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/metabolismoRESUMEN
Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.
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Células Endoteliales , Hígado , Animales , Humanos , Ratones , Células Endoteliales/metabolismo , Hepatocitos/metabolismo , Macrófagos del Hígado/metabolismo , Hígado/citología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fibrosis/metabolismoRESUMEN
Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.
Asunto(s)
Ceramidas , Proteínas de Unión al GTP , Animales , Humanos , Longevidad/genética , Células Endoteliales/metabolismo , Mamíferos/metabolismoRESUMEN
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Proteínas Morfogenéticas Óseas/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Compartimento Celular , Línea Celular Tumoral , Quimiocinas/metabolismo , Estudios de Cohortes , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN/genética , Células Endoteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunidad , Inflamación/patología , Monocitos/patología , Células Mieloides/patología , Neutrófilos/patología , Células del Estroma/metabolismo , Linfocitos T/metabolismo , Transcripción GenéticaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.
Asunto(s)
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteogenómica , Adenocarcinoma/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Carcinoma Ductal Pancreático/diagnóstico , Estudios de Cohortes , Células Endoteliales/metabolismo , Epigénesis Genética , Femenino , Dosificación de Gen , Genoma Humano , Glucólisis , Glicoproteínas/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Pancreáticas/diagnóstico , Fenotipo , Fosfoproteínas/metabolismo , Fosforilación , Pronóstico , Proteínas Quinasas/metabolismo , Proteoma/metabolismo , Especificidad por Sustrato , Transcriptoma/genéticaRESUMEN
The heterogeneity of endothelial cells (ECs) across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomes from 11 mouse tissues and identified 78 EC subclusters, including Aqp7+ intestinal capillaries and angiogenic ECs in healthy tissues. ECs from brain/testis, liver/spleen, small intestine/colon, and skeletal muscle/heart pairwise expressed partially overlapping marker genes. Arterial, venous, and lymphatic ECs shared more markers in more tissues than did heterogeneous capillary ECs. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) exhibited transcriptome similarity across tissues, but the tissue (rather than the vessel) type contributed to the EC heterogeneity. Metabolic transcriptome analysis revealed a similar tissue-grouping phenomenon of ECs and heterogeneous metabolic gene signatures in ECs between tissues and between vascular beds within a single tissue in a tissue-type-dependent pattern. The EC atlas taxonomy enabled identification of EC subclusters in public scRNA-seq datasets and provides a powerful discovery tool and resource value.
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Células Endoteliales/metabolismo , Análisis de la Célula Individual , Transcriptoma , Animales , Encéfalo/citología , Sistema Cardiovascular/citología , Células Endoteliales/clasificación , Células Endoteliales/citología , Tracto Gastrointestinal/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Músculos/citología , Especificidad de Órganos , RNA-Seq , Testículo/citologíaRESUMEN
We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of â¼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.
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Carcinoma Hepatocelular/patología , Células Endoteliales/metabolismo , Microambiente Tumoral/genética , Adulto , Animales , Carcinoma Hepatocelular/genética , Línea Celular , Modelos Animales de Enfermedad , Células Endoteliales/patología , Femenino , Receptor 2 de Folato/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Hígado/patología , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Transcriptoma/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.
Asunto(s)
Circulación Colateral/fisiología , Corazón/crecimiento & desarrollo , Regeneración/fisiología , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Quimiocina CXCL12/metabolismo , Vasos Coronarios/crecimiento & desarrollo , Células Endoteliales/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Receptores CXCR4/metabolismo , Transducción de SeñalRESUMEN
Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.
Asunto(s)
Células Endoteliales/metabolismo , Hepatocitos/metabolismo , Péptidos y Proteínas de Señalización Intercelular/fisiología , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Receptores TIE/metabolismo , Animales , Biomarcadores/metabolismo , Capilares/metabolismo , Células Endoteliales/citología , Células Endoteliales/patología , Células HEK293 , Hepatocitos/citología , Hepatocitos/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Hígado/irrigación sanguínea , Hígado/patología , Cirrosis Hepática/diagnóstico , Ratones Endogámicos C57BLRESUMEN
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/terapia , Mucosa Intestinal/patología , Antígenos CD/metabolismo , Apirasa/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Muerte Celular/efectos de los fármacos , Microambiente Celular/efectos de los fármacos , Niño , Estudios de Cohortes , Colon/patología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Dipiridamol/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Homeostasis/efectos de los fármacos , Humanos , Inmunoglobulina G/sangre , Memoria Inmunológica , Inflamación/patología , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/genética , Interferón Tipo I/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metilprednisolona/farmacología , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismoRESUMEN
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
Asunto(s)
Proteína C-Reactiva/genética , COVID-19/genética , Perfilación de la Expresión Génica/métodos , Macrófagos/metabolismo , SARS-CoV-2/aislamiento & purificación , Componente Amiloide P Sérico/genética , Células A549 , Adulto , Proteína C-Reactiva/metabolismo , COVID-19/epidemiología , COVID-19/virología , Línea Celular Tumoral , Células Cultivadas , Estudios de Cohortes , Células Endoteliales/metabolismo , Epidemias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Neutrófilos/metabolismo , Pronóstico , SARS-CoV-2/fisiología , Componente Amiloide P Sérico/metabolismoRESUMEN
Bacterial lipopolysaccharide (LPS) is implicated in disrupting the blood-brain barrier (BBB). In a recent issue of Nature, Wei et al. now show that LPS activates the inflammatory caspases (4, 5, and 11) and gasdermin D (GSDMD) in brain endothelial cells, which triggers their pyroptotic cell death and disrupts the BBB.
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Barrera Hematoencefálica , Células Endoteliales , Lipopolisacáridos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/inmunología , Animales , Humanos , Células Endoteliales/metabolismo , Células Endoteliales/inmunología , Lipopolisacáridos/inmunología , Caspasas/metabolismo , Piroptosis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Unión a Fosfato/metabolismo , RatonesRESUMEN
Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.
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Encéfalo , Interferón-alfa , Microvasos , Malformaciones del Sistema Nervioso , Receptor de Interferón alfa y beta , Animales , Humanos , Ratones , Interferón-alfa/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Receptor de Interferón alfa y beta/metabolismo , Receptor de Interferón alfa y beta/genética , Microvasos/patología , Malformaciones del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Células Endoteliales/metabolismo , Ratones Noqueados , Masculino , Femenino , Transducción de Señal , Ratones Endogámicos C57BL , Astrocitos/metabolismo , Modelos Animales de EnfermedadRESUMEN
We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knockout of caveolin 1 (cav1) protein. Although we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist among adipocytes, stromal vascular cells, and, potentially, distal organs.
Asunto(s)
Adipocitos/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Ayuno/metabolismo , Transducción de Señal , Animales , Caveolina 1/genética , Caveolina 1/metabolismo , Línea Celular , Células Cultivadas , Endotelio Vascular/citología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Characterizing cell surface receptors mediating viral infection is critical for understanding viral tropism and developing antiviral therapies. Nevertheless, due to challenges associated with detecting protein interactions on the cell surface, the host receptors of many human pathogens remain unknown. Here, we build a library consisting of most single transmembrane human receptors and implement a workflow for unbiased and high-sensitivity detection of receptor-ligand interactions. We apply this technology to elucidate the long-sought receptor of human cytomegalovirus (HCMV), the leading viral cause of congenital birth defects. We identify neuropilin-2 (Nrp2) as the receptor for HCMV-pentamer infection in epithelial/endothelial cells and uncover additional HCMV interactors. Using a combination of biochemistry, cell-based assays, and electron microscopy, we characterize the pentamer-Nrp2 interaction and determine the architecture of the pentamer-Nrp2 complex. This work represents an important approach to the study of host-pathogen interactions and provides a framework for understanding HCMV infection, neutralization, and the development of novel anti-HCMV therapies.
Asunto(s)
Infecciones por Citomegalovirus/metabolismo , Citomegalovirus/fisiología , Neuropilina-2/metabolismo , Receptores Virales/metabolismo , Anticuerpos Neutralizantes/química , Membrana Celular/metabolismo , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Mapeo Epitopo , Femenino , Células HEK293 , Humanos , Conformación Proteica , Proteínas del Envoltorio Viral/metabolismo , Internalización del VirusRESUMEN
A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.
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Envejecimiento , Sulfuro de Hidrógeno/metabolismo , NAD/metabolismo , Animales , Células Endoteliales/citología , Células Endoteliales/metabolismo , Humanos , Ratones , Ratones Noqueados , Microvasos/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Sirtuina 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A unique feature of the central nervous system (CNS) vasculature is the blood-brain barrier (BBB). The BBB regulates substance influx and efflux to maintain a homeostatic environment for proper brain function. Here, we review the development and cell biology of the BBB, focusing on the cellular and molecular regulation of barrier formation and the maintenance of the BBB through adulthood. We summarize unique features of CNS endothelial cells and highlight recent progress in and general principles of barrier regulation. Finally, we illustrate why a mechanistic understanding of the development and maintenance of the BBB could provide novel therapeutic opportunities for CNS drug delivery.
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Transporte Biológico/fisiología , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/crecimiento & desarrollo , Sistema Nervioso Central/citología , Células Endoteliales/citología , Animales , Astrocitos/citología , Membrana Basal/citología , Membrana Basal/metabolismo , Transporte Biológico/genética , Barrera Hematoencefálica/metabolismo , Encéfalo/citología , Encéfalo/fisiología , Sistema Nervioso Central/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/fisiología , Homeostasis , Humanos , Leucocitos , Acoplamiento Neurovascular/fisiología , Pericitos/citología , Uniones Estrechas , Transcitosis/fisiología , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/fisiologíaRESUMEN
Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.
Asunto(s)
Interleucina-6 , ARN , Células Endoteliales/metabolismo , Receptor gp130 de Citocinas , Endotelio/metabolismo , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismoRESUMEN
During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.
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Interleucinas , Neoplasias Hepáticas , Células T Asesinas Naturales , Animales , Ratones , Células Endoteliales/metabolismo , Interleucinas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Ratones Endogámicos C57BL , Células T Asesinas Naturales/metabolismo , Neoplasias Colorrectales/metabolismo , Interleucina-22RESUMEN
Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot illustrates key elements of angiopoietin signaling in normal and disease contexts.