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1.
Cell ; 183(5): 1282-1297.e18, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33098771

RESUMEN

Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.


Asunto(s)
Linaje de la Célula , Neutrófilos/metabolismo , Especificidad de Órganos , Animales , Cromatina/metabolismo , Femenino , Hematopoyesis , Intestinos/irrigación sanguínea , Pulmón/irrigación sanguínea , Masculino , Ratones Endogámicos C57BL , Neovascularización Fisiológica , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Receptores CXCR4/metabolismo , Análisis de la Célula Individual , Transcripción Genética , Transcriptoma/genética
2.
Immunity ; 56(5): 979-997.e11, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37100060

RESUMEN

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/metabolismo
3.
Nat Immunol ; 22(9): 1072-1074, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34326535

Asunto(s)
Neutrófilos
4.
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
5.
Nature ; 601(7893): 415-421, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34987220

RESUMEN

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


Asunto(s)
Inflamación , Leucocitos , Proteómica , Animales , Forma de la Célula , Endotelio/inmunología , Inflamación/inmunología , Leucocitos/inmunología , Ratones , Neutrófilos/inmunología , Proteínas Proto-Oncogénicas/inmunología , Familia-src Quinasas/inmunología
6.
Trends Immunol ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39030115

RESUMEN

Innate immune cells are primary effectors during host defense and in sterile inflammation. Their production in the bone marrow is tightly regulated by growth and niche factors, and their activity at sites of inflammation is orchestrated by a network of alarmins and cytokines. Yet, recent work highlights a significant role of the peripheral nervous system in these processes. Sympathetic neural pathways play a key role in regulating blood cell homeostasis, and sensory neural pathways mediate pro- or anti-inflammatory signaling in a tissue-specific manner. Here, we review emerging evidence of the fine titration of hematopoiesis, leukocyte trafficking, and tissue repair via neuro-immune crosstalk, and how its derailment can accelerate chronic inflammation, as in atherosclerosis.

7.
Nature ; 592(7853): 296-301, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33731931

RESUMEN

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1ß reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1ß or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.


Asunto(s)
Aterosclerosis/patología , Hematopoyesis Clonal , Proteínas de Unión al ADN/metabolismo , Inflamasomas/metabolismo , Animales , Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Médula Ósea/metabolismo , Caspasa 1/metabolismo , Caspasas Iniciadoras/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-1beta/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Proteínas de Unión a Fosfato/metabolismo , Piroptosis , RNA-Seq , Análisis de la Célula Individual
8.
Immunol Rev ; 314(1): 357-375, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36315403

RESUMEN

Over the past millennia, life expectancy has drastically increased. While a mere 25 years during Bronze and Iron ages, life expectancy in many European countries and in Japan is currently above 80 years. Such an increase in life expectancy is a result of improved diet, life style, and medical care. Yet, increased life span and aging also represent the most important non-modifiable risk factors for several pathologies including cardiovascular disease, neurodegenerative diseases, and cancer. In recent years, neutrophils have been implicated in all of these pathologies. Hence, this review provides an overview of how aging impacts neutrophil production and function and conversely how neutrophils drive aging-associated pathologies. Finally, we provide a perspective on how processes of neutrophil-driven pathologies in the context of aging can be targeted therapeutically.


Asunto(s)
Envejecimiento , Neutrófilos , Humanos , Longevidad , Esperanza de Vida , Factores de Riesgo
9.
Blood ; 144(3): 308-322, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-38657197

RESUMEN

ABSTRACT: Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein that serves as the final downstream effector of the pyroptosis/interleukin-1ß (IL-1ß) pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd deficiency ameliorated immunothrombosis, acute tissue injury, and failure. Gsdmd-/- mice exhibited a decrease in mature IL-1ß, as well as in neutrophil maturation, ß2-integrin activation, and recruitment to TMA lesions, in which they formed reduced neutrophil extracellular traps in both arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD-deficient, human-induced, pluripotent stem cell-derived neutrophils confirmed the involvement of GSDMD in neutrophil ß2-integrin activation, maturation, and pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected the mice from focal TMA, acute tissue injury, and failure. Our data identified GSDMD as a key mediator of focal crystalline TMA and its consequences, including ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for the systemic forms of TMA.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular , Ratones Noqueados , Neutrófilos , Proteínas de Unión a Fosfato , Microangiopatías Trombóticas , Animales , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Ratones , Microangiopatías Trombóticas/patología , Microangiopatías Trombóticas/metabolismo , Microangiopatías Trombóticas/inmunología , Microangiopatías Trombóticas/etiología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Humanos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Piroptosis , Interleucina-1beta/metabolismo , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Inflamación/patología , Inflamación/metabolismo , Ratones Endogámicos C57BL , Antígenos CD18/metabolismo , Antígenos CD18/genética , Modelos Animales de Enfermedad , Gasderminas
10.
Nature ; 569(7755): 236-240, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31043745

RESUMEN

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis-a major underlying cause of mortality worldwide-to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.


Asunto(s)
Aterosclerosis/patología , Muerte Celular , Membrana Celular/metabolismo , Histonas/metabolismo , Inflamación/metabolismo , Inflamación/patología , Porosidad , Animales , Arterias/patología , Membrana Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Histonas/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/patología , Neutrófilos/citología , Unión Proteica/efectos de los fármacos
11.
Arterioscler Thromb Vasc Biol ; 43(9): 1700-1712, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37409530

RESUMEN

BACKGROUND: Platelets and neutrophils are the first blood cells accumulating at sites of arterial thrombus formation, and both cell types contribute to the pathology of thrombotic events. We aimed to identify key interaction mechanisms between these cells using microfluidic approaches. METHODS: Whole-blood perfusion was performed over a collagen surface at arterial shear rate. Platelet and leukocyte (in majority neutrophil) activation were microscopically visualized using fluorescent markers. The contributions of platelet-adhesive receptors (integrin, P-selectin, CD40L) and chemokines were studied by using inhibitors or antibodies and using blood from patients with GT (Glanzmann thrombasthenia) lacking platelet-expressed αIIbß3. RESULTS: We observed (1) an unknown role of activated platelet integrin αIIbß3 preventing leukocyte adhesion, which was overcome by short-term flow disturbance provoking massive adhesion; (2) that platelet-expressed CD40L controls the crawling pattern and thrombus fidelity of the cells on a thrombus; (3) that continued secretion of platelet substances promotes activation of identified neutrophils, as assessed by (fMLP [N-formylmethionyl-leucyl-phenylalanine, a potent chemotactic agent and leukocyte activator] induced) [Ca2+]i rises and antigen expression; (4) and that platelet-released chemokines activate the adhered cells in the order of CXCL7>CCL5>CXCL4. Furthermore, postsilencing of the platelets in a thrombus suppressed the leukocyte activation. However, the leukocytes on thrombi did no more than limitedly form neutrophil extracellular traps, unless stimulated with phorbol ester or lipopolysaccharide. CONCLUSIONS: Together, these findings reveal a multifaceted regulation of adhesion and activation of neutrophils by platelets in a thrombus, with a balanced role of several platelet-adhesive receptors and a promoting role of platelet-released substances. This multivalent nature of neutrophil-thrombus interactions offers novel prospects for pharmacological intervention.


Asunto(s)
Arterias , Plaquetas , Quimiocinas , Activación Neutrófila , Neutrófilos , Trombosis , Plaquetas/inmunología , Plaquetas/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Quimiocinas/metabolismo , Trombosis/inmunología , Ligando de CD40 , Neutrófilos/inmunología , Neutrófilos/metabolismo , Adhesión Celular , Humanos
13.
Artículo en Inglés | MEDLINE | ID: mdl-38115607

RESUMEN

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes.

14.
Eur Heart J ; 43(6): 518-533, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-34597388

RESUMEN

AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.


Asunto(s)
Aterosclerosis , Propionatos , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/etiología , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Humanos , Absorción Intestinal , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Propionatos/farmacología , Propionatos/uso terapéutico
15.
Circulation ; 144(19): 1567-1583, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-34647815

RESUMEN

BACKGROUND: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The present study assessed the functional contribution of the lncRNA myocardial infarction-associated transcript (MIAT) to atherosclerosis and carotid artery disease. METHODS: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies. The lncRNA MIAT was identified as the most upregulated noncoding RNA transcript in carotid plaques compared with nonatherosclerotic control arteries, which was confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. RESULTS: Experimental knockdown of MIAT, using site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs) but also increased their apoptosis. MIAT mechanistically regulated SMC proliferation through the EGR1 (Early Growth Response 1)-ELK1 (ETS Transcription Factor ELK1)-ERK (Extracellular Signal-Regulated Kinase) pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat-/- and Miat-/-ApoE-/- mice, and Yucatan LDLR-/- mini-pigs, as well, confirmed the regulatory role of this lncRNA in SMC de- and transdifferentiation and advanced atherosclerotic lesion formation. CONCLUSIONS: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs, and the proinflammatory properties of macrophages, as well.


Asunto(s)
Aterosclerosis/genética , Placa Aterosclerótica/genética , ARN Largo no Codificante/metabolismo , Animales , Humanos , Ratones
16.
Circulation ; 143(3): 254-266, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33167684

RESUMEN

BACKGROUND: Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here, we use a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation Methods: Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy. RESULTS: Lipopolysaccharide treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. Lipopolysaccharide treatment led to the deposition of NETs along the arterial lumen, and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we used in vitro adhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge-dependent fashion. Therapeutic neutralization of histone H2a by antibodies or by in silico designed cyclic peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia. CONCLUSIONS: Our study shows that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.


Asunto(s)
Aterosclerosis/metabolismo , Adhesión Celular/fisiología , Endotoxemia/metabolismo , Monocitos/metabolismo , Electricidad Estática , Animales , Aterosclerosis/inducido químicamente , Aterosclerosis/patología , Adhesión Celular/efectos de los fármacos , Endotoxemia/inducido químicamente , Endotoxemia/patología , Trampas Extracelulares/metabolismo , Humanos , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/efectos de los fármacos , Monocitos/patología
17.
Basic Res Cardiol ; 117(1): 30, 2022 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-35674847

RESUMEN

Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12-CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe-/- mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3's role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Receptores CXCR , Animales , Aterosclerosis/metabolismo , Adhesión Celular , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Inflamación/metabolismo , Ratones , Ratones Noqueados para ApoE , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Receptores CXCR/metabolismo , Factor de Transcripción ReIA/metabolismo
18.
Trends Immunol ; 40(7): 561-564, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31133465

RESUMEN

In recent years, great progress has been made to understand how neutrophils contribute to homeostatic regulation, tumor progression, and chronic inflammation. Here, I highlight a few salient basic questions to be addressed in the field. Ideally, future investigations along these lines can contribute to identifying possible means of therapeutically interfering with neutrophil effector functions to fine-tune innate immunity.


Asunto(s)
Susceptibilidad a Enfermedades , Homeostasis , Neutrófilos/inmunología , Neutrófilos/metabolismo , Animales , Biomarcadores , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Activación Neutrófila , Neutrófilos/patología , Transducción de Señal , Transcripción Genética
19.
Trends Immunol ; 40(7): 648-664, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31155315

RESUMEN

Neutrophils, the most abundant white blood cells in human circulation, entertain intense interactions with other leukocyte subsets, platelets, and stromal cells. Molecularly, such interactions are typically communicated through proteins generated during granulopoiesis, stored in granules, or produced on demand. Here, we provide an overview of the mammalian regulation of granule protein production in the bone marrow and the de novo synthesis of cytokines by neutrophils recruited to tissues. In addition, we discuss some of the known biological roles of these protein messengers, and how neutrophil-borne granule proteins and cytokines can synergize to modulate inflammation and tumor development. Decoding the neutrophil interactome is important for therapeutically neutralizing individual proteins to putatively dampen inflammation, or for delivering modified neutrophil-borne proteins to boost host defense.


Asunto(s)
Citocinas/metabolismo , Gránulos Citoplasmáticos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Proteostasis , Animales , Susceptibilidad a Enfermedades , Hematopoyesis , Humanos , Mielopoyesis , Neutrófilos/patología , Proteoma , Proteómica/métodos
20.
Circ Res ; 126(9): 1228-1241, 2020 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-32324499

RESUMEN

Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries and propagate and amplify the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (eg, MPO [myeloperoxidase] and various proteinases) but can gather other proteins found in blood (eg, tissue factor procoagulant). This review presents current concepts of neutrophil biology, the triggers to and mechanisms of NET formation, and the contribution of NETs to atherosclerosis and to thrombosis. We consider the use of markers of NETs in clinical studies. We aim here to integrate critically the experimental literature with the growing body of clinical information regarding NETs.


Asunto(s)
Arterias/metabolismo , Aterosclerosis/metabolismo , Trampas Extracelulares/metabolismo , Inflamación/metabolismo , Neutrófilos/metabolismo , Trombosis/metabolismo , Animales , Arterias/inmunología , Arterias/patología , Aterosclerosis/inmunología , Aterosclerosis/patología , Biomarcadores/metabolismo , Coagulación Sanguínea , Trampas Extracelulares/inmunología , Humanos , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Neutrófilos/inmunología , Neutrófilos/patología , Placa Aterosclerótica , Especies Reactivas de Oxígeno/metabolismo , Rotura Espontánea , Transducción de Señal , Trombosis/inmunología , Trombosis/patología
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