Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Nat Immunol ; 25(5): 847-859, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38658806

RESUMEN

Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice-but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wild-type mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcriptional state and helps prepare these cells for rapid response to immune stimuli.


Asunto(s)
Homeostasis , Quinasas Janus , Macrófagos , Ratones Noqueados , Factores de Transcripción STAT , Transducción de Señal , Animales , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Ratones Endogámicos C57BL , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/genética , TYK2 Quinasa/metabolismo , TYK2 Quinasa/genética , Regulación de la Expresión Génica
2.
Cell ; 175(4): 1031-1044.e18, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30318149

RESUMEN

Lung development and function arises from the interactions between diverse cell types and lineages. Using single-cell RNA sequencing (RNA-seq), we characterize the cellular composition of the lung during development and identify vast dynamics in cell composition and their molecular characteristics. Analyzing 818 ligand-receptor interaction pairs within and between cell lineages, we identify broadly interacting cells, including AT2, innate lymphocytes (ILCs), and basophils. Using interleukin (IL)-33 receptor knockout mice and in vitro experiments, we show that basophils establish a lung-specific function imprinted by IL-33 and granulocyte-macrophage colony-stimulating factor (GM-CSF), characterized by unique signaling of cytokines and growth factors important for stromal, epithelial, and myeloid cell fates. Antibody-depletion strategies, diphtheria toxin-mediated selective depletion of basophils, and co-culture studies show that lung resident basophils are important regulators of alveolar macrophage development and function. Together, our study demonstrates how whole-tissue signaling interaction map on the single-cell level can broaden our understanding of cellular networks in health and disease.


Asunto(s)
Basófilos/metabolismo , Comunicación Celular , Impresión Genómica , Macrófagos Alveolares/metabolismo , Transcriptoma , Animales , Diferenciación Celular , Línea Celular Tumoral , Células Cultivadas , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-33/metabolismo , Macrófagos Alveolares/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal , Análisis de la Célula Individual
3.
Nat Immunol ; 17(12): 1361-1372, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27798618

RESUMEN

Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.


Asunto(s)
Infecciones por Bacterias Gramnegativas/inmunología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Hemo/metabolismo , Hemólisis/inmunología , Macrófagos/inmunología , Fagocitosis , Sepsis/inmunología , Animales , Antibacterianos/uso terapéutico , Citoesqueleto/metabolismo , Femenino , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Factores de Intercambio de Guanina Nucleótido/genética , Hemo-Oxigenasa 1/genética , Hemólisis/efectos de los fármacos , Humanos , Evasión Inmune , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis/efectos de los fármacos , Quinina/uso terapéutico , Células RAW 264.7 , Sepsis/tratamiento farmacológico , Proteína de Unión al GTP cdc42/metabolismo
4.
PLoS Pathog ; 17(4): e1009487, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33905460

RESUMEN

Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.


Asunto(s)
Gripe Humana/inmunología , Lipocalina 2/metabolismo , Microbiota/inmunología , Transcriptoma , Animales , Presentación de Antígeno , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/virología , Femenino , Microbioma Gastrointestinal , Homeostasis , Humanos , Inmunidad , Gripe Humana/virología , Lipocalina 2/genética , Pulmón/inmunología , Pulmón/virología , Activación de Linfocitos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Organismos Libres de Patógenos Específicos
5.
Am J Respir Cell Mol Biol ; 66(1): 64-75, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34586974

RESUMEN

Tissue-resident macrophages are of vital importance as they preserve tissue homeostasis in all mammalian organs. Nevertheless, appropriate cell culture models are still limited. Here, we propose a novel culture model to study and expand murine primary alveolar macrophages (AMs), the tissue-resident macrophages of the lung, in vitro over several months. By providing a combination of granulocyte-macrophage colony-stimulating factor, TGFß, and the PPARγ activator rosiglitazone, we maintain and expand mouse ex vivo cultured AMs (mexAMs) over several months. MexAMs maintain typical morphologic features and stably express primary AM surface markers throughout in vitro culture. They respond to microbial ligands and exhibit an AM-like transcriptional profile, including the expression of AM-specific transcription factors. Furthermore, when transferred into AM-deficient mice, mexAMs efficiently engraft in the lung and fulfill key macrophage functions, leading to a significantly reduced surfactant load in those mice. Altogether, mexAMs provide a novel, simple, and versatile tool to study AM behavior in homeostasis and disease settings.


Asunto(s)
Macrófagos Alveolares/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Hígado/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Macrófagos Alveolares/patología , Ratones Endogámicos C57BL , Fenotipo , Proteinosis Alveolar Pulmonar/metabolismo , Proteinosis Alveolar Pulmonar/patología , Proteinosis Alveolar Pulmonar/fisiopatología , Transcripción Genética
6.
Eur Respir J ; 59(2)2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34244315

RESUMEN

RATIONALE: Lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). The mechanisms leading to CLAD remain elusive due to an insufficient understanding of the complex post-transplant adaptation processes. OBJECTIVES: To better understand these lung adaptation processes after transplantation and to investigate their association with future changes in allograft function. METHODS: We performed an exploratory cohort study of bronchoalveolar lavage samples from 78 lung recipients and donors. We analysed the alveolar microbiome using 16S rRNA sequencing, the cellular composition using flow cytometry, as well as metabolome and lipidome profiling. MEASUREMENTS AND MAIN RESULTS: We established distinct temporal dynamics for each of the analysed data sets. Comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. We further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. A decline in forced expiratory volume during the first second (FEV1) is a major characteristic of lung allograft dysfunction in transplant recipients. By using a machine learning approach, we could accurately predict future changes in FEV1 from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. CONCLUSION: Bronchoalveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The lung microbiome can predict future changes in lung function with high precision.


Asunto(s)
Trasplante de Pulmón , Microbiota , Aloinjertos , Estudios de Cohortes , Humanos , Pulmón , ARN Ribosómico 16S/genética , Estudios Retrospectivos
7.
J Virus Erad ; 8(4): 100305, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36514716

RESUMEN

Rhinoviruses (RVs) and coronaviruses (CoVs) upregulate host cell metabolic pathways such as glycolysis to meet their bioenergetic demands for rapid multiplication. Using the glycolysis inhibitor 2-deoxy-d-glucose (2-DG), we assessed the dose-dependent inhibition of viral replication of minor- and major-receptor group RVs in epithelial cells. 2-DG disrupted RV infection cycle by inhibiting template negative-strand as well as genomic positive-strand RNA synthesis, resulting in less progeny virus and RV-mediated cell death. Assessment of 2-DG's intracellular kinetics revealed that after a short-exposure to 2-DG, the active intermediate, 2-DG6P, is stored intracellularly for several hours. Finally, we confirmed the antiviral effect of 2-DG on pandemic SARS-CoV-2 and showed for the first time that it also reduces replication of endemic human coronaviruses. These results provide further evidence that 2-DG could be used as a broad-spectrum antiviral.

8.
Elife ; 112022 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-36178806

RESUMEN

Sepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multiorgan failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce. Here, we established a mouse model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils include upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted disease tolerance by improving tissue damage control via the suppression of neutrophils' tissue-damaging properties. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue damage control and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis.


Asunto(s)
Infecciones Bacterianas , Sepsis , Animales , Infecciones Bacterianas/metabolismo , Modelos Animales de Enfermedad , Ratones , Insuficiencia Multiorgánica/metabolismo , Insuficiencia Multiorgánica/patología , Neutrófilos/metabolismo , Sepsis/metabolismo
9.
Mucosal Immunol ; 15(5): 896-907, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35856089

RESUMEN

Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We discovered that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) induced a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect. Notably, adoptive transfer of trained AMs resulted in increased bacterial loads and tissue damage upon subsequent pneumococcal infection. In contrast, intranasal pre-exposure to LPS promoted bacterial clearance, highlighting the complexity of stimulus-induced immune responses, which likely involve multiple cell types and may depend on the local immunological and metabolic environment. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and reveal tissue-specific features of trained immunity.


Asunto(s)
Interferón Tipo I , Macrófagos Alveolares , Interferón Tipo I/metabolismo , Lipopolisacáridos , Pulmón , Transducción de Señal
10.
Cell Rep ; 41(6): 111614, 2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-36351402

RESUMEN

Phosphatidylinositol 3-kinase catalytic subunit p110ß is involved in tumorigenesis and hemostasis. However, it remains unclear if p110ß also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110ß inhibitors. Thus, we investigate how platelet p110ß affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110ß deficiency and pharmacologic inhibition of p110ß with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110ß mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110ß also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110ß dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.


Asunto(s)
Neumonía Neumocócica , Humanos , Fosfatidilinositol 3-Quinasas/genética , Plaquetas , Leucocitos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Streptococcus pneumoniae
11.
Diabetes ; 70(9): 2042-2057, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33627323

RESUMEN

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.


Asunto(s)
Tejido Adiposo/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Obesidad/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Dieta Alta en Grasa , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Ratones , Regulación hacia Arriba
12.
Cell Rep ; 18(8): 1893-1905, 2017 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-28228256

RESUMEN

From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33) in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s), which coincided with the appearance of alveolar macrophages (AMs) and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.


Asunto(s)
Animales Recién Nacidos/inmunología , Homeostasis/inmunología , Inmunidad Innata/inmunología , Interleucina-13/inmunología , Pulmón/inmunología , Animales , Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos C57BL , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Regulación hacia Arriba/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA