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1.
Annu Rev Immunol ; 37: 439-456, 2019 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-31026415

RESUMEN

Monocytes are innate blood cells that maintain vascular homeostasis and are early responders to pathogens in acute infections. There are three well-characterized classes of monocytes: classical (CD14+CD16- in humans and Ly6Chi in mice), intermediate (CD14+CD16+ in humans and Ly6C+Treml4+ in mice), and nonclassical (CD14-CD16+ in humans and Ly6Clo in mice). Classical monocytes are critical for the initial inflammatory response. Classical monocytes can differentiate into macrophages in tissue and can contribute to chronic disease. Nonclassical monocytes have been widely viewed as anti-inflammatory, as they maintain vascular homeostasis. They are a first line of defense in recognition and clearance of pathogens. However, their roles in chronic disease are less clear. They have been shown to be protective as well as positively associated with disease burden. This review focuses on the state of the monocyte biology field and the functions of monocytes, particularly nonclassical monocytes, in health and disease.


Asunto(s)
Artritis Reumatoide/inmunología , Aterosclerosis/inmunología , Vasos Sanguíneos/fisiología , Monocitos/inmunología , Infarto del Miocardio/inmunología , Animales , Autoinmunidad , Hematopoyesis , Homeostasis , Humanos , Inflamación , Ratones
2.
Annu Rev Immunol ; 37: 125-144, 2019 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-30485751

RESUMEN

Platelets have dual physiologic roles as both cellular mediators of thrombosis and immune modulatory cells. Historically, the thrombotic function of platelets has received significant research and clinical attention, but emerging research indicates that the immune regulatory roles of platelets may be just as important. We now know that in addition to their role in the acute thrombotic event at the time of myocardial infarction, platelets initiate and accelerate inflammatory processes that are part of the pathogenesis of atherosclerosis and myocardial infarction expansion. Furthermore, it is increasingly apparent from recent studies that platelets impact the pathogenesis of many vascular inflammatory processes such as autoimmune diseases, sepsis, viral infections, and growth and metastasis of many types of tumors. Therefore, we must consider platelets as immune cells that affect all phases of immune responses.


Asunto(s)
Aterosclerosis/inmunología , Enfermedades Autoinmunes/inmunología , Plaquetas/inmunología , Inflamación , Infarto del Miocardio/inmunología , Trombosis/inmunología , Virosis/inmunología , Animales , Carcinogénesis/inmunología , Humanos , Inmunomodulación
3.
Cell ; 187(17): 4637-4655.e26, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39043180

RESUMEN

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1ß was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1ß or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1ß-mediated comorbidities, offering a framework for secondary prevention immunotherapy.


Asunto(s)
Lesiones Encefálicas , Inmunidad Innata , Memoria Inmunológica , Inflamación , Interleucina-1beta , Ratones Endogámicos C57BL , Monocitos , Animales , Ratones , Interleucina-1beta/metabolismo , Lesiones Encefálicas/inmunología , Humanos , Masculino , Monocitos/metabolismo , Monocitos/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/inmunología , Cardiopatías/inmunología , Femenino , Receptores CCR2/metabolismo , Fibrosis , Epigénesis Genética , Inmunidad Entrenada
4.
Cell ; 187(2): 228-234, 2024 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-38242080

RESUMEN

This personal story recounts the accidental observation, the struggles, the breakthroughs, and the collaborative spirit of a few individuals that led to the discovery that bacterial cells expend energy to effectively fluidize their otherwise "glass-like" cytoplasm and promote the dispersal of large cytoplasmic components. This adventure, which led us into an uncharted world at the intersection of cell biology and condensed matter physics about ten years ago, forever transformed the way I view cells and conduct research.


Asunto(s)
Bacterias , Citoplasma , Humanos , Citosol , Bacterias/citología
5.
Cell ; 187(9): 2117-2119, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38670068

RESUMEN

While some people pore over the textbook and train through the classics of the field, many scientists come to immunology when they discover it intersecting with their "first love" interests. Five of these "accidental immunologists" tell us how they found their way to a fascination with the immune system.


Asunto(s)
Alergia e Inmunología , Humanos , Historia del Siglo XX , Historia del Siglo XXI , Animales , Sistema Inmunológico
6.
Cell ; 187(8): 1874-1888.e14, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38518773

RESUMEN

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.


Asunto(s)
Infecciones por Escherichia coli , Escherichia coli , Pulmón , Polisacáridos Bacterianos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Femenino , Masculino , Ratones , Biopelículas , Escherichia coli/fisiología , Hipotermia/metabolismo , Hipotermia/patología , Inflamación/metabolismo , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Neumonía/microbiología , Neumonía/patología , Pseudomonas aeruginosa/fisiología , Células Receptoras Sensoriales , Polisacáridos Bacterianos/metabolismo , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Nociceptores/metabolismo
7.
Cell ; 185(9): 1445-1448, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35487187

RESUMEN

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity.


Asunto(s)
National Institute of Neurological Disorders and Stroke (U.S.) , Planificación Estratégica , Estados Unidos
8.
Nat Immunol ; 25(2): 357-370, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38177281

RESUMEN

Cerebral ischemia triggers a powerful inflammatory reaction involving peripheral leukocytes and brain resident cells that contribute to both tissue injury and repair. However, their dynamics and diversity remain poorly understood. To address these limitations, we performed a single-cell transcriptomic study of brain and blood cells 2 or 14 days after ischemic stroke in mice. We observed a strong divergence of post-ischemic microglia, monocyte-derived macrophages and neutrophils over time, while endothelial cells and brain-associated macrophages showed altered transcriptomic signatures at 2 days poststroke. Trajectory inference predicted the in situ trans-differentiation of macrophages from blood monocytes into day 2 and day 14 phenotypes, while neutrophils were projected to be continuously de novo recruited from the blood. Brain single-cell transcriptomes from both female and male aged mice were similar to that of young male mice, but aged and young brains differed in their immune cell composition. Although blood leukocyte analysis also revealed altered transcriptomes after stroke, brain-infiltrating leukocytes displayed higher transcriptomic divergence than their circulating counterparts, indicating that phenotypic diversification occurs within the brain in the early and recovery phases of ischemic stroke. A portal ( https://anratherlab.shinyapps.io/strokevis/ ) is provided to allow user-friendly access to our data.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Masculino , Ratones , Animales , Células Endoteliales , Accidente Cerebrovascular/genética , Encéfalo , Monocitos , Microglía , Perfilación de la Expresión Génica , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
9.
Cell ; 184(4): 912-930.e20, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33571430

RESUMEN

Electrical stimulation is a promising tool for modulating brain networks. However, it is unclear how stimulation interacts with neural patterns underlying behavior. Specifically, how might external stimulation that is not sensitive to the state of ongoing neural dynamics reliably augment neural processing and improve function? Here, we tested how low-frequency epidural alternating current stimulation (ACS) in non-human primates recovering from stroke interacted with task-related activity in perilesional cortex and affected grasping. We found that ACS increased co-firing within task-related ensembles and improved dexterity. Using a neural network model, we found that simulated ACS drove ensemble co-firing and enhanced propagation of neural activity through parts of the network with impaired connectivity, suggesting a mechanism to link increased co-firing to enhanced dexterity. Together, our results demonstrate that ACS restores neural processing in impaired networks and improves dexterity following stroke. More broadly, these results demonstrate approaches to optimize stimulation to target neural dynamics.


Asunto(s)
Potenciales de Acción/fisiología , Accidente Cerebrovascular/fisiopatología , Animales , Conducta Animal/fisiología , Fenómenos Biomecánicos/fisiología , Estimulación Eléctrica , Haplorrinos , Corteza Motora/fisiopatología , Redes Neurales de la Computación , Neuronas/fisiología , Análisis y Desempeño de Tareas , Factores de Tiempo
10.
Nat Immunol ; 24(6): 925-940, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37188941

RESUMEN

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101+CD62Llo mature and CD177hiCD101loCD62Llo and CD177loCD101loCD62Lhi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62Llo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Llo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratones , Animales , Neutrófilos , Leucocitos , Accidente Cerebrovascular/patología , Envejecimiento , Accidente Cerebrovascular Isquémico/patología
11.
Nat Immunol ; 24(7): 1110-1123, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37248420

RESUMEN

Cerebrovascular injury (CVI) is a common pathology caused by infections, injury, stroke, neurodegeneration and autoimmune disease. Rapid resolution of a CVI requires a coordinated innate immune response. In the present study, we sought mechanistic insights into how central nervous system-infiltrating monocytes program resident microglia to mediate angiogenesis and cerebrovascular repair after an intracerebral hemorrhage. In the penumbrae of human stroke brain lesions, we identified a subpopulation of microglia that express vascular endothelial growth factor A. These cells, termed 'repair-associated microglia' (RAMs), were also observed in a rodent model of CVI and coexpressed interleukin (IL)-6Ra. Cerebrovascular repair did not occur in IL-6 knockouts or in mice lacking microglial IL-6Ra expression and single-cell transcriptomic analyses revealed faulty RAM programming in the absence of IL-6 signaling. Infiltrating CCR2+ monocytes were the primary source of IL-6 after a CVI and were required to endow microglia with proliferative and proangiogenic properties. Faulty RAM programming in the absence of IL-6 or inflammatory monocytes resulted in poor cerebrovascular repair, neuronal destruction and sustained neurological deficits that were all restored via exogenous IL-6 administration. These data provide a molecular and cellular basis for how monocytes instruct microglia to repair damaged brain vasculature and promote functional recovery after injury.


Asunto(s)
Monocitos , Accidente Cerebrovascular , Ratones , Humanos , Animales , Microglía , Interleucina-6/genética , Interleucina-6/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Accidente Cerebrovascular/patología , Encéfalo/metabolismo , Ratones Endogámicos C57BL
12.
Cell ; 180(5): 862-877.e22, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32142679

RESUMEN

Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and ß2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.


Asunto(s)
Enfermedades Cardiovasculares/sangre , Microbioma Gastrointestinal/genética , Glutamina/análogos & derivados , Trombosis/metabolismo , Animales , Arterias/lesiones , Arterias/metabolismo , Arterias/microbiología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Plaquetas/metabolismo , Plaquetas/microbiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/microbiología , Enfermedades Cardiovasculares/patología , Muerte Súbita Cardíaca/patología , Glutamina/sangre , Glutamina/genética , Humanos , Masculino , Metaboloma/genética , Metabolómica/métodos , Ratones , Infarto del Miocardio/sangre , Infarto del Miocardio/microbiología , Activación Plaquetaria/genética , Receptores Adrenérgicos alfa/sangre , Receptores Adrenérgicos alfa/genética , Receptores Adrenérgicos beta/sangre , Receptores Adrenérgicos beta/genética , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/microbiología , Accidente Cerebrovascular/patología , Trombosis/genética , Trombosis/microbiología , Trombosis/patología
13.
Cell ; 180(4): 780-795.e25, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-32059781

RESUMEN

The cerebral vasculature is a dense network of arteries, capillaries, and veins. Quantifying variations of the vascular organization across individuals, brain regions, or disease models is challenging. We used immunolabeling and tissue clearing to image the vascular network of adult mouse brains and developed a pipeline to segment terabyte-sized multichannel images from light sheet microscopy, enabling the construction, analysis, and visualization of vascular graphs composed of over 100 million vessel segments. We generated datasets from over 20 mouse brains, with labeled arteries, veins, and capillaries according to their anatomical regions. We characterized the organization of the vascular network across brain regions, highlighting local adaptations and functional correlates. We propose a classification of cortical regions based on the vascular topology. Finally, we analysed brain-wide rearrangements of the vasculature in animal models of congenital deafness and ischemic stroke, revealing that vascular plasticity and remodeling adopt diverging rules in different models.


Asunto(s)
Adaptación Fisiológica , Encéfalo/irrigación sanguínea , Capilares/anatomía & histología , Arterias Cerebrales/anatomía & histología , Venas Cerebrales/anatomía & histología , Remodelación Vascular , Animales , Capilares/patología , Arterias Cerebrales/patología , Venas Cerebrales/patología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Privación Sensorial , Estrés Psicológico/etiología , Estrés Psicológico/patología , Accidente Cerebrovascular/patología
14.
Cell ; 183(1): 16-27.e1, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32882182

RESUMEN

Neurological complications have emerged as a significant cause of morbidity and mortality in the ongoing COVID-19 pandemic. Beside respiratory insufficiency, many hospitalized patients exhibit neurological manifestations ranging from headache and loss of smell, to confusion and disabling strokes. COVID-19 is also anticipated to take a toll on the nervous system in the long term. Here, we will provide a critical appraisal of the potential for neurotropism and mechanisms of neuropathogenesis of SARS-CoV-2 as they relate to the acute and chronic neurological consequences of the infection. Finally, we will examine potential avenues for future research and therapeutic development.


Asunto(s)
Encefalopatías/etiología , Infecciones por Coronavirus/complicaciones , Trastornos del Olfato/etiología , Neumonía Viral/complicaciones , Accidente Cerebrovascular/etiología , Animales , Encefalopatías/epidemiología , COVID-19 , Reanimación Cardiopulmonar/efectos adversos , Infecciones por Coronavirus/terapia , Humanos , Trastornos del Olfato/epidemiología , Pandemias , Neumonía Viral/terapia , Accidente Cerebrovascular/epidemiología
15.
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
16.
Cell ; 177(5): 1262-1279.e25, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-31056284

RESUMEN

Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.


Asunto(s)
Isquemia Encefálica , Péptidos de Penetración Celular/farmacología , Ferroptosis/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hemorragias Intracraneales , Neuronas , Fosfolípido Hidroperóxido Glutatión Peroxidasa/biosíntesis , Selenio/farmacología , Accidente Cerebrovascular , Transcripción Genética/efectos de los fármacos , Animales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Hemorragias Intracraneales/tratamiento farmacológico , Hemorragias Intracraneales/metabolismo , Hemorragias Intracraneales/patología , Masculino , Ratones , Neuronas/metabolismo , Neuronas/patología , Factor de Transcripción Sp1/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Factor de Transcripción AP-2/metabolismo
17.
Cell ; 176(5): 1143-1157.e13, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30794775

RESUMEN

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.


Asunto(s)
Lesiones Traumáticas del Encéfalo/terapia , Receptores CCR5/metabolismo , Accidente Cerebrovascular/terapia , Anciano , Anciano de 80 o más Años , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Corteza Motora/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Receptores CCR5/fisiología , Rehabilitación de Accidente Cerebrovascular/métodos
18.
Nat Immunol ; 22(9): 1093-1106, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34282331

RESUMEN

Neutrophils display distinct gene expression patters depending on their developmental stage, activation state and tissue microenvironment. To determine the transcription factor networks that shape these responses in a mouse model, we integrated transcriptional and chromatin analyses of neutrophils during acute inflammation. We showed active chromatin remodeling at two transition stages: bone marrow-to-blood and blood-to-tissue. Analysis of differentially accessible regions revealed distinct sets of putative transcription factors associated with control of neutrophil inflammatory responses. Using ex vivo and in vivo approaches, we confirmed that RUNX1 and KLF6 modulate neutrophil maturation, whereas RELB, IRF5 and JUNB drive neutrophil effector responses and RFX2 and RELB promote survival. Interfering with neutrophil activation by targeting one of these factors, JUNB, reduced pathological inflammation in a mouse model of myocardial infarction. Therefore, our study represents a blueprint for transcriptional control of neutrophil responses in acute inflammation and opens possibilities for stage-specific therapeutic modulation of neutrophil function in disease.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Inflamación/inmunología , Neutrófilos/inmunología , Activación Transcripcional/genética , Animales , Células CHO , Línea Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Cricetulus , Femenino , Factores Reguladores del Interferón/metabolismo , Factor 6 Similar a Kruppel/metabolismo , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Factores de Transcripción del Factor Regulador X/metabolismo , Factor de Transcripción ReIB/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética/genética
19.
Immunity ; 57(9): 2157-2172.e7, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39079536

RESUMEN

Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.


Asunto(s)
Aterosclerosis , Isquemia Encefálica , Proteínas de Unión al Calcio , Células Endoteliales , Proteína Jagged-1 , Receptor Notch1 , Molécula 1 de Adhesión Celular Vascular , Animales , Receptor Notch1/metabolismo , Células Endoteliales/metabolismo , Ratones , Humanos , Aterosclerosis/metabolismo , Aterosclerosis/inmunología , Proteína Jagged-1/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Isquemia Encefálica/metabolismo , Proteínas de Unión al Calcio/metabolismo , Transducción de Señal , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Senescencia Celular , Adhesión Celular , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/inmunología
20.
Immunity ; 57(2): 349-363.e9, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38309272

RESUMEN

Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1(Spp1) to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1+ microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.


Asunto(s)
Lesiones Encefálicas , Accidente Cerebrovascular , Animales , Ratones , Microglía , Encéfalo/metabolismo , Osteopontina/metabolismo
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