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1.
Cell ; 183(1): 94-109.e23, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32937105

RESUMEN

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.


Asunto(s)
Macrófagos/metabolismo , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Anciano , Animales , Apoptosis , Autofagia , Femenino , Corazón/fisiología , Homeostasis , Humanos , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mitocondrias/fisiología , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/fisiología , Fagocitosis/fisiología , Especies Reactivas de Oxígeno/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Tirosina Quinasa c-Mer/metabolismo
2.
Cell ; 177(6): 1436-1447.e12, 2019 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-31150620

RESUMEN

Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to "remember" time in the absence of external cues.


Asunto(s)
Factores de Transcripción ARNTL/fisiología , Relojes Circadianos/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/genética , Conducta Alimentaria/fisiología , Femenino , Homeostasis , Luz , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Especificidad de Órganos/fisiología , Fotoperiodo , Núcleo Supraquiasmático/metabolismo
3.
Nat Immunol ; 21(2): 135-144, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31932813

RESUMEN

The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.


Asunto(s)
Ritmo Circadiano/inmunología , Inflamación/metabolismo , Neutrófilos/metabolismo , Neumonía/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Animales , Degranulación de la Célula/inmunología , Gránulos Citoplasmáticos/inmunología , Gránulos Citoplasmáticos/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Humanos , Inflamación/inmunología , Ratones , Neutrófilos/inmunología , Neumonía/complicaciones , Neumonía/inmunología , Proteoma/inmunología , Proteoma/metabolismo , Síndrome de Dificultad Respiratoria/inmunología
5.
Immunity ; 50(2): 390-402.e10, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30709741

RESUMEN

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.


Asunto(s)
Vasos Sanguíneos/inmunología , Ritmo Circadiano/inmunología , Neutrófilos/inmunología , Fagocitosis/inmunología , Animales , Vasos Sanguíneos/metabolismo , Candida albicans/inmunología , Candida albicans/fisiología , Células Cultivadas , Senescencia Celular/inmunología , Quimiocina CXCL2/inmunología , Quimiocina CXCL2/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiología , Receptores CXCR4/inmunología , Receptores CXCR4/metabolismo , Factores de Tiempo
6.
Nature ; 601(7893): 415-421, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34987220

RESUMEN

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.


Asunto(s)
Inflamación , Leucocitos , Proteómica , Animales , Forma de la Célula , Endotelio/inmunología , Inflamación/inmunología , Leucocitos/inmunología , Ratones , Neutrófilos/inmunología , Proteínas Proto-Oncogénicas/inmunología , Familia-src Quinasas/inmunología
7.
Eur J Immunol ; 52(8): 1228-1242, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35491946

RESUMEN

ICAP-1 regulates ß1-integrin activation and cell adhesion. Here, we used ICAP-1-null mice to study ICAP-1 potential involvement during immune cell development and function. Integrin α4ß1-dependent adhesion was comparable between ICAP-1-null and control thymocytes, but lack of ICAP-1 caused a defective single-positive (SP) CD8+ cell generation, thus, unveiling an ICAP-1 involvement in SP thymocyte development. ICAP-1 bears a nuclear localization signal and we found it displayed a strong nuclear distribution in thymocytes. Interestingly, there was a direct correlation between the lack of ICAP-1 and reduced levels in SP CD8+ thymocytes of Runx3, a transcription factor required for CD8+ thymocyte generation. In the spleen, ICAP-1 was found evenly distributed between cytoplasm and nuclear fractions, and ICAP-1-/- spleen T and B cells displayed upregulation of α4ß1-mediated adhesion, indicating that ICAP-1 negatively controls their attachment. Furthermore, CD3+ - and CD19+ -selected spleen cells from ICAP-1-null mice showed reduced proliferation in response to T- and B-cell stimuli, respectively. Finally, loss of ICAP-1 caused a remarkable decrease in marginal zone B- cell frequencies and a moderate increase in follicular B cells. Together, these data unravel an ICAP-1 involvement in the generation of SP CD8+ thymocytes and in the control of marginal zone B-cell numbers.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Linfocitos B , Linfocitos T CD8-positivos , Activación de Linfocitos , Timocitos , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Linfocitos B/citología , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Integrina beta1/metabolismo , Ratones , Ratones Noqueados , Bazo/citología , Timocitos/citología , Timo/citología
9.
EMBO J ; 35(5): 536-52, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26843485

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen-activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.


Asunto(s)
Hígado/metabolismo , Proteína Quinasa 12 Activada por Mitógenos/metabolismo , Proteína Quinasa 13 Activada por Mitógenos/metabolismo , Infiltración Neutrófila , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Adulto , Anciano , Animales , Femenino , Intolerancia a la Glucosa , Humanos , Masculino , Ratones Noqueados , Persona de Mediana Edad , Proteína Quinasa 12 Activada por Mitógenos/genética , Proteína Quinasa 12 Activada por Mitógenos/inmunología , Proteína Quinasa 13 Activada por Mitógenos/genética , Proteína Quinasa 13 Activada por Mitógenos/inmunología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Obesidad/inmunología , ARN Mensajero/metabolismo , Triglicéridos/metabolismo
10.
Comput Biol Med ; 168: 107827, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38086138

RESUMEN

Identifying the most relevant variables or features in massive datasets for dimensionality reduction can lead to improved and more informative display, faster computation times, and more explainable models of complex systems. Despite significant advances and available algorithms, this task generally remains challenging, especially in unsupervised settings. In this work, we propose a method that constructs correlation networks using all intervening variables and then selects the most informative ones based on network bootstrapping. The method can be applied in both supervised and unsupervised scenarios. We demonstrate its functionality by applying Uniform Manifold Approximation and Projection for dimensionality reduction to several high-dimensional biological datasets, derived from 4D live imaging recordings of hundreds of morpho-kinetic variables, describing the dynamics of thousands of individual leukocytes at sites of prominent inflammation. We compare our method with other standard ones in the field, such as Principal Component Analysis and Elastic Net, showing that it outperforms them. The proposed method can be employed in a wide range of applications, encompassing data analysis and machine learning.


Asunto(s)
Algoritmos , Aprendizaje Automático , Análisis de Componente Principal
11.
J Exp Med ; 220(6)2023 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-36976180

RESUMEN

Clodronate liposomes (Clo-Lip) have been widely used to deplete mononuclear phagocytes (MoPh) to study the function of these cells in vivo. Here, we revisited the effects of Clo-Lip together with genetic models of MoPh deficiency, revealing that Clo-Lip exert their anti-inflammatory effects independent of MoPh. Notably, not only MoPh but also polymorphonuclear neutrophils (PMN) ingested Clo-Lip in vivo, which resulted in their functional arrest. Adoptive transfer of PMN, but not of MoPh, reversed the anti-inflammatory effects of Clo-Lip treatment, indicating that stunning of PMN rather than depletion of MoPh accounts for the anti-inflammatory effects of Clo-Lip in vivo. Our data highlight the need for a critical revision of the current literature on the role of MoPh in inflammation.


Asunto(s)
Ácido Clodrónico , Liposomas , Humanos , Ácido Clodrónico/farmacología , Neutrófilos , Inflamación , Antiinflamatorios/farmacología
12.
Front Immunol ; 14: 1125984, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37234176

RESUMEN

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1 cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.


Asunto(s)
Asma , Hipersensibilidad , Surfactantes Pulmonares , Ratones , Animales , Macrófagos Alveolares/metabolismo , Hipersensibilidad/complicaciones , Asma/metabolismo , Inflamación/complicaciones , Tensoactivos
13.
Med Image Anal ; 77: 102358, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35066392

RESUMEN

Cell detection and tracking applied to in vivo fluorescence microscopy has become an essential tool in biomedicine to characterize 4D (3D space plus time) biological processes at the cellular level. Traditional approaches to cell motion analysis by microscopy imaging, although based on automatic frameworks, still require manual supervision at some points of the system. Hence, when dealing with a large amount of data, the analysis becomes incredibly time-consuming and typically yields poor biological information. In this paper, we propose a fully-automated system for segmentation, tracking and feature extraction of migrating cells within blood vessels in 4D microscopy imaging. Our system consists of a robust 3D convolutional neural network (CNN) for joint blood vessel and cell segmentation, a 3D tracking module with collision handling, and a novel method for feature extraction, which takes into account the particular geometry in the cell-vessel arrangement. Experiments on a large 4D intravital microscopy dataset show that the proposed system achieves a significantly better performance than the state-of-the-art tools for cell segmentation and tracking. Furthermore, we have designed an analytical method of cell behaviors based on the automatically extracted features, which supports the hypotheses related to leukocyte migration posed by expert biologists. This is the first time that such a comprehensive automatic analysis of immune cell migration has been performed, where the total population under study reaches hundreds of neutrophils and thousands of time instances.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Redes Neurales de la Computación , Movimiento Celular , Diagnóstico por Imagen , Humanos , Microscopía Intravital
15.
J Exp Med ; 215(11): 2778-2795, 2018 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-30282719

RESUMEN

Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states.


Asunto(s)
Neoplasias Pulmonares/inmunología , Pulmón/inmunología , Melanoma/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Animales , Femenino , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/inmunología , Interleucina-23/genética , Interleucina-23/inmunología , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Macrófagos/inmunología , Macrófagos/patología , Masculino , Melanoma/genética , Melanoma/patología , Ratones , Ratones Noqueados , Invasividad Neoplásica/genética , Invasividad Neoplásica/inmunología , Neutrófilos/patología , Transcripción Genética/inmunología
16.
J Exp Med ; 214(5): 1281-1296, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28432199

RESUMEN

Tissue-resident macrophages display varying phenotypic and functional properties that are largely specified by their local environment. One of these functions, phagocytosis, mediates the natural disposal of billions of cells, but its mechanisms and consequences within living tissues are poorly defined. Using a parabiosis-based strategy, we identified and isolated macrophages from multiple tissues as they phagocytosed blood-borne cellular material. Phagocytosis was circadianally regulated and mediated by distinct repertoires of receptors, opsonins, and transcription factors in macrophages from each tissue. Although the tissue of residence defined the core signature of macrophages, phagocytosis imprinted a distinct antiinflammatory profile. Phagocytic macrophages expressed CD206, displayed blunted expression of Il1b, and supported tissue homeostasis. Thus, phagocytosis is a source of macrophage heterogeneity that acts together with tissue-derived factors to preserve homeostasis.


Asunto(s)
Macrófagos/fisiología , Fagocitosis/fisiología , Animales , Femenino , Interleucina-1beta/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Receptor de Manosa , Lectinas de Unión a Manosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Opsoninas/fisiología , Receptores de Superficie Celular/metabolismo , Factores de Transcripción/fisiología
17.
Nat Commun ; 8: 14780, 2017 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-28416795

RESUMEN

The ß1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.


Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Metoprolol/farmacología , Metoprolol/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Metoprolol/administración & dosificación , Ratones , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Neutrófilos/citología , Agregación Plaquetaria/efectos de los fármacos , ARN Mensajero/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo
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