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1.
Immunity ; 51(5): 949-965.e6, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31653482

RESUMEN

Mast cells (MCs) are versatile immune cells capable of rapidly responding to a diverse range of extracellular cues. Here, we mapped the genomic and transcriptomic changes in human MCs upon diverse stimuli. Our analyses revealed broad H3K4me3 domains and enhancers associated with activation. Notably, the rise of intracellular calcium concentration upon immunoglobulin E (IgE)-mediated crosslinking of the high-affinity IgE receptor (FcεRI) resulted in genome-wide reorganization of the chromatin landscape and was associated with a specific chromatin signature, which we term Ca2+-dependent open chromatin (COC) domains. Examination of differentially expressed genes revealed potential effectors of MC function, and we provide evidence for fibrinogen-like protein 2 (FGL2) as an MC mediator with potential relevance in chronic spontaneous urticaria. Disease-associated single-nucleotide polymorphisms mapped onto cis-regulatory regions of human MCs suggest that MC function may impact a broad range of pathologies. The datasets presented here constitute a resource for the further study of MC function.


Asunto(s)
Cromatina/genética , Susceptibilidad a Enfermedades , Estudio de Asociación del Genoma Completo , Genómica , Mastocitos/inmunología , Mastocitos/metabolismo , Biomarcadores , Células Cultivadas , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Fibrinógeno/genética , Fibrinógeno/metabolismo , Perfilación de la Expresión Génica , Genómica/métodos , Histonas/metabolismo , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Inmunoglobulina E/inmunología , Inflamación/etiología , Inflamación/metabolismo , Polimorfismo de Nucleótido Simple
2.
Nat Immunol ; 14(6): 564-73, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23603794

RESUMEN

Type 2 immunity is critical for defense against cutaneous infections but also underlies the development of allergic skin diseases. We report the identification in normal mouse dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depended on interleukin 7 (IL-7) and constitutively produced IL-13. Intravital multiphoton microscopy showed that dermal ILC2 cells specifically interacted with mast cells, whose function was suppressed by IL-13. Treatment of mice deficient in recombination-activating gene 1 (Rag1(-/-)) with IL-2 resulted in the population expansion of activated, IL-5-producing dermal ILC2 cells, which led to spontaneous dermatitis characterized by eosinophil infiltrates and activated mast cells. Our data show that ILC2 cells have both pro- and anti-inflammatory properties and identify a previously unknown interactive pathway between two innate populations of cells of the immune system linked to type 2 immunity and allergic diseases.


Asunto(s)
Dermatitis/inmunología , Inmunidad Innata/inmunología , Linfocitos/inmunología , Piel/inmunología , Animales , Comunicación Celular/inmunología , Células Cultivadas , Dermatitis/genética , Dermatitis/metabolismo , Dermis/citología , Dermis/inmunología , Dermis/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Citometría de Flujo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Proteínas de Homeodominio/metabolismo , Inmunidad Innata/genética , Interleucina-13/inmunología , Interleucina-13/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-2/inmunología , Interleucina-2/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Piel/metabolismo , Grabación de Cinta de Video
3.
Am J Respir Cell Mol Biol ; 70(5): 414-423, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38315810

RESUMEN

The role of alternative splicing in chronic obstructive pulmonary disease (COPD) is still largely unknown. We aimed to investigate the differences in alternatively splicing events between patients with mild-to-moderate and severe COPD compared with non-COPD control subjects and to identify splicing factors associated with aberrant alternative splicing in COPD. For this purpose, we performed genome-wide RNA-sequencing analysis of bronchial brushings from 23 patients with mild-to-moderate COPD, 121 with severe COPD, and 23 non-COPD control subjects. We found a significant difference in the frequency of alternative splicing events in patients with mild-to-moderate and severe COPD compared with non-COPD control subjects. There were from two to eight times (depending on event type) more differential alternative splicing events in the severe than in the mild-to-moderate stage. The severe COPD samples showed less intron retention and more exon skipping. It is interesting that the transcript levels of the top 10 differentially expressed splicing factors were significantly correlated with the percentage of many alternatively spliced transcripts in severe COPD. The aberrant alternative splicing in severe COPD was predicted to increase the overall protein-coding capacity of gene products. In conclusion, we observed large and significant differences in alternative splicing between bronchial samples of patients with COPD and control subjects, with more events observed in severe than in mild-to-moderate COPD. The changes in the expression of several splicing factors correlated with prevalence of alternative splicing in severe COPD. Alternative splicing can indirectly impact gene expression by changing the relative abundance of protein-coding isoforms potentially influencing pathophysiological changes. The results provide a better understanding of COPD-related alternative splicing changes.


Asunto(s)
Empalme Alternativo , Enfermedad Pulmonar Obstructiva Crónica , Transcriptoma , Humanos , Enfermedad Pulmonar Obstructiva Crónica/genética , Empalme Alternativo/genética , Masculino , Femenino , Transcriptoma/genética , Anciano , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Estudios de Casos y Controles , Exones/genética
4.
J Allergy Clin Immunol ; 152(3): 725-735.e10, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37127225

RESUMEN

BACKGROUND: Mast cells (MCs) are tissue-resident immune cells that mediate IgE-dependent allergic responses. Downstream of FcεRI, an intricate network of receptor-specific signaling pathways and adaptor proteins govern MC function. The 14-3-3 family of serine-threonine phosphorylation-dependent adapter proteins are known to organize intracellular signaling. However, the role of 14-3-3 in IgE-dependent activation remains poorly defined. OBJECTIVE: We sought to determine whether 14-3-3 proteins are required for IgE-dependent MC activation and whether 14-3-3 is a viable target for the treatment of MC-mediated inflammatory diseases. METHODS: Genetic manipulation of 14-3-3ζ expression in human and mouse MCs was performed and IgE-dependent mediator release assessed. Pharmacologic inhibitors of 14-3-3 and 14-3-3ζ knockout mice were used to assess 14-3-3ζ function in a MC-dependent in vivo passive cutaneous anaphylaxis (PCA) model of allergic inflammation. Expression and function of 14-3-3ζ were assessed in human nasal polyp tissue MCs. RESULTS: IgE-dependent mediator release from human MCs was decreased by 14-3-3ζ knockdown and increased by 14-3-3ζ overexpression. Deletion of the 14-3-3ζ gene decreased IgE-dependent activation of mouse MCs in vitro and PCA responses in vivo. Furthermore, the 14-3-3 inhibitor, RB-11, which impairs dimerization of 14-3-3, inhibited cultured MC and polyp tissue MC activation and signaling downstream of the FcεRI receptor and dose-dependently attenuated PCA responses. CONCLUSION: IgE/FcεRI-mediated MC activation is positively regulated by 14-3-3ζ. We identify a critical role for this p-Ser/Thr-binding protein in the regulation of MC FcεRI signaling and IgE-dependent immune responses and show that this pathway may be amenable to pharmacologic targeting.


Asunto(s)
Anafilaxia , Receptores de IgE , Humanos , Ratones , Animales , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Mastocitos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Inmunoglobulina E , Inflamación/metabolismo , Degranulación de la Célula
5.
J Allergy Clin Immunol ; 150(6): 1517-1524, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36041655

RESUMEN

BACKGROUND: The binding of IL-33 to its receptor ST2 (alias of IL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG2 mAb that binds to ST2 and inhibits IL-33 signaling. OBJECTIVES: This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis. METHODS: This was a randomized, placebo-controlled, phase 2 study in which adults with chronic atopic dermatitis were randomized 1:1 to receive astegolimab 490 mg every 4 weeks or placebo, for 16 weeks. The primary outcome was the percentage of change from baseline to week 16 of the Eczema Area and Severity Index score. RESULTS: A total of 65 patients were enrolled in the study (placebo, n = 32; astegolimab, n = 33). The adjusted mean percentage of change from baseline to week 16 in the Eczema Area and Severity Index score was -51.47% for astegolimab compared with -58.24% for placebo, with a nonsignificant treatment difference of 6.77% (95% CI: -16.57-30.11; P = .5624). No differences were observed between treatment groups for secondary efficacy outcomes and in exploratory biomarkers (blood eosinophils, serum IL-5, serum CCL13). With the use of loading dose, pharmacokinetic exposure was sufficient from week 1. Astegolimab was well-tolerated, with a safety profile consistent with that observed in previous clinical trials. CONCLUSIONS: In patients with atopic dermatitis, astegolimab did not show a significant difference compared to placebo for the primary or secondary outcomes.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Interleucina-33 , Anticuerpos Monoclonales Humanizados/uso terapéutico
6.
Pulm Pharmacol Ther ; 75: 102133, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35644305

RESUMEN

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.


Asunto(s)
Asma , Inhibidores de las Cinasas Janus , Adulto , Asma/tratamiento farmacológico , Australia , Biomarcadores , Pruebas Respiratorias , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inhibidores de las Cinasas Janus/efectos adversos , Masculino , Óxido Nítrico
7.
BMC Pulm Med ; 21(1): 301, 2021 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-34556083

RESUMEN

BACKGROUND: Chronic obstructive pulmonary disease (COPD) exacerbations are heterogenous and profoundly impact the disease trajectory. Bioactive lipid lysophosphatidic acid (LPA) has been implicated in airway inflammation but the significance of LPA in COPD exacerbation is not known. The aim of the study was to investigate the utility of serum LPA species (LPA16:0, 18:0, 18:1, 18:2, 20:4) as biomarkers of COPD exacerbation. PATIENTS AND METHODS: LPA species were measured in the baseline placebo sera of a COPD randomized controlled trial. Tertile levels of each LPA were used to assign patients into biomarker high, medium, and low subgroups. Exacerbation rate and risk were compared among the LPA subgroups. RESULTS: The levels of LPA species were intercorrelated (rho 0.29-0.91). Patients with low and medium levels of LPA (LPA16:0, 20:4) had significantly higher exacerbation rate compared to the respective LPA-high patients [estimated rate per patient per year (95% CI)]: LPA16:0-low = 1.2 (0.8-1.9) (p = 0.019), LPA16:0-medium = 1.3 (0.8-2.0) (p = 0.013), LPA16:0-high = 0.5 (0.2-0.9); LPA20:4-low = 1.4 (0.9-2.1) (p = 0.0033), LPA20:4-medium = 1.2 (0.8-1.8) (p = 0.0089), LPA20:4-high = 0.4 (0.2-0.8). These patients also had earlier time to first exacerbation (hazard ratio (95% CI): LPA16:0-low = 2.6 (1.1-6.0) (p = 0.028), LPA16:0-medium = 2.7 (1.2-6.3) (p = 0.020); LPA20.4-low = 2.8 (1.2-6.6) (p = 0.017), LPA20:4-medium = 2.7 (1.2-6.4) (p = 0.021). Accordingly, these patients had a significant increased exacerbation risk compared to the respective LPA-high subgroups [odd ratio (95% CI)]: LPA16:0-low = 3.1 (1.1-8.8) (p = 0.030), LPA16:0-medium = 3.0 (1.1-8.3) (p = 0.031); LPA20:4-low = 3.8 (1.3-10.9) (p = 0.012), LPA20:4-medium = 3.3 (1.2-9.5) (p = 0.025). For the other LPA species (LPA18:0, 18:1, 18:2), the results were mixed; patients with low and medium levels of LPA18:0 and 18:2 had increased exacerbation rate, but only LPA18:0-low patients had significant increase in exacerbation risk and earlier time to first exacerbation compared to the LPA18:0-high subgroup. CONCLUSIONS: The study provided evidence of association between systemic LPA levels and exacerbation in COPD. Patients with low and medium levels of specific LPA species (LPA16:0, 20:4) had increased exacerbation rate, risk, and earlier time to first exacerbation. These non-invasive biomarkers may aid in identifying high risk patients with dysregulated LPA pathway to inform risk management and drug development.


Asunto(s)
Lisofosfolípidos/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad
8.
Eur Respir J ; 52(3)2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30072506

RESUMEN

Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of MUC5AC-related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1, as potential key miRNA-mRNA networks regulating CMH in COPD.


Asunto(s)
MicroARNs/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Mucosa Respiratoria/metabolismo , Anciano , Bronquios/patología , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras)/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , ARN Mensajero/genética
9.
J Immunol ; 196(9): 3854-64, 2016 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-27001955

RESUMEN

The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation.


Asunto(s)
Dermatitis/tratamiento farmacológico , Clorhidrato de Fingolimod/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Piel/efectos de los fármacos , Administración Tópica , Animales , Permeabilidad Capilar/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Clorhidrato de Fingolimod/farmacología , Histamina/metabolismo , Humanos , Inmunoglobulina E/sangre , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Piel/inmunología
11.
PLoS Pathog ; 10(10): e1004466, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25340820

RESUMEN

Human Papillomavirus (HPV) 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions.


Asunto(s)
Quimiocina CCL2/inmunología , Quimiocina CCL5/inmunología , Epitelio/virología , Mastocitos/virología , Proteínas E7 de Papillomavirus/metabolismo , Animales , Animales Modificados Genéticamente , Ambiente , Humanos , Ratones Endogámicos C57BL , Piel/virología
12.
Immunol Rev ; 250(1): 277-302, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23046136

RESUMEN

Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are members of a discrete family of cytokines that regulates the growth, differentiation, migration and effector function activities of many hematopoietic cells and immunocytes. These cytokines are involved in normal responses to infectious agents, bridging innate and adaptive immunity. However, in certain cases, the overexpression of these cytokines or their receptors can lead to excessive or aberrant initiation of signaling resulting in pathological conditions, with chronic inflammatory diseases and myeloid leukemias the most notable examples. Recent crystal structures of the GM-CSF receptor ternary complex and the IL-5 binary complex have revealed new paradigms of cytokine receptor activation. Together with a wealth of associated structure-function studies, they have significantly enhanced our understanding of how these receptors recognize cytokines and initiate signals across cell membranes. Importantly, these structures provide opportunities for structure-based approaches for the discovery of novel and disease-specific therapeutics. In addition, recent biochemical evidence has suggested that the GM-CSF/IL-3/IL-5 receptor family is capable of interacting productively with other membrane proteins at the cell surface. Such interactions may afford additional or unique biological activities and might be harnessed for selective modulation of the function of these receptors in disease.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/química , Interleucina-3/química , Interleucina-5/química , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/química , Receptores de Interleucina-3/química , Receptores de Interleucina-5/química , Cristalografía por Rayos X , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucina-3/inmunología , Interleucina-3/metabolismo , Interleucina-5/inmunología , Interleucina-5/metabolismo , Leucemia Mieloide/inmunología , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/patología , Modelos Moleculares , Unión Proteica , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Receptores de Interleucina-3/inmunología , Receptores de Interleucina-3/metabolismo , Receptores de Interleucina-5/inmunología , Receptores de Interleucina-5/metabolismo , Transducción de Señal , Relación Estructura-Actividad
13.
Immunol Cell Biol ; 93(6): 540-7, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25601274

RESUMEN

Atopic dermatitis is a common pruritic and inflammatory skin disorder with unknown etiology. Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin. In this study, we report an atopic dermatitis-like pathophysiology results in a murine model following the expression of the high-risk human papillomavirus (HPV) 16 oncoprotein E7 in keratinocytes under the keratin 14 promoter. We show that HPV16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis. Locally, HPV16 E7-expressing skin secreted high levels of thymic stromal lymphopoietin (TSLP) and contained increased numbers of innate lymphoid cells (ILCs). High levels of circulating immunoglobulin E were associated with increased susceptibility to skin allergy in a model of cutaneous challenge, and to airway bronchiolar inflammation, enhanced airway goblet cell metaplasia and mucus production in a model of atopic march. Surprisingly, skin pathology occurred independently of T cells and mast cells. Thus, our findings suggest that the expression of a single HPV oncogene in the skin can drive the onset of atopic dermatitis-like pathology through the induction of TSLP and type 2 ILC infiltration.


Asunto(s)
Citocinas/biosíntesis , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Expresión Génica , Proteínas E7 de Papillomavirus/genética , Piel/inmunología , Piel/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Dermatitis Atópica/patología , Dermatitis Atópica/virología , Modelos Animales de Enfermedad , Inmunidad Innata , Interleucina-33/metabolismo , Interleucinas/metabolismo , Mastocitos/inmunología , Mastocitos/patología , Ratones , Ratones Transgénicos , Fenotipo , Piel/patología , Piel/virología , Subgrupos de Linfocitos T/patología , Linfopoyetina del Estroma Tímico
14.
Am J Pathol ; 184(9): 2493-504, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25134760

RESUMEN

Stroke is the leading cause of adult disability and the fourth most common cause of death in the United States. Inflammation is thought to play an important role in stroke pathology, but the factors that promote inflammation in this setting remain to be fully defined. An understudied but important factor is the role of meningeal-located immune cells in modulating brain pathology. Although different immune cells traffic through meningeal vessels en route to the brain, mature mast cells do not circulate but are resident in the meninges. With the use of genetic and cell transfer approaches in mice, we identified evidence that meningeal mast cells can importantly contribute to the key features of stroke pathology, including infiltration of granulocytes and activated macrophages, brain swelling, and infarct size. We also obtained evidence that two mast cell-derived products, interleukin-6 and, to a lesser extent, chemokine (C-C motif) ligand 7, can contribute to stroke pathology. These findings indicate a novel role for mast cells in the meninges, the membranes that envelop the brain, as potential gatekeepers for modulating brain inflammation and pathology after stroke.


Asunto(s)
Mastocitos/inmunología , Meninges/inmunología , Accidente Cerebrovascular/inmunología , Animales , Encéfalo/inmunología , Encéfalo/patología , Modelos Animales de Enfermedad , Citometría de Flujo , Técnicas de Sustitución del Gen , Imagen por Resonancia Magnética , Masculino , Mastocitos/patología , Meninges/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Accidente Cerebrovascular/patología
16.
J Immunol ; 190(11): 5471-84, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23636055

RESUMEN

Alterations to dendritic cell (DC) progenitors in the bone marrow (BM) may contribute to long-lasting systemic immunosuppression (>28 d) following exposure of the skin of mice to erythemal UV radiation (UVR). DCs differentiated in vitro from the BM of mice 3 d after UVR (8 kJ/m(2)) have a reduced capacity to initiate immunity (both skin and airways) when adoptively transferred into naive mice. Studies in IL-10(-/-) mice suggested that UV-induced IL-10 was not significantly involved. To investigate the immune capabilities of peripheral tissue DCs generated in vivo from the BM of UV-irradiated mice, chimeric mice were established. Sixteen weeks after reconstitution, contact hypersensitivity responses were significantly reduced in mice reconstituted with BM from UV-irradiated mice (UV-chimeric). When the dorsal skin of UV-chimeric mice was challenged with innate inflammatory agents, the hypertrophy induced in the draining lymph nodes was minimal and significantly less than that measured in control-chimeric mice challenged with the same inflammatory agent. When DCs were differentiated from the BM of UV-chimeric mice using FLT3 ligand or GM-CSF + IL-4, the cells maintained a reduced priming ability. The diminished responses in UV-chimeric mice were not due to different numerical or proportional reconstitution of BM or the hematopoietic cells in blood, lymph nodes, and skin. Erythemal UVR may imprint a long-lasting epigenetic effect on DC progenitors in the BM and alter the function of their terminally differentiated progeny.


Asunto(s)
Trasplante de Médula Ósea , Células Dendríticas/inmunología , Células Dendríticas/efectos de la radiación , Supervivencia de Injerto/inmunología , Rayos Ultravioleta , Traslado Adoptivo , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Diferenciación Celular/efectos de la radiación , Movimiento Celular/inmunología , Quimerismo/efectos de la radiación , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Dermatitis por Contacto/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Hipertrofia , Inmunidad Innata , Interleucina-4/farmacología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ganglios Linfáticos/efectos de la radiación , Proteínas de la Membrana/farmacología , Ratones , Linfocitos T/inmunología , Linfocitos T/efectos de la radiación
17.
J Allergy Clin Immunol ; 133(5): 1356-64, 1364.e1-14, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24461581

RESUMEN

BACKGROUND: Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to what extent 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. OBJECTIVE: We sought to assess whether the vitamin D3 metabolites 25OHD3 and 1α,25(OH)2D3 can repress IgE-dependent mast cell activation through mast cell-25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell-VDR activity. METHODS: We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D3-induced curtailment of PCA responses in WBB6F1-Kit(W/W-v) or C57BL/6J-Kit(W-sh/W-sh) mice engrafted with mast cells that did or did not express VDR or CYP27B1. RESULTS: Here we show that mouse and human mast cells can convert 25OHD3 to 1α,25(OH)2D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell-derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin D3 metabolites significantly reduced the magnitude of skin swelling associated with IgE-mediated PCA reactions in vivo; a response that required functional mast cell-VDRs and mast cell-CYP27B1. CONCLUSION: Taken together, our findings provide a mechanistic explanation for the anti-inflammatory effects of vitamin D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.


Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Anafilaxia/metabolismo , Calcifediol/metabolismo , Mastocitos/metabolismo , Receptores de Calcitriol/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Anafilaxia/genética , Anafilaxia/patología , Animales , Línea Celular , Dermatitis Atópica/genética , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Humanos , Inmunoglobulina E , Mastocitos/patología , Ratones , Ratones Noqueados , Receptores de Calcitriol/genética
18.
Eur Respir Rev ; 32(167)2023 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-36697211

RESUMEN

Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments. The epithelial cytokines/alarmins are involved in exacerbations; biologics targeting TSLP and IL-33 have been shown to reduce exacerbations in moderate-to-severe asthma, either in a broad population or in specific subgroups, respectively. For COPD, while there is clinical evidence for IL-33 blockade impacting exacerbations in COPD, clinical data from anti-TSLP therapies is awaited. Clinical data to date support an acceptable safety profile for patients with airway diseases for both anti-IL-33 and anti-TSLP antibodies in development. We examine the roles of IL-33 and TSLP, their potential use as drug targets, and the evidence for target patient populations for COPD and asthma, together with ongoing and future trials focused on these targets.


Asunto(s)
Asma , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Linfopoyetina del Estroma Tímico , Inmunidad Innata , Interleucina-33/uso terapéutico , Alarminas/uso terapéutico , Linfocitos/metabolismo , Citocinas/metabolismo , Citocinas/uso terapéutico , Inflamación , Pulmón , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico
19.
J Invest Dermatol ; 142(4): 1103-1113.e11, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34537191

RESUMEN

Allergic contact dermatitis (ACD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (ßc) cytokines GM-CSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit ßc, a property that has made ßc an attractive target to simultaneously inhibit these cytokines. However, the species specificity of ßc has precluded testing of inhibitors of human ßc in mouse models. To overcome this problem, we developed a human ßc receptor transgenic mouse strain with a hematopoietic cell‒specific expression of human ßc instead of mouse ßc. Human ßc receptor transgenic cells responded to mouse GM-CSF and IL-5 but not to IL-3 in vitro and developed tissue pathology and cellular inflammation comparable with those in wild-type mice in a model of ACD. Similarly, Il3-/- mice developed ACD pathology comparable with that of wild-type mice. Importantly, the blocking anti-human ßc antibody CSL311 strongly suppressed ear pinna thickening and histopathological changes typical of ACD and reduced accumulation of neutrophils, mast cells, and eosinophils in the skin. These results show that GM-CSF and IL-5 but not IL-3 are major mediators of ACD and define the human ßc receptor transgenic mouse as a unique platform to test the inhibitors of ßc in vivo.


Asunto(s)
Dermatitis por Contacto , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Animales , Citocinas , Eosinófilos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Interleucina-3/metabolismo , Interleucina-5/metabolismo , Ratones , Ratones Transgénicos
20.
Lancet Respir Med ; 10(5): 469-477, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35339234

RESUMEN

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD. METHODS: COPD-ST2OP was a single-centre, randomised, double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD. Participants were randomly assigned (1:1) with a web-based system to received 490 mg subcutaneous astegolimab or subcutaneous placebo, every 4 weeks for 44 weeks. The primary endpoint was exacerbation rate assessed for 48 weeks assessed with a negative binomial count model in the intention-to-treat population, with prespecified subgroup analysis by baseline blood eosinophil count. The model was the number of exacerbations over the 48-week treatment period, with treatment group as a covariate. Safety was assessed in the whole study population until week 60. Secondary endpoints included Saint George's Respiratory Questionnaire for COPD (SGRQ-C), FEV1, and blood and sputum cell counts. The trial was registered with ClinicalTrials.gov, NCT03615040. FINDINGS: The exacerbation rate at 48 weeks in the intention-to-treat analysis was not significantly different between the astegolimab group (2·18 [95% CI 1·59 to 2·78]) and the placebo group (2·81 [2·05 to 3·58]; rate ratio 0·78 [95% CI 0·53 to 1·14]; p=0·19]). In the prespecified analysis stratifying patients by blood eosinophil count, patients with 170 or fewer cells per µL had 0·69 exacerbations (0·39 to 1·21), whereas those with more than 170 cells per µL had 0·83 exacerbations (0·49 to 1·40). For the secondary outcomes, the mean difference between the SGRQ-C in the astegolimab group versus placebo group was -3·3 (95% CI -6·4 to -0·2; p=0·039), and mean difference in FEV1 between the two groups was 40 mL (-10 to 90; p=0·094). The difference in geometric mean ratios between the two groups for blood eosinophil counts was 0·59 (95% CI 0·51 to 0·69; p<0·001) and 0·25 (0·19 to 0·33; p<0·001) for sputum eosinophil counts. Incidence of treatment-emergent adverse events was similar between groups. INTERPRETATION: In patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo. FUNDING: Funded by Genentech and National Institute for Health Research Biomedical Research Centres.


Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1 , Enfermedad Pulmonar Obstructiva Crónica , Anticuerpos Monoclonales Humanizados/uso terapéutico , Progresión de la Enfermedad , Método Doble Ciego , Eosinófilos , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico
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