.


Assuntos
Movimento Celular/imunologia , Células Dendríticas/fisiologia , Gânglios Sensitivos/imunologia , Pneumonia/imunologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Feminino , Gânglios Sensitivos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/patologia , Hipersensibilidade Respiratória/patologia
2.
Clin Sci (Lond) ; 126(1): 55-65, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23822145

RESUMO

Severe asthma and viral-induced asthma exacerbations represent a high unmet medical need as no therapy is currently available for these patients. HRV (human rhinovirus) is prominently associated with asthma exacerbations in humans. The aim of the present study was to establish a mouse model of severe asthma with additional rhinovirus infection to investigate the interplay between chronic allergic airway inflammation and acute respiratory viral infection. Balb/c mice were sensitized with HDM (house dust mite) extract (25 µg in 50 µl of saline) by i.n. (intranasal) delivery to the lung over 7 weeks. HRV1B (HRV serotype 1B) inoculation was performed i.n. on the last 3 days. Therapeutic treatment with FP (fluticasone propionate) was performed to assess steroid efficacy. Lung resistance was measured invasively to assess AHR (airway hyper-responsiveness). BAL (bronchoalveolar lavage) differential cell count, cytokines, lung histology and the proliferative and cytokine response of MLN (mediastinal lymph node) cells upon in vitro restimulation were analysed. Chronic HDM application induced a strong Th2-skewed eosinophilic airway inflammation and AHR, which was not exacerbated by superimposed HRV1B infection. Therapeutic steroid intervention in the chronic HDM model reduced BAL eosinophil cell counts, cytokine levels and AHR, while neutrophil numbers were unaffected. Steroid efficacy against inflammatory readouts was maintained during additional HRV1B infection. Animals with chronic allergic airway inflammation exhibited a diminished immune response towards superimposed HRV1B infection compared with HRV1B alone, as induction of the anti-viral and pro-inflammatory cytokines IFN (interferon)-α, IFN-γ and IL (interleukin)-12 were suppressed. Although superimposed HRV1B infection did not provoke asthma exacerbation in this severe model, a deficient anti-viral immune response to HRV1B was present under chronic allergic airway inflammatory conditions. Thus, this model is able to reflect some aspects of the complex interplay of respiratory virus infection in chronic allergic asthma.


Assuntos
Asma/virologia , Infecções por Picornaviridae/complicações , Infecções Respiratórias/complicações , Rhinovirus/isolamento & purificação , Doença Aguda , Alérgenos/imunologia , Androstadienos/uso terapêutico , Animais , Asma/tratamento farmacológico , Asma/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Doença Crônica , Citocinas/biossíntese , Modelos Animais de Doenças , Fluticasona , Glucocorticoides/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , Pyroglyphidae/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Rhinovirus/imunologia , Carga Viral
3.
PLoS One ; 7(9): e45951, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23049899

RESUMO

The airway mucosal epithelium is permanently exposed to airborne particles. A network of immune cells patrols at this interface to the environment. The interplay of immune cells is orchestrated by different mediators. In the current study we investigated the impact of neuronal signals on key functions of dendritic cells (DC). Using two-photon microscopic time-lapse analysis of living lung sections from CD11c-EYFP transgenic mice we studied the influence of neuropeptides on airway DC motility. Additionally, using a confocal microscopic approach, the phagocytotic capacity of CD11c(+) cells after neuropeptide stimulation was determined. Electrical field stimulation (EFS) leads to an unspecific release of neuropeptides from nerves. After EFS and treatment with the neuropeptides vasoactive intestinal peptide (VIP) or calcitonin gene-related peptide (CGRP), airway DC in living lung slices showed an altered motility. Furthermore, the EFS-mediated effect could partially be blocked by pre-treatment with the receptor antagonist CGRP(8-37). Additionally, the phagocytotic capacity of bone marrow-derived and whole lung CD11c(+) cells could be inhibited by neuropeptides CGRP, VIP, and Substance P. We then cross-linked these data with the in vivo situation by analyzing DC motility in two different OVA asthma models. Both in the acute and prolonged OVA asthma model altered neuropeptide amounts and DC motility in the airways could be measured. In summary, our data suggest that neuropeptides modulate key features motility and phagocytosis of mouse airway DC. Therefore altered neuropeptide levels in airways during allergic inflammation have impact on regulation of airway immune mechanisms and therefore might contribute to the pathophysiology of asthma.


Assuntos
Células Dendríticas/citologia , Mucosa/citologia , Neuropeptídeos/farmacologia , Animais , Asma/metabolismo , Células da Medula Óssea/citologia , Brônquios/metabolismo , Antígeno CD11c/biossíntese , Hipersensibilidade/metabolismo , Sistema Imunitário , Inflamação/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia/métodos , Microscopia Confocal/métodos , Neurônios/metabolismo , Neuropeptídeos/química , Fagocitose , Substância P/metabolismo
4.
Exp Lung Res ; 36(9): 522-30, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20815657

RESUMO

Pollen starch granules (PSGs) are allergen particles that get into contact with pulmonary surfactant and phagocytes in the terminal airways. In this study, the effects of surfactant protein D (SP-D) on the interaction of PSGs with phagocytes and on the pulmonary clearance of PSGs were determined. Fluorescently labeled PSGs were incubated in vitro with murine lung macrophages or dendritic cells (DCs) ± recombinant rat SP-D (rrSP-D). In addition, the effect of SP-D on uptake of PSGs by lung macrophages and DCs was studied in vivo. Furthermore, PSGs were instilled in Balb/c mice and the effects of SP-D on total lung clearance were assessed by optical imaging. SP-D treatment increased the number of PSG-positive macrophages and DCs in vitro. Furthermore, SP-D accelerated uptake/binding by alveolar macrophages and reduced the number of PSG-positive tissue macrophages and DCs at 24 hours. However, SP-D did not affect total lung clearance of PSGs and it did not enhance the T-cell proliferation induced by PSG-positive DCs. In conclusion, SP-D increased PSG-positive cells in vitro and accelerated PSG binding/uptake in vivo. The observed effects were limited to cellular clearance mechanisms and did not affect the total clearance of PSGs from the lung.


Assuntos
Alérgenos/metabolismo , Pulmão/efeitos dos fármacos , Depuração Mucociliar/efeitos dos fármacos , Pólen/metabolismo , Proteína D Associada a Surfactante Pulmonar/farmacologia , Amido/metabolismo , Alérgenos/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Citometria de Fluxo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pólen/imunologia , Ratos , Proteínas Recombinantes , Amido/imunologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
5.
Int Arch Allergy Immunol ; 152(2): 131-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20016195

RESUMO

BACKGROUND: The hygiene hypothesis negatively correlates the microbial burden of the environment with the prevalence of T helper type 2 (Th2)-related disorders, e.g. allergy and asthma. This is explained by Th1 triggering through pathogen-associated molecular patterns via Toll-like receptors (TLRs). In this study, the biological effects of a TLR2/6 agonist as a potential treatment of allergic inflammation are explored. METHODS: In a model of chronic allergic airway inflammation induced by intranasal administration of Timothy grass pollen allergen extract, early TLR agonism and/or interferon (IFN)-gamma administration was compared to the therapeutic and immune-modulating effects of dexamethasone with regard to the cellular inflammation and cytokine profiles. RESULTS: Eosinophilic inflammation was clearly reduced by TLR2/6 agonism. This effect was also seen without simultaneous administration of IFN-gamma. However, lymphocyte counts were not affected among the different treatment groups. More precise determination of the lymphocyte-mediated immune reaction showed that TLR2/6 agonism induced neither CD4+foxp3+ regulatory T cells in draining lymph nodes nor a pronounced Th1 immune response. In contrast, dexamethasone reduced both sensitisation as well as allergic inflammation and, in addition, CD11c+ antigen-presenting cells in lymph nodes. Our data clearly point to the potential to rebalance Th2-skewed allergic immune responses by therapeutic TLR2/6 agonist administration. CONCLUSION: The use of the TLR2/6 agonist is a promising therapeutic approach in diseases with an imbalance in T cell responses, such as allergy and asthma.


Assuntos
Antígenos de Plantas/imunologia , Lipopeptídeos/uso terapêutico , Phleum/imunologia , Pólen/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Receptor 2 Toll-Like/agonistas , Receptor 6 Toll-Like/agonistas , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Plantas/administração & dosagem , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Antígeno CD11c/metabolismo , Contagem de Células , Quimiocinas/metabolismo , Citocinas/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Feminino , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Interferon gama/farmacologia , Interferon gama/uso terapêutico , Interleucina-5/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Lipopeptídeos/química , Lipopeptídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th1/metabolismo
6.
Pharmacol Ther ; 122(2): 203-14, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19292991

RESUMO

Despite recent advances in the development of anti-asthmatic medication, asthma continues to be a major health problem worldwide. The symptoms of asthmatic patients include wheezing, chest tightness, cough and shortness of breath, which, together with airway hyperresponiveness, previously have been attributed to a dysfunction of airway nerves. However, research in the last two decades identified Th2-sensitization and the subsequent allergic reaction to innocuous environmental antigens as a basic immunological mechanism leading to chronic airway inflammation. Recent evidence suggests that the development of allergic asthma is influenced by events and circumstances in early childhood and even in utero. Allergen, ozone or stress exposure, as well as RSV infection in early life could be able to induce irreversible changes in the developing epithelial-mesenchymal trophic unit of the airways. The co-existence of chronic inflammation and neural dysfunction have recently drawn attention to the involvement of interaction pathways between the nervous and the immune system in the airways. Intensive basic research has accumulated morphological as well as functional evidence for the interaction between nerves and immune cells. Neuropeptides and neurotrophins have come into focus of attention as the key mediators of neuro-immune interactions, which lead to the development of several pharmacological compounds specifically targeting these molecules. This review will integrate our current knowledge on the involvement of neuro-immune pathways in asthma on the cellular and molecular level. It will summarize the results of pharmacological studies addressing the potential of neuropeptides and neurotrophins as novel therapeutic targets in asthma.


Assuntos
Asma/imunologia , Neuroimunomodulação , Antialérgicos/farmacologia , Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Asma/etiologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Pneumonia/imunologia , Receptor Cross-Talk , Sistema Respiratório/inervação , Estresse Psicológico , Linfócitos T/citologia , Linfócitos T/imunologia
7.
Am J Pathol ; 174(3): 808-17, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19179611

RESUMO

Interactions between T cells and dendritic cells in the airway mucosa precede secondary immune responses to inhaled antigen. The purpose of this study was to identify the anatomical locations where dendritic cell-T cell interactions occur, resulting in T cells activation by dendritic cells. In a mouse model of allergic airway inflammation, we applied whole-mount immunohistology and confocal microscopy to visualize dendritic cells and T cells together with nerves, epithelium, and smooth muscle in three dimensions. Proliferating T cells were identified by the detection of the incorporation of the nucleotide analogue 5-ethynyl-2'-deoxyuridine into the DNA. We developed a novel quantification method that enabled the accurate determination of cell-cell contacts in a semi-automated fashion. Dendritic cell-T cell interactions occurred beneath the smooth muscle layer, but not in the epithelium. Approximately 10% of the dendritic cells were contacted by nerves, and up to 4% of T cells formed clusters with these dendritic cells. T cells that were clustered with nerve-contacting dendritic cells proliferated only in the airways of mice with allergic inflammation but not in the airways of negative controls. Taken together, these results suggest that during the secondary immune response, sensory nerves influence dendritic cell-driven T cell activation in the airway mucosa.


Assuntos
Células Dendríticas/patologia , Hipersensibilidade/patologia , Inflamação/patologia , Sistema Respiratório/patologia , Linfócitos T/patologia , Animais , Antígeno CD11c/genética , Divisão Celular , Células Dendríticas/imunologia , Células Dendríticas/ultraestrutura , Modelos Animais de Doenças , Hipersensibilidade/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Fibras Nervosas/patologia , Neurônios/imunologia , Neurônios/patologia , Ovalbumina , Sistema Respiratório/imunologia , Linfócitos T/imunologia , Linfócitos T/ultraestrutura
8.
Am J Respir Cell Mol Biol ; 37(5): 553-61, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17600312

RESUMO

Neuroimmune interactions play a critical role in the pathogenesis of asthma. Symptoms like wheezing and cough have been attributed to neural dysregulation, whereas sensitization and the induction of allergic inflammation have been linked with the activity of dendritic cells. Neuropeptides were previously shown to control dendritic cell function in vitro, suggesting interactions between dendritic cells and sensory nerves. Here we characterized the anatomical basis of the interactions between dendritic cells and nerves in the airways of mice and monitored the changes during allergic inflammation. Airway microdissection, whole-mount immunohistology, and confocal microscopy were used for the three-dimensional quantitative mapping of airway nerves and dendritic cells along the main axial pathway of nonsensitized versus ovalbumin-sensitized and -challenged CD11c-enhanced yellow fluorescent protein (CD11c-EYFP) transgenic mice. CD11c-EYFP-positive airway mucosal dendritic cells were contacted by calcitonin gene-related peptide-immunoreactive sensory fibers and their co-localization increased in allergic inflammation. Moreover, protein gene product 9.5-positive neuroepithelial bodies and airway ganglia were associated with dendritic cells. In human airways, human leukocyte antigen DR-positive mucosal dendritic cells were found in the close proximity of sensory nerves and neuroepithelial cells. These results provide morphologic evidence of the interactions between dendritic cells and the neural network of the airways at multiple anatomical sites.


Assuntos
Asma/imunologia , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Neurônios Aferentes/imunologia , Nervos Periféricos/imunologia , Sistema Respiratório/inervação , Animais , Asma/patologia , Asma/fisiopatologia , Células Dendríticas/patologia , Equidae , Cobaias , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Aferentes/patologia , Nervos Periféricos/patologia , Coelhos , Sistema Respiratório/patologia
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