Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23.679
Filtrar
1.
Int J Mol Sci ; 22(10)2021 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-34065210

RESUMEN

Previous studies have shown that COVID-19 leads to thrombotic complications, which have been associated with high morbidity and mortality rates. Neutrophils are the largest population of white blood cells and play a pivotal role in innate immunity. During an infection, neutrophils migrate from circulation to the infection site, contributing to killing pathogens. This mechanism is regulated by chemokines such as IL-8. Moreover, it was shown that neutrophils play an important role in thromboinflammation. Through a diverse repertoire of mechanisms, neutrophils, apart from directly killing pathogens, are able to activate the formation of thrombi. In COVID-19 patients, neutrophil activation promotes neutrophil extracellular trap (NET) formation, platelet aggregation, and cell damage. Furthermore, neutrophils participate in the pathogenesis of endothelitis. Overall, this review summarizes recent progress in research on the pathogenesis of COVID-19, highlighting the role of the prothrombotic action of neutrophils in NET formation.


Asunto(s)
COVID-19/inmunología , Trampas Extracelulares/inmunología , Inmunidad Innata , Pulmón/inmunología , Neutrófilos/inmunología , Trombosis/inmunología , COVID-19/complicaciones , COVID-19/patología , COVID-19/terapia , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/virología , Trampas Extracelulares/virología , Humanos , Inflamación/inmunología , Inflamación/patología , Riñón/citología , Riñón/inmunología , Riñón/patología , Riñón/virología , Pulmón/citología , Pulmón/patología , Pulmón/virología , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/virología , SARS-CoV-2 , Trombosis/complicaciones , Trombosis/patología , Trombosis/virología
2.
Biomolecules ; 11(5)2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-34066385

RESUMEN

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.


Asunto(s)
COVID-19/patología , Trampas Extracelulares/metabolismo , Trombosis/inmunología , Trombosis/patología , Biomarcadores/metabolismo , COVID-19/inmunología , COVID-19/virología , Proteínas del Sistema Complemento/metabolismo , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Coagulación Intravascular Diseminada/etiología , Coagulación Intravascular Diseminada/patología , Humanos , Neutrófilos/citología , Neutrófilos/inmunología , Neutrófilos/metabolismo , SARS-CoV-2/aislamiento & purificación , Trombosis/metabolismo
3.
Nat Commun ; 12(1): 3213, 2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-34050141

RESUMEN

Apart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate or insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show that members of sand fly yellow salivary proteins induce in vitro chemotaxis of mouse, canine and human neutrophils in transwell migration or EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment in vivo using flow cytometry and two-photon intravital microscopy in Lysozyme-M-eGFP transgenic mice. We establish that the structure of this ~ 45 kDa neutrophil chemotactic protein does not resemble that of known chemokines. This chemoattractant acts through a G-protein-coupled receptor and is dependent on calcium influx. Of significance, this chemoattractant protein enhances lesion pathology (P < 0.0001) and increases parasite burden (P < 0.001) in mice upon co-injection with Leishmania parasites, underlining the impact of the sand fly salivary yellow proteins on disease outcome. These findings show that some arthropod vector-derived factors, such as this chemotactic salivary protein, activate rather than inhibit the host innate immune response, and that pathogens take advantage of these inflammatory responses to establish in the host.


Asunto(s)
Factores Quimiotácticos/metabolismo , Proteínas de Insectos/metabolismo , Leishmaniasis Cutánea/inmunología , Neutrófilos/inmunología , Proteínas y Péptidos Salivales/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Células Cultivadas , Quimiotaxis de Leucocito/inmunología , Modelos Animales de Enfermedad , Perros , Femenino , Voluntarios Sanos , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Proteínas de Insectos/genética , Proteínas de Insectos/aislamiento & purificación , Insectos Vectores/inmunología , Insectos Vectores/metabolismo , Insectos Vectores/parasitología , Leishmania major/inmunología , Leishmania major/patogenicidad , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/transmisión , Masculino , Ratones , Persona de Mediana Edad , Infiltración Neutrófila/inmunología , Cultivo Primario de Células , Psychodidae/inmunología , Psychodidae/metabolismo , Psychodidae/parasitología , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Proteínas y Péptidos Salivales/genética , Proteínas y Péptidos Salivales/aislamiento & purificación , Adulto Joven
4.
Cell Prolif ; 54(6): e13040, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33942422

RESUMEN

Acetaminophen (APAP) is a widely applied drug for the alleviation of pain and fever, which is also a dose-depedent toxin. APAP-induced acute liver injury has become one of the primary causes of liver failure which is an increasingly serious threat to human health. Neutrophils are the major immune cells in human serving as the first barrier against the invasion of pathogen. It has been reported that neutrophils patriciate in the occurrence and development of APAP-induced liver injury. However, evolving evidences suggest that neutrophils also contribute to tissue repair and actively orchestrate resolution of inflammation. Here, we addressed the complex roles in APAP-induced liver injury on the basis of brief introduction of neutrophil's activation, recruitment and migration.


Asunto(s)
Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Neutrófilos/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Humanos , Neutrófilos/inmunología , Neutrófilos/patología
5.
Biomed Res Int ; 2021: 6655425, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33959663

RESUMEN

The central component of sepsis pathogenesis is inflammatory disorder, which is related to dysfunction of the immune system. However, the specific molecular mechanism of sepsis has not yet been fully elucidated. The aim of our study was to identify genes that are significantly changed during sepsis development, for the identification of potential pathogenic factors. Differentially expressed genes (DEGs) were identified in 88 control and 214 septic patient samples. Gene ontology (GO) and pathway enrichment analyses were performed using David. A protein-protein interaction (PPI) network was established using STRING and Cytoscape. Further validation was performed using real-time polymerase chain reaction (RT-PCR). We identified 37 common DEGs. GO and pathway enrichment indicated that enzymes and transcription factors accounted for a large proportion of DEGs; immune system and inflammation signaling demonstrated the most significant changes. Furthermore, eight hub genes were identified via PPI analysis. Interestingly, four of the top five upregulated and all downregulated DEGs were involved in immune and inflammation signaling. In addition, the most intensive hub gene AKT1 and the top DEGs in human clinical samples were validated using RT-PCR. This study explored the possible molecular mechanisms underpinning the inflammatory, immune, and PI3K/AKT pathways related to sepsis development.


Asunto(s)
Neutrófilos , Sepsis , Transcriptoma , Adulto , Anciano , Humanos , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Mapas de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas/inmunología , Sepsis/genética , Sepsis/inmunología , Sepsis/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Transcriptoma/genética , Transcriptoma/inmunología , Adulto Joven
6.
Nat Commun ; 12(1): 2776, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33986291

RESUMEN

Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.


Asunto(s)
Trampas Extracelulares/metabolismo , Neutrófilos/inmunología , Tolerancia a Radiación/inmunología , Neoplasias de la Vejiga Urinaria/radioterapia , Anciano , Anciano de 80 o más Años , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Femenino , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Microambiente Tumoral/inmunología , Neoplasias de la Vejiga Urinaria/patología
7.
JCI Insight ; 6(10)2021 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-34027897

RESUMEN

The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1ß, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures.


Asunto(s)
/genética , Citocinas/genética , Redes Reguladoras de Genes , Adulto , Factores de Edad , Anciano , /inmunología , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/metabolismo , /aislamiento & purificación , Factores Sexuales , Transcriptoma
8.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33946542

RESUMEN

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb-neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.


Asunto(s)
Mycobacterium tuberculosis/inmunología , Neutrófilos/inmunología , Tuberculosis/inmunología , Animales , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Mycobacterium tuberculosis/fisiología , Neutrófilos/microbiología , Neutrófilos/patología , Fagocitosis , Tuberculosis/microbiología , Tuberculosis/patología
9.
JCI Insight ; 6(9)2021 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-33986193

RESUMEN

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.


Asunto(s)
Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/etiología , /complicaciones , Neutrófilos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Trastornos de la Coagulación Sanguínea/inmunología , Citocinas/sangre , Femenino , Proteínas Ligadas a GPI/sangre , Hospitalización , Humanos , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Neutrófilos/clasificación , Pandemias , Fagocitosis , Activación Plaquetaria , Receptores de IgG/sangre , /etiología , Índice de Severidad de la Enfermedad
10.
EBioMedicine ; 67: 103357, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33979758

RESUMEN

BACKGROUND: Perhaps reflecting that children with COVID-19 rarely exhibit severe respiratory symptoms and often remain asymptomatic, little attention has been paid to explore the immune response in pediatric COVID-19. Here, we analyzed the phenotype and function of circulating neutrophils from children with COVID-19. METHODS: An observational study including 182 children with COVID-19, 21 children with multisystem inflammatory syndrome (MIS-C), and 40 healthy children was performed in Buenos Aires, Argentina. Neutrophil phenotype was analyzed by flow cytometry in blood samples. Cytokine production, plasma levels of IgG antibodies directed to the spike protein of SARS-CoV-2 and citrullinated histone H3 were measured by ELISA. Cell-free DNA was quantified by fluorometry. FINDINGS: Compared with healthy controls, neutrophils from children with COVID-19 showed a lower expression of CD11b, CD66b, and L-selectin but a higher expression of the activation markers HLA-DR, CD64 and PECAM-1 and the inhibitory receptors LAIR-1 and PD-L1. No differences in the production of cytokines and NETs were observed. Interestingly, the expression of CD64 in neutrophils and the serum concentration of IgG antibodies directed to the spike protein of SARS-CoV-2 distinguished asymptomatic from mild and moderate COVID-19. INTERPRETATION: Acute lung injury is a prominent feature of severe COVID-19 in adults. A low expression of adhesion molecules together with a high expression of inhibitory receptors in neutrophils from children with COVID-19 might prevent tissue infiltration by neutrophils preserving lung function. FUNDING: This study was supported by the Ministry of Science and Technology (National Agency for Scientific and Technological Promotion, IP-COVID-19-0277 and PMO BID PICT 2018-2548), and University of Buenos Aires from Argentina (20020170100573BA).


Asunto(s)
Biomarcadores/sangre , COVID-19/inmunología , Neutrófilos/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Anticuerpos Antivirales/sangre , Argentina , COVID-19/sangre , Estudios de Casos y Controles , Niño , Preescolar , Citocinas/sangre , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina G/sangre , Lactante , Masculino , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/sangre
11.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-33946935

RESUMEN

Interferons (IFNs) are induced by viruses and are the main regulators of the host antiviral response. They balance tissue tolerance and immune resistance against viral challenges. Like all cells in the human body, neutrophils possess the receptors for IFNs and contribute to antiviral host defense. To combat viruses, neutrophils utilize various mechanisms, such as viral sensing, neutrophil extracellular trap formation, and antigen presentation. These mechanisms have also been linked to tissue damage during viral infection and inflammation. In this review, we presented evidence that a complex cross-regulatory talk between IFNs and neutrophils initiates appropriate antiviral immune responses and regulates them to minimize tissue damage. We also explored recent exciting research elucidating the interactions between IFNs, neutrophils, and severe acute respiratory syndrome-coronavirus-2, as an example of neutrophil and IFN cross-regulatory talk. Dissecting the IFN-neutrophil paradigm is needed for well-balanced antiviral therapeutics and development of novel treatments against many major epidemic or pandemic viral infections, including the ongoing pandemic of the coronavirus disease that emerged in 2019.


Asunto(s)
/inmunología , Interferón Tipo I/inmunología , Neutrófilos/inmunología , Virosis/inmunología , Animales , Antivirales/inmunología , Trampas Extracelulares/inmunología , Humanos , Transducción de Señal , Virus/inmunología
12.
Nat Commun ; 12(1): 3006, 2021 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-34021143

RESUMEN

Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity.


Asunto(s)
/inmunología , Inflamación/inmunología , Activación de Linfocitos/inmunología , Neumonía/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Basófilos/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Neutrófilos/inmunología , Adulto Joven
13.
Nat Commun ; 12(1): 2717, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33976150

RESUMEN

Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. In simulations, CelFiE accurately estimates known and unknown cell type proportions from low coverage and noisy cfDNA mixtures, including from cell types composing less than 1% of the total mixture. When used in two clinically-relevant situations, CelFiE correctly estimates a large placenta component in pregnant women, and an elevated skeletal muscle component in amyotrophic lateral sclerosis (ALS) patients, consistent with the occurrence of muscle wasting typical in these patients. Together, these results show how CelFiE could be a useful tool for biomarker discovery and monitoring the progression of degenerative disease.


Asunto(s)
Algoritmos , Esclerosis Amiotrófica Lateral/genética , Ácidos Nucleicos Libres de Células/genética , Metilación de ADN , Epigénesis Genética , Adulto , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/clasificación , Femenino , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Especificidad de Órganos , Embarazo , Trimestres del Embarazo/sangre , Trimestres del Embarazo/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo
14.
Nat Rev Immunol ; 21(5): 319-329, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33824483

RESUMEN

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.


Asunto(s)
/inmunología , Síndrome de Liberación de Citoquinas/patología , Trombosis de la Vena/inmunología , Trombosis de la Vena/patología , Coagulación Sanguínea/inmunología , Plaquetas/inmunología , Enfermedad Crítica/terapia , Síndrome de Liberación de Citoquinas/inmunología , Endotelio Vascular/patología , Fibrinolíticos/uso terapéutico , Humanos , Inmunidad Innata/inmunología , Pulmón/irrigación sanguínea , Pulmón/patología , Pulmón/virología , Monocitos/inmunología , Neutrófilos/inmunología , /patogenicidad , Trombosis de la Vena/prevención & control
15.
Front Immunol ; 12: 653344, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33868293

RESUMEN

Sepsis is a heterogeneous syndrome caused by a dysregulated host response during the process of infection. Neutrophils are involved in the development of sepsis due to their essential role in host defense. COVID-19 is a viral sepsis. Disfunction of neutrophils in sepsis has been described in previous studies, however, little is known about the role of microRNA-let-7b (miR-let-7b), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) activity in neutrophils and how they participate in the development of sepsis. In this study, we investigated the regulatory pathway of miR-let-7b/TLR4/NF-κB in neutrophils. We also explored the downstream cytokines released by neutrophils following miR-let-7b treatment and its therapeutic effects in cecal ligation and puncture (CLP)-induced septic mice. Six-to-eight-week-old male C57BL/6 mice underwent CLP following treatment with miR-let-7b agomir. Survival (n=10), changes in liver and lungs histopathology (n=4), circulating neutrophil counts (n=4), the liver-body weight ratio (n=4-7), and the lung wet-to-dry ratio (n=5-6) were recorded. We found that overexpression of miR-let-7b could significantly down-regulate the expression of human-derived neutrophilic TLR4 at a post-transcriptional level, a decreased level of proinflammatory factors including interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), and an upregulation of anti-inflammatory factor IL-10 in vitro. After miR-let-7b agomir treatment in vivo, neutrophil recruitment was inhibited and thus the injuries of liver and lungs in CLP-induced septic mice were alleviated (p=0.01 and p=0.04, respectively), less weight loss was reduced, and survival in septic mice was also significantly improved (p=0.013). Our study suggested that miR-let-7b could be a potential target of sepsis.


Asunto(s)
/inmunología , MicroARNs/inmunología , FN-kappa B/inmunología , Neutrófilos/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 4/inmunología , /patología , Humanos , Inflamación/inmunología , Inflamación/patología , Neutrófilos/patología
16.
Front Immunol ; 12: 656350, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33868301

RESUMEN

The new SARS-CoV-2 virus differs from the pandemic Influenza A virus H1N1 subtype (H1N1pmd09) how it induces a pro-inflammatory response in infected patients. This study aims to evaluate the involvement of SNPs and tissue expression of IL-17A and the neutrophils recruitment in post-mortem lung samples from patients who died of severe forms of COVID-19 comparing to those who died by H1N1pdm09. Twenty lung samples from patients SARS-CoV-2 infected (COVID-19 group) and 10 lung samples from adults who died from a severe respiratory H1N1pdm09 infection (H1N1 group) were tested. The tissue expression of IL-8/IL-17A was identified by immunohistochemistry, and hematoxylin and eosin (H&E) stain slides were used for neutrophil scoring. DNA was extracted from paraffin blocks, and genotyping was done in real time-PCR for two IL17A target polymorphisms. Tissue expression increasing of IL-8/IL-17A and a higher number of neutrophils were identified in samples from the H1N1 group compared to the COVID-19 group. The distribution of genotype frequencies in the IL17A gene was not statistically significant between groups. However, the G allele (GG and GA) of rs3819025 was correlated with higher tissue expression of IL-17A in the COVID-19 group. SARS-CoV-2 virus evokes an exacerbated response of the host's immune system but differs from that observed in the H1N1pdm09 infection since the IL-8/IL-17A tissue expression, and lung neutrophilic recruitment may be decreased. In SNP rs3819025 (G/A), the G allele may be considered a risk allele in the patients who died for COVID-19.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Interleucina-17 , Interleucina-8 , Pulmón/inmunología , Neutrófilos/inmunología , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , /inmunología , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/genética , Gripe Humana/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Pulmón/patología , Pulmón/virología , Masculino , Persona de Mediana Edad , Neutrófilos/patología , Neutrófilos/virología , /inmunología
17.
BMC Infect Dis ; 21(1): 384, 2021 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-33902476

RESUMEN

BACKGROUND: The aim of the study was to conduct a meta-analysis to evaluate the accuracy of neutrophil CD64, procalcitonin (PCT), and interleukin-6 (IL-6) as markers for the diagnosis of sepsis in adult patients. METHODS: Various databases were searched to collect published studies on the diagnosis of sepsis in adult patients using neutrophil CD64, PCT, and IL-6 levels. Utilizing the Stata SE 15.0 software, forest plots and the area under the summary receiver operating characteristic curves were drawn. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve (AUC) were calculated. RESULTS: Fifty-four articles were included in the study. The pooled sensitivity, specificity, and AUC of neutrophil CD64 for the diagnosis of sepsis were 0.88 (95% confidence interval [CI], 0.81-0.92), 0.88 (95% CI, 0.83-0.91), and 0.94 (95% CI, 0.91-0.96), respectively. The pooled sensitivity, specificity, and AUC of PCT for the diagnosis of sepsis were 0.82 (95% CI, 0.78-0.85), 0.78 (95% CI, 0.74-0.82), and 0.87 (95% CI, 0.83-0.89), respectively. Subgroup analysis showed that the AUC for PCT diagnosis of intensive care unit (ICU) sepsis was 0.86 (95% CI, 0.83-0.89) and the AUC for PCT diagnosis of non-ICU sepsis was 0.82 (95% CI, 0.78-0.85). The pooled sensitivity, specificity, and AUC of IL-6 for the diagnosis of sepsis were 0.72 (95% CI, 0.65-0.78), 0.70 (95% CI, 0.62-0.76), and 0.77 (95% CI, 0.73-0.80), respectively. CONCLUSIONS: Of the three biomarkers studied, neutrophil CD64 showed the highest diagnostic value for sepsis, followed by PCT, and IL-6. On the other hand, PCT showed a better diagnostic potential for the diagnosis of sepsis in patients with severe conditions compared with that in patients with non-severe conditions.


Asunto(s)
Interleucina-6/sangre , Neutrófilos/inmunología , Polipéptido alfa Relacionado con Calcitonina/sangre , Receptores de IgG/sangre , Sepsis/sangre , Sepsis/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Biomarcadores/sangre , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Curva ROC
18.
Front Immunol ; 12: 652470, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33841435

RESUMEN

Strong evidence has been accumulated since the beginning of the COVID-19 pandemic that neutrophils play an important role in the pathophysiology, particularly in those with severe disease courses. While originally considered to be a rather homogeneous cell type, recent attention to neutrophils has uncovered their fascinating transcriptional and functional diversity as well as their developmental trajectories. These new findings are important to better understand the many facets of neutrophil involvement not only in COVID-19 but also many other acute or chronic inflammatory diseases, both communicable and non-communicable. Here, we highlight the observed immune deviation of neutrophils in COVID-19 and summarize several promising therapeutic attempts to precisely target neutrophils and their reactivity in patients with COVID-19.


Asunto(s)
/epidemiología , Neutrófilos/inmunología , Pandemias , /inmunología , Humanos
19.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-33804806

RESUMEN

Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb- "peritoneal-like" macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large "peritoneal-like" macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis.


Asunto(s)
Carga Bacteriana , Macrófagos/inmunología , Macrófagos/metabolismo , Proteínas Proto-Oncogénicas c-myb/deficiencia , Sepsis/etiología , Sepsis/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Recuento de Leucocitos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fagocitosis/inmunología , Pronóstico , Ratas , Sepsis/diagnóstico , Sepsis/mortalidad , Índice de Severidad de la Enfermedad
20.
Nat Commun ; 12(1): 2298, 2021 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-33863903

RESUMEN

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.


Asunto(s)
Enfermedades Autoinmunes/genética , Elementos de Facilitación Genéticos/genética , Regulación de la Expresión Génica/inmunología , Neutrófilos/inmunología , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Adulto , Anciano , Enfermedades Autoinmunes/inmunología , Cromatina/metabolismo , Secuenciación de Inmunoprecipitación de Cromatina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Regiones Promotoras Genéticas/genética , Sitios de Carácter Cuantitativo/genética , Sitios de Carácter Cuantitativo/inmunología , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...