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1.
Clin Exp Allergy ; 52(1): 149-161, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34418187

RESUMEN

BACKGROUND: Myeloid differentiation protein-2 (MD-2) is a lipopolysaccharide-binding protein involved in lipopolysaccharide signalling via Toll-like receptor 4 (TLR4). TLR4 plays an essential role in HDM-mediated allergic airway inflammation. Moreover, MD-2 is structurally similar to Der f 2, a major allergen from house dust mite (HDM). OBJECTIVES: We aimed to clarify the role of MD-2 in the pathogenesis of HDM-mediated allergic airway inflammation. METHODS: Wild-type (WT), TLR4 knockout and MD-2 knockout mice were subjected to intranasal instillation of HDM extract, and asthmatic features were evaluated. We also evaluated gene sets regulated by MD-2 in HDM-treated airway epithelial cells and examined the function of dendritic cells from lymph nodes and from lungs. RESULTS: Aggravated allergic airway inflammation with increased airway hyperresponsiveness was observed in MD-2 knockout mice compared with WT and TLR4 knockout mice. Global gene expression analysis revealed an MD-2 regulated proinflammatory response and reconstituted TLR4 signalling in airway epithelial cells. The ability of dendritic cells to evoke an allergic immune response was enhanced in MD-2 knockout mice. CONCLUSIONS & CLINICAL RELEVANCE: MD-2 plays a protective role in HDM-induced airway allergy with the proinflammatory regulation of airway epithelial cells and dendritic cells. MD-2 may serve as a therapeutic target in the treatment of asthma.


Asunto(s)
Asma , Pyroglyphidae , Animales , Asma/genética , Células Dendríticas , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Humanos , Pulmón , Ratones , Ratones Noqueados
2.
Clin Exp Allergy ; 49(12): 1624-1632, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31494992

RESUMEN

BACKGROUND: Type 2 innate lymphoid cells (ILC2s) are one of the sources of IL-5 and IL-13 in allergic airway inflammation. Innate immune receptors such as Toll-like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL-33 production, but a direct effect of TLRs on ILC2s remains to be elucidated. OBJECTIVES: We hypothesized that TLRs can directly activate lung ILC2s and participate in the pathogenesis of asthma. METHODS: After intranasal administration of IL-33 to wild-type (WT), TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs. ILC2s were incubated with IL-2 and TLR stimulants (pam3csk4 (PAM), house dust mite extract (HDM)). In some experiments, TLR2 or dectin-1 signalling inhibitors were used. As an in vivo model, the mice were treated with IL-33 and rested until lung recruitment of eosinophils regressed. Then they were treated intranasally with PAM + HDM or vehicle and analysed. RESULTS: In vitro stimulation of isolated ILC2s showed that PAM could induce IL-13 and IL-5 production, and HDM had a synergistic effect on this stimulation. Both effects were dependent on TLR2 and NF-κB signalling. PAM + HDM stimulation of WT mice led to increased ILC2s, airway hyperresponsiveness and increased levels of both neutrophils and eosinophils in bronchoalveolar lavage fluid. These observations were dependent on TLR2. CONCLUSIONS & CLINICAL RELEVANCE: TLR2 can directly activate lung ILC2s, an effect that is augmented by HDM. Asthmatic characteristics mediated through the TLR2 pathway were evident in the in vivo mice model. These data implicate a new pathway of ILC2 activation in the pathogenesis of asthma.


Asunto(s)
Asma/inmunología , Inmunidad Innata , Linfocitos/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 2/inmunología , Animales , Asma/inducido químicamente , Asma/genética , Asma/patología , Mezclas Complejas/química , Mezclas Complejas/toxicidad , Femenino , Interleucina-33/inmunología , Interleucina-33/farmacología , Pulmón/inmunología , Pulmón/patología , Linfocitos/patología , Ratones , Ratones Noqueados , Pyroglyphidae/química , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Receptor Toll-Like 2/genética
3.
BMC Infect Dis ; 19(1): 761, 2019 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-31477059

RESUMEN

BACKGROUND: Aspiration pneumonia is a serious problem among elderly patients; it is caused by many risk factors including dysphagia, poor oral hygiene, malnutrition, and sedative medications. The aim of this study was to define a convenient procedure to objectively evaluate the risk of aspiration pneumonia in the clinical setting. METHODS: This prospective study included an aspiration pneumonia (AP) group, a community-acquired pneumonia (CAP) group, and a control (Con) group (patients hospitalized for lung cancer chemotherapy). We used the Oral Health Assessment Tool (OHAT), which assesses oral hygiene, and evaluated performance status, body mass index, serum albumin levels, substance P values in plasma, and oral bacterial counts. RESULTS: The oral health as assessed by the OHAT of the aspiration pneumonia group was significantly impaired compared with that of the CAP group and the control (5.13 ± 0.18, 4.40 ± 0.26, 3.90 ± 0.22, respectively; p < 0.05). The oral bacterial count in the aspiration pneumonia group (7.20 ± 0.11) was significantly higher than that in the CAP group (6.89 ± 0.12), consistent with the OHAT scores. Oral bacterial count was significantly reduced by oral care. CONCLUSIONS: OHAT and oral bacterial counts can be a tool to assess the requirement of taking oral care and other preventive procedures in patients at high risk of aspiration pneumonia.


Asunto(s)
Bacterias/aislamiento & purificación , Biomarcadores/sangre , Evaluación Geriátrica/métodos , Mucosa Bucal/microbiología , Neumonía por Aspiración/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Estudios de Casos y Controles , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/microbiología , Femenino , Humanos , Masculino , Microbiota/fisiología , Persona de Mediana Edad , Higiene Bucal , Proyectos Piloto , Neumonía por Aspiración/sangre , Neumonía por Aspiración/microbiología , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo
4.
J Immunol ; 198(9): 3637-3649, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28363903

RESUMEN

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-κB, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3-/- male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3-/- mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3-/- mice had decreased mRNA transcripts for MCP-1, MIP-1α, TNF-α, and IFN-γ-inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3-/- neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD.


Asunto(s)
Enfisema/inmunología , Factor 3 Regulador del Interferón/metabolismo , Pulmón/inmunología , Neutrófilos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Animales , Apoptosis/genética , Autofagia/genética , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Humanos , Factor 3 Regulador del Interferón/genética , Interferón gamma/metabolismo , Lipopolisacáridos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
5.
Allergol Int ; 66S: S21-S26, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28647381

RESUMEN

BACKGROUND: Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. METHODS: A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. RESULTS: Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. CONCLUSIONS: This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.


Asunto(s)
Antiasmáticos/farmacología , Asma/etiología , Asma/metabolismo , Antagonistas de Leucotrieno/farmacología , ARN Bicatenario/efectos adversos , Acetatos/farmacología , Compuestos de Alumbre/efectos adversos , Animales , Asma/tratamiento farmacológico , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Ciclopropanos , Cisteína/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Eosinófilos/metabolismo , Inmunización , Mediadores de Inflamación/metabolismo , Leucotrienos/metabolismo , Masculino , Ratones , Ovalbúmina/efectos adversos , Poli I-C/administración & dosificación , Quinolinas/farmacología , ARN Viral/efectos adversos , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , Sulfuros
6.
Biochem Biophys Res Commun ; 461(4): 642-7, 2015 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-25912141

RESUMEN

Biological differences between the sexes greatly impact the development and severity of pulmonary disorders such as emphysema. Recent studies have demonstrated crucial roles for osteopontin (OPN, also known as SPP1) in lung inflammation and alveolar destruction in human and experimental emphysema, but the impact of gender on OPN action remains unknown. Here, we report ovary-dependent induction of Opn mRNA with augmentation of experimental emphysema in adult female mice. Both male and female mice developed emphysematous lungs following intra-tracheal administration of porcine pancreatic elastase; however, compared with male mice, female mice developed more severe injury-related inflammation and pathologic alterations of the lungs. Notably, we observed female-specific induction of the Opn gene upon lung injury. Ovariectomy blocked this induction, with attenuation of lung inflammation and alveolar destruction, demonstrating the essential role of ovaries in injury-related Opn induction and augmentation of emphysema in adult female mice. Lastly, pre-treatment of adult female mice with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, which blocks ATP-mediated wound response, suppressed Opn mRNA induction upon lung injury, resulting in attenuation of enhanced lung inflammation. Together, our findings define a novel, ovary-dependent mechanism underlying gender-specific augmentation of emphysema through transcriptional control of the Opn gene.


Asunto(s)
Osteopontina/metabolismo , Ovario/metabolismo , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Elastasa Pancreática , Enfisema Pulmonar/inducido químicamente , Caracteres Sexuales
7.
Biol Pharm Bull ; 37(1): 74-80, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24389483

RESUMEN

Body and excrement extracts from Dermatophagoides farinae were used to study stimulation of Toll-like receptors (TLRs). The excrement extract stimulated nuclear factor (NF)-κB-dependent reporter activity to an extent similar to lipopolysaccharide (LPS) in a mouse macrophage cell line, J774A.1, but the activity of the body extract was negligible. The excrement extract also activated NF-κB in HEK293 cells expressing TLR1/TLR2, TLR2/TLR6 and CD14/TLR4/MD-2, whereas no activation was observed in cells expressing TLR3, TLR5, TLR7, TLR8 or TLR9. Although the excrement extract required co-expression of CD14, TLR4 and MD-2 in HEK293 cells to activate NF-κB, efficient activation was still observed in I-13.35 cells, a bone-marrow macrophage cell line established from LPS-hypo-responsive C3H/HeJ mice. The excrement extract activated NF-κB in HEK293 cells expressing TLR2 alone, but the activation was significantly increased by co-expression of CD14. Polymyxin B inhibited CD14/TLR4/MD-2- and CD14/TLR2-mediated activation of NF-κB but not the activation in I-13.35 cells. These results indicate that CD14/TLR4/MD-2-dependent and CD14/TLR2-dependent mechanisms are involved in the activation of NF-κB by the excrement extract of D. farinae and suggest that the extract also contains substances that activate NF-κB through non-TLR-mediated mechanisms.


Asunto(s)
Dermatophagoides farinae , Hipersensibilidad/metabolismo , Macrófagos/metabolismo , FN-kappa B/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Antibacterianos/farmacología , Línea Celular , Células HEK293 , Humanos , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos , Antígeno 96 de los Linfocitos/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Polimixina B/farmacología
8.
Front Robot AI ; 11: 1303440, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38646473

RESUMEN

Conventional techniques for sharing paper documents in teleconferencing tend to introduce two inconsistencies: 1) media inconsistency: a paper document is converted into a digital image on the remote site; 2) space inconsistency: a workspace deliberately inverts the partner's handwriting to make a document easy to read. In this paper, we present a novel system that eliminates these inconsistencies. The media and space inconsistencies are resolved by reproducing a real paper document on a remote site and allowing a user to handover the paper document to a remote partner across a videoconferencing display. From a series of experiments, we found that reproducing a real paper document contributes to a higher sense of information sharing. We also found that handing over a document enhances a sense of space sharing, regardless of whether the document is digital or paper-based. These findings provide insights into designing systems for sharing paper documents across distances.

9.
J Leukoc Biol ; 115(4): 771-779, 2024 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-38159043

RESUMEN

Eosinophils are typical effector cells associated with type 2 immune responses and play key roles in the pathogenesis of allergic diseases. These cells are activated by various stimuli, such as cytokines, chemokines, and growth factors, but the regulatory mechanisms of eosinophil effector functions remain unclear. Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), a transmembrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily, is a well-known regulatory molecule for T cell activation. Here, we show that GITR is also constitutively expressed on eosinophils and functions as a costimulatory molecule for these cells. Although degranulation was unaffected by GITR engagement of murine bone marrow-derived eosinophils, secretion of inflammatory cytokines such as interleukin (IL)-4, IL-6, and IL-13 from IL-33-activated bone marrow-derived eosinophils was augmented by anti-mouse GITR agonistic antibody (DTA-1). In conclusion, our results provide a new regulatory pathway of cytokine secretion from eosinophils in which GITR functions as a costimulatory molecule.


Asunto(s)
Eosinófilos , Glucocorticoides , Animales , Ratones , Eosinófilos/metabolismo , Proteína Relacionada con TNFR Inducida por Glucocorticoide , Receptores del Factor de Necrosis Tumoral , Citocinas/metabolismo , Factores de Necrosis Tumoral , Factores de Transcripción
10.
Biochem Biophys Res Commun ; 438(1): 175-9, 2013 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-23876317

RESUMEN

Acetylcholine (ACh) exerts various anti-inflammatory effects through α7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α7 nAChR, in the pathophysiology of airway inflammation. Cytokine production was examined using human epithelial cells. Ciliary beat frequency of murine trachea was measured using a high speed camera. The IL-6 and TNF-α production by human epithelial cells was augmented by siRNA of SLURP-1 and α7 nicotinic ACh receptor. The cytokine production was also dose-dependently suppressed by human recombinant SLURP-1 (rSLURP-1). The ciliary beat frequency and amplitude of murine epithelial cells were augmented by PNU282987, a selective α7 nAChR agonist. Those findings suggested that SLURP-1 and stimulus through α7 nicotinic ACh receptors actively controlled asthmatic condition by stimulating ciliary beating and also by suppressing airway inflammation.


Asunto(s)
Células Epiteliales/inmunología , Depuración Mucociliar/inmunología , Mucosa Respiratoria/inmunología , Antígenos Ly/farmacología , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Humanos , Depuración Mucociliar/efectos de los fármacos , Mucosa Respiratoria/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/farmacología
11.
Cell Immunol ; 275(1-2): 24-32, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22521241

RESUMEN

House dust mite (HDM), the most common allergen, activate both the IgE-associated and innate immune responses. To clarify the process of sensitization, we investigated the role of the CCL21, CCL19, and CCR7 axis in a mouse model of HDM-induced allergic asthma. HDM inhalation without systemic immunization resulted in a HDM-specific IgE response. CCR7-knockout (CCR7KO) mice exhibited greater airway inflammation and IgE responses compared to wild-type mice. We examined FoxP3 expression in these mice to clarify the contribution of regulatory cells to the responses. FoxP3 expression was higher in the lungs but not in the lymph nodes of CCR7KO mice compared to wild-type mice. In CCR7KO mice, FoxP3-positive cells were found in lung, but we observed higher release of IL-13, IL-5, TGF-ß, IL-17, and HMGB1 in bronchoalveolar lavage fluid. We demonstrate here that immuno-regulation through CCR7 expression in T cells plays a role in HDM-specific sensitization in the airway.


Asunto(s)
Asma/inmunología , Pyroglyphidae/inmunología , Receptores CCR7/inmunología , Animales , Asma/genética , Asma/patología , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/inmunología , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR7/deficiencia
12.
Exp Mol Pathol ; 93(1): 18-25, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22542791

RESUMEN

To advance the control of airway epithelial cell function and asthma, we investigated the effects of a new curcumin derivative, CNB001, which possesses improved pharmacological properties. Normal human bronchial epithelial (NHBE) cells were stimulated with synthetic double-stranded RNA, Poly(I:C). CNB001 significantly suppressed IL-6, TNF-α, and GM-CSF production by NHBE cells, and did so more effectively than did curcumin or dexamethasone (DEX). CNB001 significantly inhibited the decrease of E-cadherin mRNA expression and increase of vimentin mRNA expression observed in NHBE cells induced by a combination of TGF-ß1 and TNF-α, which are markers of airway remodeling. In NHBE cells stimulated by TGF-ß1, CNB001 significantly downregulated the level of active serine peptidase inhibitor clade E member (SERPINE) 1, which is also reported to be related to airway remodeling. Whereas DEX alone significantly increased the active SERPINE1 level, the combination of DEX and CNB001 significantly suppressed active SERPINE1. In addition, CNB001 significantly suppressed neutrophil infiltration, IL-6, TNF-α, IL-13 and active SERPINE1 production in bronchoalveolar lavage fluid of the murine asthma model, which was not observed in the case of DEX. In conclusion, the curcumin derivative, CNB001, is a promising candidate to treat asthma associated with neutrophilic airway inflammation and remodeling.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma/tratamiento farmacológico , Bronquios/efectos de los fármacos , Curcumina/análogos & derivados , Curcumina/farmacología , Pirazoles/farmacología , Animales , Cadherinas/biosíntesis , Curcumina/síntesis química , Curcumina/química , Citocinas/biosíntesis , Dexametasona/farmacología , Femenino , Glucocorticoides/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Pirazoles/síntesis química , Pirazoles/química , ARN Bicatenario/toxicidad
13.
Psychiatry Clin Neurosci ; 66(1): 26-33, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22250607

RESUMEN

AIM: The purpose of the present study was to investigate whether individuals with pervasive developmental disorders (PDD) show differential activation during an emotional activation task compared with age- and sex-matched controls, by measuring changes in the concentration of oxygenated (oxyHb) and deoxygenated (deoxyHb) hemoglobin, using near-infrared spectroscopy (NIRS). METHODS: Fourteen patients with PDD and 14 age- and sex-matched healthy controls participated in the study. The relative changes of concentrations of oxyHb and deoxyHb were measured on NIRS during an implicit processing task of fearful expression using Japanese standard faces. RESULTS: PDD patients had significantly reduced oxyHb changes in the prefrontal cortex (PFC) compared to healthy controls. CONCLUSION: PFC dysfunction may exist in PDD.


Asunto(s)
Mapeo Encefálico/psicología , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Trastornos Generalizados del Desarrollo Infantil/psicología , Procesos Mentales/fisiología , Corteza Prefrontal/fisiopatología , Espectroscopía Infrarroja Corta/métodos , Adulto , Mapeo Encefálico/métodos , Mapeo Encefálico/estadística & datos numéricos , Estudios de Casos y Controles , Niño , Expresión Facial , Miedo/fisiología , Femenino , Humanos , Masculino , Corteza Prefrontal/irrigación sanguínea
14.
Sci Rep ; 11(1): 13157, 2021 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-34162937

RESUMEN

Stimulator of interferon genes (STING) is a DNA sensor that responds to pathogens and induces type I interferon production. Herein, the role of STING in house dust mite extract (HDM)-induced allergic asthma was investigated. C57BL/6 wild-type (WT) and Sting-/- mice were intratracheally sensitized with HDM, and the bronchoalveolar lavage fluid (BALF), sera, lungs, and mediastinal lymph nodes (MLNs) were analyzed. The total and HDM-specific serum IgE levels were lower in Sting-/- mice than in WT mice. B cell and IgE-positive B cell proportion in BALF and MLNs, respectively, was significantly lower in Sting-/- mice than in WT mice. Additionally, cyclic GMP-AMP, a STING ligand, augmented total and HDM-specific serum IgE levels and B cell proportion in BALF when applied in combination with HDM. To elucidate the role of STING in IgE production, follicular helper T (Tfh) cells, which are involved in B cell maturation, were investigated. Tfh cell proportion in MLNs decreased in Sting-/- mice, and IL-4 and IL-13 production by HDM-restimulated MLN cells from HDM-sensitized mice was decreased in Sting-/- mice compared with WT mice. Thus, STING plays an important role in the maturation and class switching of IgE-producing B cells in allergic inflammation via Tfh cells.


Asunto(s)
Alérgenos/inmunología , Asma/genética , Inmunoglobulina E/biosíntesis , Proteínas de la Membrana/fisiología , Extractos de Tejidos/inmunología , Animales , Asma/etiología , Asma/inmunología , Linfocitos B/inmunología , Líquido del Lavado Bronquioalveolar/citología , Femenino , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Interleucina-13/biosíntesis , Interleucina-13/genética , Interleucina-4/biosíntesis , Interleucina-4/genética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Nucleótidos Cíclicos/farmacología , Pyroglyphidae , Reacción en Cadena en Tiempo Real de la Polimerasa , Células T Auxiliares Foliculares/inmunología
15.
Front Immunol ; 12: 777197, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34868046

RESUMEN

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.


Asunto(s)
Autoanticuerpos/inmunología , Linfocitos B/inmunología , Nefritis Lúpica/etiología , Nefritis Lúpica/metabolismo , Monocitos/inmunología , Receptor Toll-Like 7/antagonistas & inhibidores , Receptor Toll-Like 7/inmunología , Animales , Autoantígenos/inmunología , Autoinmunidad , Linfocitos B/metabolismo , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Regulación de la Expresión Génica , Inmunoglobulina G/inmunología , Inmunohistoquímica , Inmunofenotipificación , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/patología , Ratones , Monocitos/metabolismo
16.
Biochem Biophys Res Commun ; 398(4): 713-8, 2010 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-20621062

RESUMEN

Whereas acetylcholine (ACh) acts as a bronchoconstrictor and stimulator of mucus secretion from bronchial epithelium, it acts via alpha7 nicotinic Ach receptors (nAChRs) on macrophages in the airways to exert anti-inflammatory effects by reducing synthesis of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). Moreover, the effects of ACh are modified by secreted ly-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of alpha7 nAChR signaling. Our aim was to explore the roles played by SLURP-1 in the pathophysiology of asthma by assessing SLURP-1 expression in the OVA-sensitized murine asthma model and in cultured human bronchial epithelial cells. Using real-time PCR we found that expression of SLURP-1 mRNA is down-regulated in the lungs of asthmatic model mice, as compared to healthy mice. In addition, immunohistochemical studies confirmed the diminished expression of SLURP-1 in the bronchioles of asthmatic mice, and showed it was due to extensive metaplasia of mucus-secreting cells and the concomitant loss of ciliated epithelial cells. Expression of SLURP-1 mRNA and protein was also significantly down-regulated in human epithelial cells stimulated with the pro-inflammatory cytokine interleukin-13 (IL-13), which is related to asthmatic condition. Thus SLURP-1 appears to be down-regulated in both an animal model of asthma and human epithelial cells treated with an inflammatory cytokine related to asthma. Those findings suggest that diminished expression of SLURP-1 in asthma attenuates its negative regulation of airway inflammation, and that perhaps changes in SLURP-1 expression could serve as a marker of airway damage in asthma.


Asunto(s)
Antígenos Ly/metabolismo , Asma/metabolismo , Receptores Nicotínicos/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Antígenos Ly/genética , Asma/patología , Biomarcadores/metabolismo , Bronquios/metabolismo , Bronquios/patología , Células Cultivadas , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/metabolismo , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Activador de Plasminógeno de Tipo Uroquinasa/genética , Receptor Nicotínico de Acetilcolina alfa 7
17.
Sci Rep ; 10(1): 18110, 2020 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-33093516

RESUMEN

Allergic asthma is one of most famous allergic diseases, which develops lung and airway inflammation. Recent studies have revealed the relationship between the pathology of allergic asthma and the increase of host-derived DNA in inflamed lung, but the role of the DNA-recognizing innate immune receptor for the inflammation is unknown well. Here we investigated the role of Toll-Like Receptor 9 in the pathogenesis of allergic asthma without synthesized CpG-ODNs. To examine that, we analyzed the pathology and immunology of house-dust-mite (HDM)-induced allergic asthma in Tlr9-/- mice and TLR9-inhibitory-antibody-treated mice. In Tlr9-/- mice, airway hyperresponsiveness (AHR) and the number of eosinophils decreased, and production of the Th2 cytokines IL-13, IL-5, and IL-4 was suppressed, compared with in wild-type mice. Interestingly, unlike Th2 cytokine production, IL-17A production was increased in Tlr9-/- mice. Furthermore, production of IL-2, which decreases IL-17A production, was reduced in Tlr9-/- mice. Blockade of TLR9 by treatment with TLR9-inhibitory-antibody, NaR9, effectively suppressed the development of allergic asthma pathology. IL-17A production in NaR9-treated mice was enhanced, which is comparable to Tlr9-/- mice. These results suggest that the TLR9-IL-2 axis plays an important role in Th2 inflammation by modulating IL-17A production in HDM-induced allergic asthma and that targeting of TLR9 might be a novel therapeutic method for allergic asthma.


Asunto(s)
Asma/patología , Biomarcadores/metabolismo , Inflamación/patología , Interleucina-17/metabolismo , Interleucina-2/metabolismo , Hipersensibilidad Respiratoria/patología , Receptor Toll-Like 9/fisiología , Alérgenos/inmunología , Animales , Asma/etiología , Asma/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Interleucina-17/genética , Interleucina-2/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/metabolismo , Células Th2
18.
J Neurosci Res ; 87(12): 2740-7, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19396877

RESUMEN

Mammalian secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) is a positive allosteric ligand for alpha7 nicotinic acetylcholine (ACh) receptors (alpha7 nAChRs) that potentiates responses to ACh and elicits proapoptotic activity in human keratinocytes. Mutations in the gene encoding SLURP-1 have been detected in patients with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma. On the basis of these findings, SLURP-1 is postulated to be involved in regulating tumor necrosis factor-alpha (TNF-alpha) release from keratinocytes and macrophages via alpha7 nAChR-mediated pathways. In the present study, we assessed SLURP-1 expression in lung tissue from C57BL/6J mice to investigate the functions of SLURP-1 in pulmonary physiology and pathology. Immunohistochemical and in situ hybridization analyses revealed expression of SLURP-1 protein and mRNA, respectively, exclusively in ciliated bronchial epithelial cells. This was supported by Western blotting showing the presence of the 9.5-kDa SLURP-1 protein in whole-lung tissue and trachea. In addition, high-affinity choline transporter (CHT1) was detected in apical regions of bronchial epithelial cells and in neurons located in the lamina propria of the bronchus, suggesting that bronchial epithelial cells are able to synthesize both SLURP-1 and ACh. We also observed direct contact between F4/80-positive macrophages and bronchial epithelial cells and the presence of invading macrophages in close proximity to CHT1-positive nerve elements. Collectively, these results suggest that SLURP-1 contributes to the maintenance of bronchial epithelial cell homeostasis and to the regulation of TNF-alpha release from macrophages in bronchial tissue.


Asunto(s)
Antígenos Ly/metabolismo , Bronquios/metabolismo , Receptores Nicotínicos/metabolismo , Mucosa Respiratoria/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Acetilcolina/biosíntesis , Regulación Alostérica/fisiología , Animales , Antígenos Ly/genética , Bronquios/citología , Bronquios/inervación , Fibras Colinérgicas/metabolismo , Inmunohistoquímica , Ligandos , Macrófagos/metabolismo , Masculino , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Mucosa Respiratoria/citología , Factor de Necrosis Tumoral alfa/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Receptor Nicotínico de Acetilcolina alfa 7
19.
Cell Immunol ; 260(1): 33-8, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19716124

RESUMEN

Although inhaled steroids are the treatment of first choice to control asthma, administration of systemic steroids is required for treatment of asthmatic exacerbation and intractable asthma. To improve efficacy and reduce side effects, we examine the effects of betamethasone disodium phosphate (BP) encapsulated in biocompatible, biodegradable blended nanoparticles (stealth nanosteroids) on a murine model of asthma. These stealth nanosteroids were found to accumulate at the site of airway inflammation and exhibit anti-inflammatory activity. Significant decreases in BALF eosinophil number were maintained for 7 days with a single injection of nanosteroids containing 40 microg BP. Airway responsiveness was also attenuated by the injection of stealth nanosteroids. A single injection of 40 microg of free BP and 8 microg of free BP once daily for 5 days did not show any significant effects. We conclude that stealth nanosteroids achieve prolonged and higher benefits at the site of airway inflammation compared to free steroids.


Asunto(s)
Asma/tratamiento farmacológico , Betametasona/análogos & derivados , Sistemas de Liberación de Medicamentos/métodos , Glucocorticoides/administración & dosificación , Nanopartículas/administración & dosificación , Animales , Betametasona/administración & dosificación , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Femenino , Interleucina-13/biosíntesis , Interleucina-4/biosíntesis , Ácido Láctico , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Poliésteres , Polietilenglicoles , Polímeros
20.
J Allergy Clin Immunol ; 121(1): 95-104.e7, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17920666

RESUMEN

BACKGROUND: Dendritic cells (DCs) are crucial for the induction of immunity and tolerance. Despite an improved understanding of the DC-mediated control of T(H)1-biased immunity, little is known about how DCs regulate T(H)2-mediated immunity. OBJECTIVE: The effects of immunostimulatory mature DCs (maDCs) and regulatory DCs (DCregs) on T(H)2-driven allergic immunity involving IgE production were examined. METHODS: A murine model of airway hyperresponsiveness; the adoptive transfer of maDCs, DCregs, and T cells; and T-cell function were studied. RESULTS: Antigen-pulsed maDCs inhibited antigen-specific IgE production but enhanced the production of antigen-specific IgG1 and IgG2a. Analysis of Ifng-/- mice and Il21r-/- mice revealed that the inhibitory effect of antigen-pulsed maDCs on antigen-specific IgE production involved IL-21-producing T follicular helper cells but not IFN-gamma-producing T(H)1 cells. In contrast, antigen-pulsed DCregs impaired the production of antigen-specific IgE, IgG1, and IgG2a. In vivo blockade experiments showed that antigen-specific CD4+CD25+Foxp3+ regulatory T cells mainly mediated the suppressive effect of antigen-pulsed DCregs on the production of antigen-specific IgE. Antigen-pulsed maDCs promoted airway inflammation, whereas antigen-pulsed DCregs markedly suppressed the pathogenesis. CONCLUSION: DCregs abolish T(H)2-mediated IgE production and allergic inflammation based on antigen-specific dominant tolerance, whereas maDCs exacerbate the pathogenesis despite inhibiting the IgE response through the activation of diverse types of T(H) cell responses.


Asunto(s)
Asma/inmunología , Hiperreactividad Bronquial/inmunología , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Modelos Animales de Enfermedad , Hipersensibilidad/inmunología , Inflamación/inmunología , Traslado Adoptivo , Animales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T Reguladores
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