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1.
Annu Rev Immunol ; 41: 301-316, 2023 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-36750315

RESUMEN

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1ß and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, the active NLRP3-NEK7 (NIMA-related kinase 7)-ASC inflammasome disk, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome.


Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Animales , Inflamasomas/química , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Apoptosis , Citocinas/metabolismo , Caspasa 1/metabolismo , Interleucina-1beta/metabolismo
2.
Cell ; 187(17): 4637-4655.e26, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39043180

RESUMEN

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


Asunto(s)
Lesiones Encefálicas , Inmunidad Innata , Memoria Inmunológica , Inflamación , Interleucina-1beta , Ratones Endogámicos C57BL , Monocitos , Animales , Ratones , Interleucina-1beta/metabolismo , Lesiones Encefálicas/inmunología , Humanos , Masculino , Monocitos/metabolismo , Monocitos/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/inmunología , Cardiopatías/inmunología , Femenino , Receptores CCR2/metabolismo , Fibrosis , Epigénesis Genética , Inmunidad Entrenada
3.
Annu Rev Immunol ; 33: 79-106, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25493335

RESUMEN

Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity, or immunodeficiency. Programmed necrosis or necroptosis is a form of nonapoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate, mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF, or DAI to signal for necroptosis in response to death receptor or Toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membranes. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury.


Asunto(s)
Inflamación/metabolismo , Inflamación/patología , Necrosis/metabolismo , Transducción de Señal , Animales , Infecciones Bacterianas/genética , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/patología , Evolución Biológica , Muerte Celular , Humanos , Inflamasomas/metabolismo , Inflamación/genética , Interleucina-1beta/metabolismo , FN-kappa B/metabolismo , Enfermedades Parasitarias/genética , Enfermedades Parasitarias/metabolismo , Enfermedades Parasitarias/patología , Fosforilación , Unión Proteica , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Ubiquitinación , Virosis/genética , Virosis/metabolismo , Virosis/patología
4.
Nat Immunol ; 25(5): 820-833, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38600356

RESUMEN

Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.


Asunto(s)
Factor Activador de Células B , Interleucina-1beta , Mieloma Múltiple , Neutrófilos , Células del Estroma , Microambiente Tumoral , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Humanos , Microambiente Tumoral/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Células del Estroma/metabolismo , Células del Estroma/inmunología , Factor Activador de Células B/metabolismo , Interleucina-1beta/metabolismo , Activación Neutrófila , Factor de Transcripción STAT3/metabolismo , Médula Ósea/inmunología , Médula Ósea/patología
5.
Nat Immunol ; 25(7): 1158-1171, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38902519

RESUMEN

Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1ß and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1ß during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1ß as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.


Asunto(s)
COVID-19 , Hipocampo , Interleucina-1beta , Trastornos de la Memoria , Ratones Endogámicos C57BL , Neurogénesis , SARS-CoV-2 , Animales , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Ratones , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Hipocampo/inmunología , Hipocampo/metabolismo , Trastornos de la Memoria/inmunología , Neurogénesis/inmunología , Vacunación , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas contra la COVID-19/inmunología , Masculino , Humanos , Microglía/inmunología , Microglía/metabolismo , Modelos Animales de Enfermedad , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/genética , Monocitos/inmunología , Monocitos/metabolismo , Femenino
6.
Nat Immunol ; 25(9): 1704-1717, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39143398

RESUMEN

The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling that are commonly mutated in several cancers, including germinal center (GC)-derived B cell lymphomas. However, the specific roles of different BAF complexes in GC B cell biology are not well understood. Here we show that the AT-rich interaction domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and high-affinity antibody responses. While Arid1a-deficient B cells undergo initial activation, they fail to sustain the GC program. Arid1a establishes permissive chromatin landscapes for B cell activation and is concomitantly required to suppress inflammatory gene programs. The inflammatory signatures instigated by Arid1a deficiency promoted the recruitment of neutrophils and inflammatory monocytes. Dampening of inflammatory cues through interleukin-1ß blockade or glucocorticoid receptor agonist partially rescued Arid1a-deficient GCs, highlighting a critical role for inflammation in impeding GCs. Our work reveals essential functions of Arid1a-dependent cBAF in promoting efficient GC responses.


Asunto(s)
Linfocitos B , Proteínas de Unión al ADN , Centro Germinal , Inflamación , Ratones Noqueados , Factores de Transcripción , Animales , Centro Germinal/inmunología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Ratones Endogámicos C57BL , Activación de Linfocitos/inmunología , Interleucina-1beta/metabolismo , Cromatina/metabolismo
7.
Nat Immunol ; 24(2): 295-308, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36604548

RESUMEN

It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity.


Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Células Th17 , Humanos , Caspasa 1/metabolismo , Gasderminas , Inmunidad Innata , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis
8.
Nat Immunol ; 24(4): 585-594, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36941399

RESUMEN

Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1ß and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.


Asunto(s)
Proteínas Reguladoras de la Apoptosis , Inflamasomas , Ratones , Humanos , Animales , Inflamasomas/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Apoptosis , Caspasa 1/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-1beta/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo
9.
Nat Immunol ; 24(4): 595-603, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36941400

RESUMEN

Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adapter ASC and caspase-1, inducing gasdermin D (GSDMD)-dependent cell death and maturation and release of IL-1ß and IL-18. The triggers and activation mechanisms of several inflammasome-forming sensors are not well understood. Here we show that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. While the AIM2 inflammasome can also sense mitochondrial demise by detecting mitochondrial DNA (mtDNA) in the cytosol, NLRP10 monitors mitochondrial integrity in an mtDNA-independent manner, suggesting the recognition of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, in which it can also assemble an inflammasome. Our study shows that this inflammasome surveils mitochondrial integrity. These findings might also lead to a better understanding of mitochondria-linked inflammatory diseases.


Asunto(s)
Citocinas , Inflamasomas , Humanos , Inflamasomas/metabolismo , Caspasa 1/metabolismo , Citocinas/metabolismo , Muerte Celular , ADN Mitocondrial/genética , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo
10.
Cell ; 182(2): 447-462.e14, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32758418

RESUMEN

The precise mechanism by which oral infection contributes to the pathogenesis of extra-oral diseases remains unclear. Here, we report that periodontal inflammation exacerbates gut inflammation in vivo. Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation. In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut. When in the gut, Th17 cells of oral origin can be activated by translocated oral pathobionts and cause development of colitis, but they are not activated by gut-resident microbes. Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells.


Asunto(s)
Colitis/patología , Enterobacter/fisiología , Microbioma Gastrointestinal , Klebsiella/fisiología , Boca/microbiología , Animales , Colitis/microbiología , Colon/microbiología , Colon/patología , Modelos Animales de Enfermedad , Enterobacter/aislamiento & purificación , Femenino , Inflamasomas/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-1beta/metabolismo , Klebsiella/aislamiento & purificación , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodontitis/microbiología , Periodontitis/patología , Células Th17/citología , Células Th17/inmunología , Células Th17/metabolismo
11.
Nat Immunol ; 23(5): 705-717, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35487985

RESUMEN

Caspase-11 detection of intracellular lipopolysaccharide (LPS) from invasive Gram-negative bacteria mediates noncanonical activation of the NLRP3 inflammasome. While avirulent bacteria do not invade the cytosol, their presence in tissues necessitates clearance and immune system mobilization. Despite sharing LPS, only live avirulent Gram-negative bacteria activate the NLRP3 inflammasome. Here, we found that bacterial mRNA, which signals bacterial viability, was required alongside LPS for noncanonical activation of the NLRP3 inflammasome in macrophages. Concurrent detection of bacterial RNA by NLRP3 and binding of LPS by pro-caspase-11 mediated a pro-caspase-11-NLRP3 interaction before caspase-11 activation and inflammasome assembly. LPS binding to pro-caspase-11 augmented bacterial mRNA-dependent assembly of the NLRP3 inflammasome, while bacterial viability and an assembled NLRP3 inflammasome were necessary for activation of LPS-bound pro-caspase-11. Thus, the pro-caspase-11-NLRP3 interaction nucleated a scaffold for their interdependent activation explaining their functional reciprocal exclusivity. Our findings inform new vaccine adjuvant combinations and sepsis therapy.


Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Caspasa 1/metabolismo , Caspasas , Bacterias Gramnegativas , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , ARN Mensajero
12.
Nat Immunol ; 23(6): 892-903, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35624206

RESUMEN

Intracellular sensing of stress and danger signals initiates inflammatory innate immune responses by triggering inflammasome assembly, caspase-1 activation and pyroptotic cell death as well as the release of interleukin 1ß (IL-1ß), IL-18 and danger signals. NLRP3 broadly senses infectious patterns and sterile danger signals, resulting in the tightly coordinated and regulated assembly of the NLRP3 inflammasome, but the precise mechanisms are incompletely understood. Here, we identified NLRP11 as an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacted with NLRP3 and ASC, and deletion of NLRP11 specifically prevented NLRP3 inflammasome activation by preventing inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis and cytokine release but did not affect other inflammasomes. Restored expression of NLRP11, but not NLRP11 lacking the PYRIN domain (PYD), restored inflammasome activation. NLRP11 was also necessary for inflammasome responses driven by NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS). Because NLRP11 is not expressed in mice, our observations emphasize the specific complexity of inflammasome regulation in humans.


Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Caspasa 1/genética , Caspasas/metabolismo , Humanos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Concesión de Licencias , Macrófagos , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo
13.
Nat Immunol ; 23(7): 1021-1030, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35794369

RESUMEN

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.


Asunto(s)
Alérgenos , Interleucina-33 , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Animales , Caspasa 1/metabolismo , Inflamación , Interleucina-1beta/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Péptido Hidrolasas/metabolismo , Gránulos de Estrés
14.
Cell ; 179(1): 74-89.e10, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31495570

RESUMEN

During neural tube closure and spinal cord development, many cells die in both the central and peripheral nervous systems (CNS and PNS, respectively). However, myeloid-derived professional phagocytes have not yet colonized the trunk region during early neurogenesis. How apoptotic cells are removed from this region during these stages remains largely unknown. Using live imaging in zebrafish, we demonstrate that neural crest cells (NCCs) respond rapidly to dying cells and phagocytose cellular debris around the neural tube. Additionally, NCCs have the ability to enter the CNS through motor exit point transition zones and clear debris in the spinal cord. Surprisingly, NCCs phagocytosis mechanistically resembles macrophage phagocytosis and their recruitment toward cellular debris is mediated by interleukin-1ß. Taken together, our results reveal a role for NCCs in phagocytosis of debris in the developing nervous system before the presence of professional phagocytes.


Asunto(s)
Movimiento Celular/fisiología , Cresta Neural/fisiología , Neurogénesis/fisiología , Sistema Nervioso Periférico/crecimiento & desarrollo , Fagocitosis/fisiología , Médula Espinal/crecimiento & desarrollo , Animales , Animales Modificados Genéticamente , Apoptosis/fisiología , Diferenciación Celular/fisiología , Interleucina-1beta/metabolismo , Fagocitos/fisiología , Fagosomas/fisiología , Pez Cebra/embriología
15.
Cell ; 176(5): 998-1013.e16, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30712876

RESUMEN

Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1ß and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention.


Asunto(s)
Interacciones Microbiota-Huesped/inmunología , Linfocitos Intraepiteliales/inmunología , Neoplasias Pulmonares/inmunología , Animales , Proliferación Celular , Femenino , Interleucina-17/inmunología , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/fisiología , Pulmón/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta , Simbiosis/inmunología , Linfocitos T/inmunología
16.
Nat Immunol ; 22(3): 322-335, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33531712

RESUMEN

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Asunto(s)
COVID-19/inmunología , Interferón-alfa/inmunología , Interleucina-18/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Lavado Broncoalveolar , Estudios de Casos y Controles , Chlorocebus aethiops , Estudios de Cohortes , Femenino , Francia , Humanos , Inmunofenotipificación , Interleucina-10/inmunología , Interleucina-15/inmunología , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , RNA-Seq , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Análisis de la Célula Individual , Células Vero , Adulto Joven
17.
Immunity ; 57(9): 2095-2107.e8, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39153479

RESUMEN

Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1ß secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.


Asunto(s)
Vacuna BCG , Epigénesis Genética , Inmunidad Innata , Vacunación , Humanos , Vacuna BCG/inmunología , Epigénesis Genética/inmunología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Interleucina-1beta/metabolismo , Médula Ósea/inmunología , Tuberculosis/inmunología , Tuberculosis/prevención & control , Adulto , Leucocitos Mononucleares/inmunología , Cromatina/metabolismo , Femenino , Masculino , Diferenciación Celular/inmunología , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/inmunología
18.
Cell ; 175(6): 1651-1664.e14, 2018 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-30392956

RESUMEN

The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and caspase-1 via the adaptor ASC. NLRP6 activation by LTA induced processing of caspase-11, which promoted caspase-1 activation and interleukin-1ß (IL-1ß)/IL-18 maturation in macrophages. Nlrp6-/- and Casp11-/- mice were less susceptible to L. monocytogenes infection, which was associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to Nlrp6-/- or Casp11-/- mice restored the susceptibility of mutant mice to L. monocytogenes infection. These results reveal a previously unrecognized innate immunity pathway triggered by cytosolic LTA that is sensed by NLRP6 and exacerbates systemic Gram-positive pathogen infection via the production of IL-18.


Asunto(s)
Inmunidad Innata , Inflamasomas/inmunología , Lipopolisacáridos/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Receptores de Superficie Celular/inmunología , Ácidos Teicoicos/inmunología , Animales , Caspasa 1/genética , Caspasa 1/inmunología , Caspasas/genética , Caspasas/inmunología , Caspasas Iniciadoras , Inflamasomas/genética , Interleucina-18/genética , Interleucina-18/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Listeriosis/genética , Listeriosis/patología , Ratones , Ratones Noqueados , Receptores de Superficie Celular/genética
19.
Cell ; 172(1-2): 147-161.e12, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29328910

RESUMEN

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of ß-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1ß and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.


Asunto(s)
Inmunidad Innata , Memoria Inmunológica , Células Progenitoras Mieloides/inmunología , Animales , Células Cultivadas , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Progenitoras Mieloides/efectos de los fármacos , Mielopoyesis/inmunología , beta-Glucanos/farmacología
20.
Nat Immunol ; 21(7): 736-745, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32367036

RESUMEN

Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1ß) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1ß and GSDMD processing, but abrogates pore formation, thereby preventing IL-1ß release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.


Asunto(s)
Disulfiram/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas de Unión a Fosfato/antagonistas & inhibidores , Piroptosis/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Caspasa 1/genética , Caspasa 1/metabolismo , Inhibidores de Caspasas/farmacología , Caspasas/metabolismo , Caspasas Iniciadoras/genética , Caspasas Iniciadoras/metabolismo , Línea Celular Tumoral , Disulfiram/uso terapéutico , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Femenino , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Liposomas , Ratones , Mutagénesis Sitio-Dirigida , Proteínas de Unión a Fosfato/genética , Proteínas de Unión a Fosfato/metabolismo , Piroptosis/inmunología , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sepsis/inmunología , Células Sf9 , Spodoptera
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