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1.
Cell ; 187(4): 846-860.e17, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38262409

RESUMEN

RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.


Asunto(s)
Células Endoteliales , Infiltración Neutrófila , Neutrófilos , ARN , Animales , Ratones , Células Endoteliales/metabolismo , Neutrófilos/metabolismo , ARN/química , ARN/metabolismo , Proteínas de Transporte de Nucleótidos/genética , Proteínas de Transporte de Nucleótidos/metabolismo
2.
Cell ; 185(5): 759-761, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-35245478

RESUMEN

Neutrophil recruitment from blood into tissues is a hallmark of inflammation and anti-microbial host defense. In this issue, De Giovanni et al. describe an unanticipated role for a serotonin metabolite, 5-HIAA, which is produced by activated platelets and mast cells and engages the orphan receptor, GPR35, to recruit neutrophils to inflamed tissues.


Asunto(s)
Plaquetas , Neutrófilos , Plaquetas/metabolismo , Humanos , Inflamación/metabolismo , Mastocitos/metabolismo , Infiltración Neutrófila , Neutrófilos/metabolismo
3.
Cell ; 185(5): 815-830.e19, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-35148838

RESUMEN

Rapid neutrophil recruitment to sites of inflammation is crucial for innate immune responses. Here, we reveal that the G-protein-coupled receptor GPR35 is upregulated in activated neutrophils, and it promotes their migration. GPR35-deficient neutrophils are less recruited from blood vessels into inflamed tissue, and the mice are less efficient in clearing peritoneal bacteria. Using a bioassay, we find that serum and activated platelet supernatant stimulate GPR35, and we identify the platelet-derived serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) as a GPR35 ligand. GPR35 function in neutrophil recruitment is strongly dependent on platelets, with the receptor promoting transmigration across platelet-coated endothelium. Mast cells also attract GPR35+ cells via 5-HIAA. Mice deficient in 5-HIAA show a loss of GPR35-mediated neutrophil recruitment to inflamed tissue. These findings identify 5-HIAA as a GPR35 ligand and neutrophil chemoattractant and establish a role for platelet- and mast cell-produced 5-HIAA in cell recruitment to the sites of inflammation and bacterial clearance.


Asunto(s)
Ácido Hidroxiindolacético/metabolismo , Neutrófilos , Receptores Acoplados a Proteínas G/metabolismo , Animales , Inflamación/metabolismo , Ligandos , Ratones , Infiltración Neutrófila , Neutrófilos/metabolismo , Serotonina/metabolismo
4.
Cell ; 184(2): 460-475.e21, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33278358

RESUMEN

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.


Asunto(s)
Antiinflamatorios/administración & dosificación , Azetidinas/administración & dosificación , Tratamiento Farmacológico de COVID-19 , COVID-19/inmunología , Macaca mulatta , Infiltración Neutrófila/efectos de los fármacos , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , COVID-19/fisiopatología , Muerte Celular/efectos de los fármacos , Degranulación de la Célula/efectos de los fármacos , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Quinasas Janus/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Macrófagos Alveolares/inmunología , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Replicación Viral/efectos de los fármacos
5.
Cell ; 183(1): 110-125.e11, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32888431

RESUMEN

During respiration, humans breathe in more than 10,000 liters of non-sterile air daily, allowing some pathogens access to alveoli. Interestingly, alveoli outnumber alveolar macrophages (AMs), which favors alveoli devoid of AMs. If AMs, like most tissue macrophages, are sessile, then this numerical advantage would be exploited by pathogens unless neutrophils from the blood stream intervened. However, this would translate to omnipresent persistent inflammation. Developing in vivo real-time intravital imaging of alveoli revealed AMs crawling in and between alveoli using the pores of Kohn. Importantly, these macrophages sensed, chemotaxed, and, with high efficiency, phagocytosed inhaled bacterial pathogens such as P. aeruginosa and S. aureus, cloaking the bacteria from neutrophils. Impairing AM chemotaxis toward bacteria induced superfluous neutrophil recruitment, leading to inappropriate inflammation and injury. In a disease context, influenza A virus infection impaired AM crawling via the type II interferon signaling pathway, and this greatly increased secondary bacterial co-infection.


Asunto(s)
Bacterias/inmunología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Animales , Femenino , Homeostasis , Humanos , Pulmón/inmunología , Pulmón/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Neutrófilos/inmunología , Fagocitosis/inmunología , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/patogenicidad , Alveolos Pulmonares , Transducción de Señal , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad
6.
Cell ; 178(2): 346-360.e24, 2019 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-31257026

RESUMEN

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.


Asunto(s)
Resistencia a la Enfermedad , Neoplasias/patología , Neutrófilos/inmunología , Sarcoma/patología , Linfocitos T/metabolismo , Animales , Cromonas/toxicidad , Resistencia a la Enfermedad/inmunología , Humanos , Inmunidad Innata , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimación de Kaplan-Meier , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/mortalidad , Infiltración Neutrófila , Neutrófilos/citología , Neutrófilos/metabolismo , Receptores del Factor Estimulante de Colonias/metabolismo , Sarcoma/inducido químicamente , Sarcoma/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Microambiente Tumoral
7.
Cell ; 178(5): 1205-1221.e17, 2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31442408

RESUMEN

A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs.


Asunto(s)
Dipeptidasas/metabolismo , Neutrófilos/fisiología , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Animales , Cilastatina/farmacología , Cilastatina/uso terapéutico , Dipeptidasas/antagonistas & inhibidores , Dipeptidasas/genética , Modelos Animales de Enfermedad , Endotoxemia/mortalidad , Endotoxemia/patología , Endotoxemia/prevención & control , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Infiltración Neutrófila/efectos de los fármacos , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , Tasa de Supervivencia
8.
Nat Immunol ; 21(12): 1496-1505, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33106668

RESUMEN

Transected axons typically fail to regenerate in the central nervous system (CNS), resulting in chronic neurological disability in individuals with traumatic brain or spinal cord injury, glaucoma and ischemia-reperfusion injury of the eye. Although neuroinflammation is often depicted as detrimental, there is growing evidence that alternatively activated, reparative leukocyte subsets and their products can be deployed to improve neurological outcomes. In the current study, we identify a unique granulocyte subset, with characteristics of an immature neutrophil, that had neuroprotective properties and drove CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors. This pro-regenerative neutrophil promoted repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations. Our findings could ultimately lead to the development of new immunotherapies that reverse CNS damage and restore lost neurological function across a spectrum of diseases.


Asunto(s)
Axones/metabolismo , Comunicación Celular , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Regeneración Nerviosa , Neuronas/metabolismo , Neutrófilos/metabolismo , Animales , Biomarcadores , Plasticidad de la Célula/inmunología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Sistema Nervioso Central/inmunología , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Ratones , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Nervio Óptico/inmunología , Nervio Óptico/metabolismo , Receptores de Interleucina-8B/metabolismo , Médula Espinal/citología , Médula Espinal/metabolismo , Transcriptoma , Zimosan/metabolismo , Zimosan/farmacología
9.
Nat Immunol ; 21(11): 1327-1335, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32839612

RESUMEN

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/patología , Inmunidad Innata/inmunología , Peptidil-Dipeptidasa A/genética , Neumonía Viral/patología , Neumonía/patología , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Chlorocebus aethiops , Infecciones por Coronavirus/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Interferón Tipo I/inmunología , Interferón gamma/inmunología , Queratina-18/genética , Leucocitos/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Transgénicos , Monocitos/inmunología , FN-kappa B/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Pandemias , Neumonía/genética , Neumonía/virología , Neumonía Viral/inmunología , Regiones Promotoras Genéticas/genética , SARS-CoV-2 , Linfocitos T/inmunología , Células Vero , Replicación Viral/inmunología
10.
Nat Immunol ; 20(5): 559-570, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30996332

RESUMEN

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1ß served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1ß and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1ß, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1ß and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/inmunología , Candidiasis/inmunología , Quimiocina CXCL1/inmunología , Interleucina-1beta/inmunología , Microglía/inmunología , Neutrófilos/inmunología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/microbiología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Candida albicans/inmunología , Candida albicans/fisiología , Candidiasis/genética , Candidiasis/microbiología , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Ratones Noqueados , Ratones Transgénicos , Microglía/metabolismo , Microglía/microbiología , Infiltración Neutrófila/genética , Infiltración Neutrófila/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiología
11.
Nat Immunol ; 19(11): 1236-1247, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30323345

RESUMEN

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils' contribution to early tumor dissemination.


Asunto(s)
Quimiotaxis de Leucocito/inmunología , Neoplasias/inmunología , Neoplasias/patología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Anciano , Animales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad
12.
Immunity ; 54(9): 1989-2004.e9, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34363750

RESUMEN

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.


Asunto(s)
Autofagia/fisiología , Células Endoteliales/fisiología , Infiltración Neutrófila/fisiología , Migración Transendotelial y Transepitelial/fisiología , Animales , Quimiotaxis de Leucocito/fisiología , Células Endoteliales/patología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Uniones Intercelulares/fisiología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/fisiología
13.
Immunity ; 52(4): 700-715.e6, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32294409

RESUMEN

The omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs) that collects peritoneal contaminants and provides a first layer of immunological defense within the abdomen. Here, we investigated the mechanisms that mediate the capture of peritoneal contaminants during peritonitis. Single-cell RNA sequencing and spatial analysis of omental stromal cells revealed that the surface of FALCs were covered by CXCL1+ mesothelial cells, which we termed FALC cover cells. Blockade of CXCL1 inhibited the recruitment and aggregation of neutrophils at FALCs during zymosan-induced peritonitis. Inhibition of protein arginine deiminase 4, an enzyme important for the release of neutrophil extracellular traps, abolished neutrophil aggregation and the capture of peritoneal contaminants by omental FALCs. Analysis of omental samples from patients with acute appendicitis confirmed neutrophil recruitment and bacterial capture at FALCs. Thus, specialized omental mesothelial cells coordinate the recruitment and aggregation of neutrophils to capture peritoneal contaminants.


Asunto(s)
Apendicitis/inmunología , Linfocitos/inmunología , Neutrófilos/inmunología , Epiplón/inmunología , Peritonitis/inmunología , Células del Estroma/inmunología , Enfermedad Aguda , Animales , Apendicitis/genética , Apendicitis/microbiología , Comunicación Celular/inmunología , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Epitelio/inmunología , Epitelio/microbiología , Escherichia coli/crecimiento & desarrollo , Escherichia coli/patogenicidad , Trampas Extracelulares/inmunología , Femenino , Expresión Génica , Humanos , Linfocitos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/microbiología , Epiplón/microbiología , Peritonitis/inducido químicamente , Peritonitis/genética , Peritonitis/microbiología , Arginina Deiminasa Proteína-Tipo 4/genética , Arginina Deiminasa Proteína-Tipo 4/inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Células del Estroma/microbiología , Técnicas de Cultivo de Tejidos , Zimosan/administración & dosificación
14.
Nature ; 618(7967): 1072-1077, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37196676

RESUMEN

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.


Asunto(s)
Anticuerpos Monoclonales , Membrana Celular , Inflamación , Hígado , Factores de Crecimiento Nervioso , Daño por Reperfusión , Animales , Ratones , Alanina Transaminasa , Alarminas , Anticuerpos Monoclonales/inmunología , Aspartato Aminotransferasas , Moléculas de Adhesión Celular Neuronal/antagonistas & inhibidores , Moléculas de Adhesión Celular Neuronal/deficiencia , Moléculas de Adhesión Celular Neuronal/inmunología , Moléculas de Adhesión Celular Neuronal/ultraestructura , Muerte Celular , Membrana Celular/patología , Membrana Celular/ultraestructura , Concanavalina A , Galactosamina , Hepatocitos/patología , Hepatocitos/ultraestructura , Inflamación/patología , Lactato Deshidrogenasas , Hígado/patología , Microscopía Electrónica , Factores de Crecimiento Nervioso/antagonistas & inhibidores , Factores de Crecimiento Nervioso/deficiencia , Factores de Crecimiento Nervioso/inmunología , Factores de Crecimiento Nervioso/ultraestructura , Infiltración Neutrófila , Daño por Reperfusión/patología
15.
Nat Immunol ; 17(8): 930-7, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27322654

RESUMEN

Most of the known regulatory mechanisms that curb inflammatory gene expression target pre-transcription-initiation steps, and evidence for post-initiation regulation of inflammatory gene expression remains scarce. We found that the transcriptional repressor Hes1 suppressed production of CXCL1, a chemokine that is crucial for recruiting neutrophils. Hes1 negatively regulated neutrophil recruitment in vivo in a manner that was dependent on macrophage-produced CXCL1, and it attenuated the severity of inflammatory arthritis. Mechanistically, inhibition of Cxcl1 expression by Hes1 did not involve modification of transcription initiation. Instead, Hes1 inhibited signal-induced recruitment of the positive transcription-elongation complex P-TEFb and thereby prevented phosphorylation of RNA polymerase II at Ser2 and productive elongation. Thus, our results identify Hes1 as a homeostatic suppressor of inflammatory responses that exerts its suppressive function by regulating transcription elongation.


Asunto(s)
Artritis/genética , Proteínas de Ciclo Celular/metabolismo , Inflamación/genética , Macrófagos/inmunología , Factor de Transcripción HES-1/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Regulación de la Expresión Génica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Infiltración Neutrófila/genética , Factor B de Elongación Transcripcional Positiva/genética , Factor B de Elongación Transcripcional Positiva/metabolismo , ARN Polimerasa II/metabolismo , Elongación de la Transcripción Genética , Factor de Transcripción HES-1/genética
16.
Immunity ; 50(4): 1069-1083.e8, 2019 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-30926233

RESUMEN

Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor α (VEGF-α) by a minor subset of activated EpCAM+CD59+Ly-6D+ cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Guérin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.


Asunto(s)
Acné Vulgar/inmunología , Células Dendríticas/clasificación , Infecciones por Bacterias Grampositivas/inmunología , Infiltración Neutrófila/inmunología , Factor A de Crecimiento Endotelial Vascular/inmunología , Acné Vulgar/microbiología , Animales , Presentación de Antígeno , Quimiotaxis de Leucocito/inmunología , Células Dendríticas/inmunología , Oído Externo , Regulación de la Expresión Génica , Ontología de Genes , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Inyecciones Intradérmicas , Ratones , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Propionibacterium acnes , ARN Mensajero/biosíntesis , Análisis de la Célula Individual , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética
17.
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
18.
Immunity ; 48(5): 846-848, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29768171

RESUMEN

Neutrophil recruitment in response to pathogen invasion is mediated through "self" tissue damage signals (DAMPs) and pathogen associated signals (PAMPs). In this issue of Immunity, Huang and Niethammer, (2018) demonstrate that DAMP signaling is a prerequisite for neutrophil recruitment.


Asunto(s)
Inmunidad Innata , Pez Cebra , Animales , Infiltración Neutrófila , Transducción de Señal
19.
Immunity ; 48(5): 1006-1013.e6, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29768163

RESUMEN

Tissue damage and infection are deemed likewise triggers of innate immune responses. But whereas neutrophil responses to microbes are generally protective, neutrophil recruitment into damaged tissues without infection is deleterious. Why neutrophils respond to tissue damage and not just to microbes is unknown. Is it a flaw of the innate immune system that persists because evolution did not select against it, or does it provide a selective advantage? Here we dissect the contribution of tissue damage signaling to antimicrobial immune responses in a live vertebrate. By intravital imaging of zebrafish larvae, a powerful model for innate immunity, we show that prevention of tissue damage signaling upon microbial ear infection abrogates leukocyte chemotaxis and reduces animal survival, at least in part, through suppression of cytosolic phospholipase A2 (cPla2), which integrates tissue damage- and microbe-derived cues. Thus, microbial cues are insufficient, and damage signaling is essential for antimicrobial neutrophil responses in zebrafish.


Asunto(s)
Enfermedades de los Peces/inmunología , Infiltración Neutrófila/inmunología , Transducción de Señal/inmunología , Pez Cebra/inmunología , Animales , Animales Modificados Genéticamente , Enfermedades de los Peces/microbiología , Inmunidad Innata/inmunología , Larva/inmunología , Larva/microbiología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fosfolipasas A2 Citosólicas/inmunología , Fosfolipasas A2 Citosólicas/metabolismo , Pez Cebra/genética , Pez Cebra/microbiología , Proteínas de Pez Cebra/inmunología , Proteínas de Pez Cebra/metabolismo
20.
PLoS Biol ; 22(8): e3002779, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39159283

RESUMEN

Neutrophils are the first immune cells to reach inflamed sites and contribute to the pathogenesis of chronic inflammatory skin diseases. Yet, little is known about the pattern of neutrophil infiltration in inflamed skin in vivo and the mechanisms mediating their recruitment. Here, we provide insight into the dynamics of neutrophil infiltration in skin in response to acute or repeated inflammatory stress, highlighting a novel keratinocyte- and keratin 17 (K17)-dependent mechanism that regulates neutrophil recruitment to inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12 h and resolves within 24 h. A subsequent TPA treatment or a UVB challenge, when applied 24 h but not 48 h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of protein kinase Cα (PKCα) activity and release of chemoattractants by stressed keratinocytes. K17 binds RACK1, a scaffold protein essential for PKCα activity. The N-terminal head domain of K17 is crucial for its association with RACK1 and regulation of PKCα activity. Analysis of RNAseq data reveals a signature consistent with TAR and PKCα activation in inflammatory skin diseases. These findings uncover a novel, keratin-dependent mechanism that amplifies neutrophil recruitment in skin under stress, with direct implications for inflammatory skin disorders.


Asunto(s)
Queratina-17 , Queratinocitos , Infiltración Neutrófila , Neutrófilos , Proteína Quinasa C-alfa , Piel , Animales , Humanos , Masculino , Ratones , Inflamación/metabolismo , Inflamación/patología , Queratina-17/metabolismo , Queratina-17/genética , Queratinocitos/metabolismo , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Proteína Quinasa C-alfa/metabolismo , Receptores de Cinasa C Activada/metabolismo , Receptores de Cinasa C Activada/genética , Piel/metabolismo , Piel/patología , Estrés Fisiológico , Acetato de Tetradecanoilforbol/farmacología , Rayos Ultravioleta/efectos adversos
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