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2.
Nat Immunol ; 20(8): 992-1003, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31263279

RESUMEN

Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1ß and IL-23. We also report a role for transforming growth factor-ß in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.


Asunto(s)
Interleucina-17/inmunología , Linfocitos/inmunología , Psoriasis/patología , Piel/patología , Células Cultivadas , Humanos , Interleucina-1beta/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-4/inmunología , Linfocitos/citología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Psoriasis/inmunología , Receptores CCR10/metabolismo , Piel/inmunología , Factor de Crecimiento Transformador beta/metabolismo
3.
Nat Immunol ; 17(6): 646-55, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27111142

RESUMEN

Group 2 innate lymphoid cells (ILC2 cells) are important for type 2 immune responses and are activated by the epithelial cytokines interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin (TSLP). Here we demonstrated that IL-1ß was a critical activator of ILC2 cells, inducing proliferation and cytokine production and regulating the expression of epithelial cytokine receptors. IL-1ß also governed ILC2 plasticity by inducing low expression of the transcription factor T-bet and the cytokine receptor chain IL-12Rß2, which enabled the conversion of these cells into an ILC1 phenotype in response to IL-12. This transition was marked by an atypical chromatin landscape characterized by the simultaneous transcriptional accessibility of the locus encoding interferon-γ (IFN-γ) and the loci encoding IL-5 and IL-13. Finally, IL-1ß potentiated ILC2 activation and plasticity in vivo, and IL-12 acted as the switch that determined an ILC2-versus-ILC1 response. Thus, we have identified a previously unknown role for IL-1ß in facilitating ILC2 maturation and plasticity.


Asunto(s)
Plasticidad de la Célula , Inmunidad Innata , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Linfocitos/inmunología , Animales , Diferenciación Celular , Plasticidad de la Célula/inmunología , Células Cultivadas , Citocinas/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Ratones , Ratones SCID , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/metabolismo , Transducción de Señal , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Células TH1/inmunología , Balance Th1 - Th2 , Células Th2/inmunología , Linfopoyetina del Estroma Tímico
4.
Nat Immunol ; 17(6): 626-35, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27111143

RESUMEN

Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.


Asunto(s)
Infecciones por Haemophilus/inmunología , Haemophilus influenzae/inmunología , Virus de la Influenza A/inmunología , Pulmón/inmunología , Linfocitos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Células TH1/inmunología , Células Th2/inmunología , Anciano , Animales , Diferenciación Celular , Plasticidad de la Célula/inmunología , Células Cultivadas , Citocinas/metabolismo , Femenino , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Fenotipo , Fumar/efectos adversos , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo
5.
Nat Immunol ; 15(12): 1116-25, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25326751

RESUMEN

Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of γδ T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in γδ T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family.


Asunto(s)
Quitinasas/inmunología , Glicoproteínas/inmunología , Lectinas/inmunología , Infecciones por Nematodos/inmunología , Infiltración Neutrófila/inmunología , beta-N-Acetilhexosaminidasas/inmunología , Animales , Proteína 1 Similar a Quitinasa-3 , Citotoxicidad Inmunológica/inmunología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Inmunidad Innata/inmunología , Inflamación/inmunología , Interleucina-17/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nematodos , Neutrófilos/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Linfocitos T/inmunología , Transfección
6.
Nat Immunol ; 18(9): 959-960, 2017 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-28829441
7.
Immunity ; 42(3): 566-79, 2015 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-25786179

RESUMEN

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.


Asunto(s)
Inmunidad Innata/efectos de los fármacos , Interleucinas/inmunología , Infecciones por Orthomyxoviridae/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Receptores de Interleucina/inmunología , Humo/efectos adversos , Animales , Femenino , Regulación de la Expresión Génica , Humanos , Virus de la Influenza A/inmunología , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/deficiencia , Interleucinas/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/patología , Macrófagos/inmunología , Macrófagos/patología , Ratones Transgénicos , Infecciones por Orthomyxoviridae/etiología , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/patología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Receptores de Interleucina/deficiencia , Receptores de Interleucina/genética , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Transducción de Señal , Nicotiana/química , Pérdida de Peso
8.
Eur Respir J ; 62(3)2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37442582

RESUMEN

BACKGROUND: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. METHODS: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. RESULTS: We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. CONCLUSIONS: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD.


Asunto(s)
Interleucina-33 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Receptores ErbB , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33/genética , Interleucina-33/metabolismo , Oxidación-Reducción , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Receptor para Productos Finales de Glicación Avanzada/metabolismo
11.
Eur Respir J ; 59(3)2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34289975

RESUMEN

BACKGROUND: Benralizumab is a humanised, anti-interleukin-5 receptor α monoclonal antibody with anti-eosinophilic activity. Lack of fucose (afucosylation) increases its affinity to CD16a and significantly enhances antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells. Although benralizumab proved clinically efficacious in clinical trials for patients with severe asthma and hypereosinophilic syndrome, in-depth characterisation of its anti-eosinophilic mechanisms of action remains elusive. METHODS: Here, we further investigated the mechanisms involved in benralizumab's anti-eosinophilic activities by employing relevant primary human autologous cell co-cultures and real-time-lapse imaging combined with flow cytometry. RESULTS: In the presence of NK cells, benralizumab induced potent eosinophil apoptosis as demonstrated by the upstream induction of Caspase-3/7 and upregulation of cytochrome c. In addition, we uncovered a previously unrecognised mechanism whereby benralizumab can induce eosinophil phagocytosis/efferocytosis by macrophages, a process called antibody-dependent cellular phagocytosis. Using live cell imaging, we unravelled the stepwise processes leading to eosinophil apoptosis and uptake by activated macrophages. Through careful observations of cellular co-culture assays, we identified a novel role for macrophage-derived tumour necrosis factor (TNF) to further enhance benralizumab-mediated eosinophil apoptosis through activation of TNF receptor 1 on eosinophils. TNF-induced eosinophil apoptosis was associated with cytochrome c upregulation, mitochondrial membrane depolarisation and increased Caspase-3/7 activity. Moreover, activated NK cells were found to amplify this axis through the secretion of interferon-γ, subsequently driving TNF expression by macrophages. CONCLUSIONS: Our data provide deeper insights into the timely appearance of events leading to benralizumab-induced eosinophil apoptosis and suggest that additional mechanisms may contribute to the potent anti-eosinophilic activity of benralizumab in vivo. Importantly, afucosylation of benralizumab strongly enhanced its potency for all mechanisms investigated.


Asunto(s)
Antiasmáticos , Asma , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Eosinófilos , Humanos
12.
Eur Respir J ; 55(5)2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32060064

RESUMEN

Although elevated blood or sputum eosinophils are present in many patients with COPD, uncertainties remain regarding the anatomical distribution pattern of lung-infiltrating eosinophils. Basophils have remained virtually unexplored in COPD. This study mapped tissue-infiltrating eosinophils, basophils and eosinophil-promoting immune mechanisms in COPD-affected lungs.Surgical lung tissue and biopsies from major anatomical compartments were obtained from COPD patients with severity grades Global Initiative for Chronic Obstructive Lung Disease stages I-IV; never-smokers/smokers served as controls. Automated immunohistochemistry and in situ hybridisation identified immune cells, the type 2 immunity marker GATA3 and eotaxins (CCL11, CCL24).Eosinophils and basophils were present in all anatomical compartments of COPD-affected lungs and increased significantly in very severe COPD. The eosinophilia was strikingly patchy, and focal eosinophil-rich microenvironments were spatially linked with GATA3+ cells, including type 2 helper T-cell lymphocytes and type 2 innate lymphoid cells. A similarly localised and interleukin-33/ST2-dependent eosinophilia was demonstrated in influenza-infected mice. Both mice and patients displayed spatially confined eotaxin signatures with CCL11+ fibroblasts and CCL24+ macrophages.In addition to identifying tissue basophilia as a novel feature of advanced COPD, the identification of spatially confined eosinophil-rich type 2 microenvironments represents a novel type of heterogeneity in the immunopathology of COPD that is likely to have implications for personalised treatment.


Asunto(s)
Basófilos/inmunología , Eosinófilos/inmunología , Macrófagos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Eosinofilia Pulmonar/etiología , Adulto , Anciano , Animales , Biomarcadores , Quimiocina CCL11/inmunología , Quimiocina CCL24/inmunología , Femenino , Factor de Transcripción GATA3/inmunología , Humanos , Inmunidad Innata , Masculino , Ratones , Persona de Mediana Edad , Fumadores , Adulto Joven
13.
Am J Physiol Lung Cell Mol Physiol ; 316(6): L1127-L1140, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-30908937

RESUMEN

Host cell proteases are involved in influenza pathogenesis. We examined the role of tissue kallikrein 1 (KLK1) by comparing wild-type (WT) and KLK1-deficient mice infected with influenza H3N2 virus. The levels of KLK1 in lung tissue and in bronchoalveolar lavage (BAL) fluid increased substantially during infection. KLK1 did not promote virus infectivity despite its trypsin-like activity, but it did decrease the initial virus load. We examined two cell types involved in the early control of pathogen infections, alveolar macrophages (AMs) and natural killer (NK) cells to learn more about the antiviral action of KLK1. Inactivating the Klk1 gene or treating WT mice with an anti-KLK1 monoclonal antibody to remove KLK1 activity accelerated the initial virus-induced apoptotic depletion of AMs. Intranasal instillation of deficient mice with recombinant KLK1 (rKLK1) reversed the phenotype. The levels of granulocyte-macrophage colony-stimulating factor in infected BAL fluid were significantly lower in KLK1-deficient mice than in WT mice. Treating lung epithelial cells with rKLK1 increased secretion of this factor known to enhance AM resistance to pathogen-induced apoptosis. The recruitment of NK cells to the air spaces peaked 3 days after infection in WT mice but not in KLK1-deficient mice, as did increases in several NK-attracting chemokines (CCL2, CCL3, CCL5, and CXCL10) in BAL. Chronic obstructive pulmonary disease (COPD) patients are highly susceptible to viral infection, and we observed that the KLK1 mRNA levels decreased with increasing COPD severity. Our findings indicate that KLK1 intervenes early in the antiviral defense modulating the severity of influenza infection. Decreased KLK1 expression in COPD patients could contribute to the worsening of influenza.


Asunto(s)
Apoptosis/fisiología , Macrófagos Alveolares/patología , Infecciones por Orthomyxoviridae/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Calicreínas de Tejido/metabolismo , Células A549 , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/virología , Animales , Línea Celular , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Perros , Factor Estimulante de Colonias de Granulocitos y Macrófagos/análisis , Humanos , Subtipo H3N2 del Virus de la Influenza A , Células Asesinas Naturales/inmunología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunología , Enfermedad Pulmonar Obstructiva Crónica/virología , Mucosa Respiratoria/metabolismo , Calicreínas de Tejido/antagonistas & inhibidores , Calicreínas de Tejido/genética
14.
J Virol ; 91(16)2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28615200

RESUMEN

Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans.IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.


Asunto(s)
Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Interacciones Huésped-Patógeno , Subtipo H3N2 del Virus de la Influenza A/crecimiento & desarrollo , Calicreínas/metabolismo , Animales , Peso Corporal , Células Cultivadas , Modelos Animales de Enfermedad , Células Epiteliales/virología , Humanos , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Proteolisis , Análisis de Supervivencia
15.
J Immunol ; 193(6): 3134-45, 2014 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-25092891

RESUMEN

Cigarette smoke has a broad impact on the mucosal environment with the ability to alter host defense mechanisms. Within the context of a bacterial infection, this altered host response is often accompanied by exacerbated cellular inflammation, characterized by increased neutrophilia. The current study investigated the mechanisms of neutrophil recruitment in a murine model of cigarette smoke exposure and, subsequently, a model of both cigarette smoke exposure and bacterial infection. We investigated the role of IL-1 signaling in neutrophil recruitment and found that cigarette smoke-induced neutrophilia was dependent on IL-1α produced by alveolar macrophages. In addition to being the crucial source of IL-1α, alveolar macrophages isolated from smoke-exposed mice were primed for excessive IL-1α production in response to bacterial ligands. To test the relevance of exaggerated IL-1α production in neutrophil recruitment, a model of cigarette smoke exposure and nontypeable Haemophilus influenzae infection was developed. Mice exposed to cigarette smoke elaborated an exacerbated CXCR2-dependent neutrophilia in response to nontypeable Haemophilus influenzae. Exacerbated neutrophilia was dependent on IL-1α priming of the pulmonary environment by cigarette smoke as exaggerated neutrophilia was dependent on IL-1 signaling. These data characterize a novel mechanism of cigarette smoke priming the lung mucosa toward greater IL-1-driven neutrophilic responses to bacteria, with a central role for the alveolar macrophage in this process.


Asunto(s)
Haemophilus influenzae/inmunología , Interleucina-1alfa/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Receptores de Interleucina-8B/inmunología , Humo/efectos adversos , Animales , Líquido del Lavado Bronquioalveolar/citología , Células Cultivadas , Quimiocina CXCL1/biosíntesis , Quimiocina CXCL5/biosíntesis , Quimiocina CXCL5/genética , Quimiocina CXCL5/inmunología , Femenino , Infecciones por Haemophilus/inmunología , Infecciones por Haemophilus/microbiología , Inflamación/inmunología , Recuento de Leucocitos , Pulmón/patología , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/patología , ARN Mensajero/biosíntesis , Receptores de Interleucina-8B/biosíntesis , Receptores de Interleucina-8B/genética , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/microbiología , Nicotiana/efectos adversos
16.
Nature ; 460(7252): 225-30, 2009 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-19525930

RESUMEN

Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.


Asunto(s)
Degeneración Macular/diagnóstico , Degeneración Macular/terapia , Receptores CCR3/antagonistas & inhibidores , Receptores CCR3/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Células Cultivadas , Quimiocina CCL11/antagonistas & inhibidores , Quimiocina CCL11/metabolismo , Quimiocina CCL24/antagonistas & inhibidores , Quimiocina CCL24/metabolismo , Quimiocina CCL26 , Quimiocinas CC/antagonistas & inhibidores , Quimiocinas CC/metabolismo , Coroides/irrigación sanguínea , Coroides/citología , Coroides/metabolismo , Neovascularización Coroidal/diagnóstico , Neovascularización Coroidal/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Humanos , Inflamación , Leucocitos , Ligandos , Degeneración Macular/metabolismo , Ratones , Ratones Endogámicos C57BL , Puntos Cuánticos , Receptores CCR3/análisis , Receptores CCR3/genética , Receptores CCR3/inmunología , Retina/efectos de los fármacos , Retina/patología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología
17.
Respir Res ; 15: 49, 2014 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-24754996

RESUMEN

Formation of pulmonary tertiary immune structures is a characteristic feature of advanced COPD. In the current study, we investigated the mechanisms of tertiary lymphoid tissue (TLT) formation in the lungs of cigarette smoke-exposed mice. We found that cigarette smoke exposure led to TLT formation that persisted following smoking cessation. TLTs consisted predominantly of IgM positive B cells, while plasma cells in close proximity to TLTs expressed IgM, IgG, and IgA. The presence of TLT formation was associated with anti-nuclear autoantibody (ANA) production that also persisted following smoking cessation. ANAs were observed in the lungs, but not the circulation of cigarette smoke-exposed mice. Similarly, we observed ANA in the sputum of COPD patients where levels correlated with disease severity and were refractory to steroid treatment. Both ANA production and TLT formation were dependent on interleukin-1 receptor 1 (IL-1R1) expression. Contrary to TLT and ANA, lung neutrophilia resolved following smoking cessation. These data suggest a differential regulation of innate and B cell-related immune inflammatory processes associated with cigarette smoke exposure. Moreover, our study further emphasizes the importance of interleukin-1 (IL-1) signaling pathways in cigarette smoke-related pulmonary pathogenesis.


Asunto(s)
Anticuerpos Antinucleares/biosíntesis , Exposición por Inhalación/efectos adversos , Tejido Linfoide/inmunología , Cese del Hábito de Fumar , Fumar/efectos adversos , Fumar/metabolismo , Anciano , Animales , Femenino , Humanos , Tejido Linfoide/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Fumar/patología , Esputo/inmunología , Esputo/metabolismo , Factores de Tiempo
18.
J Immunol ; 188(2): 832-43, 2012 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-22174454

RESUMEN

Respiratory viral infections have been associated with an increased incidence of allergic asthma. However, the mechanisms by which respiratory infections facilitate allergic airway disease are incompletely understood. We previously showed that exposure to a low dose of house dust mite (HDM) resulted in enhanced HDM-mediated allergic airway inflammation, and, importantly, marked airway hyperreactivity only when allergen exposure occurred during an acute influenza A infection. In this study, we evaluated the impact of concurrent influenza infection and allergen exposure at the genomic level, using whole-genome microarray. Our data showed that, in contrast to exposure to a low dose of HDM, influenza A infection led to a dramatic increase in gene expression, particularly of TLRs, C-type lectin receptors, several complement components, as well as FcεR1. Additionally, we observed increased expression of a number of genes encoding chemokines and cytokines associated with the recruitment of proinflammatory cells. Moreover, HDM exposure in the context of an influenza A infection resulted in the induction of unique genes, including calgranulin A (S100a8), an endogenous damage-associated molecular pattern and TLR4 agonist. In addition, we observed significantly increased expression of serum amyloid A (Saa3) and serine protease inhibitor 3n (Serpina3n). This study showed that influenza infection markedly increased the expression of multiple gene classes capable of sensing allergens and amplifying the ensuing immune-inflammatory response. We propose that influenza A infection primes the lung environment in such a way as to lower the threshold of allergen responsiveness, thus facilitating the emergence of a clinically significant allergic phenotype.


Asunto(s)
Genoma Viral/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Análisis de Componente Principal/métodos , Pyroglyphidae/genética , Pyroglyphidae/inmunología , Alérgenos/administración & dosificación , Alérgenos/inmunología , Animales , Femenino , Regulación Viral de la Expresión Génica/inmunología , Ratones , Ratones Endogámicos BALB C , Análisis de Secuencia por Matrices de Oligonucleótidos , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Pyroglyphidae/virología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/virología , Transducción de Señal/genética , Transducción de Señal/inmunología , Factores de Tiempo
19.
J Allergy Clin Immunol ; 131(1): 187-200.e1-8, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23006545

RESUMEN

BACKGROUND: Allergen exposure at lung and gut mucosae can lead to aberrant T(H)2 immunity and allergic disease. The epithelium-associated cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are suggested to be important for the initiation of these responses. OBJECTIVE: We sought to investigate the contributions of TSLP, IL-25, and IL-33 in the development of allergic disease to the common allergens house dust mite (HDM) or peanut. METHODS: Neutralizing antibodies or mice deficient in TSLP, IL-25, or IL-33 signaling were exposed to HDM intranasally or peanut intragastrically, and immune inflammatory and physiologic responses were evaluated. In vitro assays were performed to examine specific dendritic cell (DC) functions. RESULTS: We showed that experimental HDM-induced allergic asthma and food allergy and anaphylaxis to peanut were associated with TSLP production but developed independently of TSLP, likely because these allergens functionally mimicked TSLP inhibition of IL-12 production and induction of OX40 ligand (OX40L) on DCs. Blockade of OX40L significantly lessened allergic responses to HDM or peanut. Although IL-25 and IL-33 induced OX40L on DCs in vitro, only IL-33 signaling was necessary for intact allergic immunity, likely because of its superior ability to induce DC OX40L and expand innate lymphoid cells in vivo. CONCLUSION: These data identify a nonredundant, IL-33-driven mechanism initiating T(H)2 responses to the clinically relevant allergens HDM and peanut. Our findings, along with those in infectious and transgenic/surrogate allergen systems, favor a paradigm whereby multiple molecular pathways can initiate T(H)2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease.


Asunto(s)
Alérgenos/inmunología , Arachis/inmunología , Hipersensibilidad/inmunología , Interleucinas/inmunología , Pyroglyphidae/inmunología , Timo/inmunología , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Tracto Gastrointestinal/inmunología , Humanos , Hipersensibilidad/metabolismo , Interleucina-33 , Interleucina-4/inmunología , Interleucina-4/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ligando OX40/inmunología , Ligando OX40/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Factor de Transcripción STAT6/metabolismo , Transducción de Señal , Células del Estroma/inmunología , Células del Estroma/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Timo/citología
20.
J Infect Dis ; 205(8): 1311-20, 2012 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-22262795

RESUMEN

Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.


Asunto(s)
Productos Finales de Glicación Avanzada/metabolismo , Receptores Inmunológicos/metabolismo , Infecciones por Virus Sincitial Respiratorio/metabolismo , Animales , Pulmón/metabolismo , Ratones , Ratones Noqueados , Nariz , Isoformas de Proteínas , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Carga Viral
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