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1.
Nat Immunol ; 24(8): 1256-1264, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37400674

RESUMEN

Innate lymphoid cells (ILCs) can quickly switch from a quiescent state to an active state and rapidly produce effector molecules that provide critical early immune protection. How the post-transcriptional machinery processes different stimuli and initiates robust gene expression in ILCs is poorly understood. Here, we show that deletion of the N6-methyladenosine (m6A) writer protein METTL3 has little impact on ILC homeostasis or cytokine-induced ILC1 or ILC3 responses but significantly diminishes ILC2 proliferation, migration and effector cytokine production and results in impaired antihelminth immunity. m6A RNA modification supports an increase in cell size and transcriptional activity in activated ILC2s but not in ILC1s or ILC3s. Among other transcripts, the gene encoding the transcription factor GATA3 is highly m6A methylated in ILC2s. Targeted m6A demethylation destabilizes nascent Gata3 mRNA and abolishes the upregulation of GATA3 and ILC2 activation. Our study suggests a lineage-specific requirement of m6A for ILC2 responses.


Asunto(s)
Inmunidad Innata , Linfocitos , Citocinas/metabolismo , Homeostasis , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Linfocitos/inmunología , ARN/metabolismo , Animales , Ratones
2.
Cell ; 170(6): 1096-1108.e13, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28886380

RESUMEN

Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.


Asunto(s)
Inmunoterapia/métodos , Melanoma/inmunología , Melanoma/patología , FN-kappa B/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-rel/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo
3.
Cell ; 151(3): 590-602, 2012 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-23101627

RESUMEN

Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11(-/-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.


Asunto(s)
Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Ratones , Salmonella typhi , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/microbiología , Animales , Flagelina/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de la Especie , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo
4.
Immunity ; 47(3): 450-465.e5, 2017 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-28889947

RESUMEN

Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-κB. In Tconv cells, NF-κB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-κB in Treg function remains unclear. We conditionally deleted canonical NF-κB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles. c-Rel was critical for thymic Treg development while p65 was essential for mature Treg identity and maintenance of immune tolerance. Transcriptome and NF-κB p65 binding analyses demonstrated a lineage specific, NF-κB-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-κB in Tconv and Treg cells highlight the functional plasticity of the NF-κB signaling pathway and underscores the need for more selective strategies to therapeutically target NF-κB.


Asunto(s)
Linaje de la Célula/genética , FN-kappa B/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Transcripción Genética , Animales , Autoinmunidad/genética , Autoinmunidad/inmunología , Sitios de Unión , Biomarcadores , Diferenciación Celular , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Análisis por Conglomerados , Citocinas/metabolismo , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Homeostasis/genética , Homeostasis/inmunología , Tolerancia Inmunológica , Inmunofenotipificación , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos , Ratones , Ratones Transgénicos , FN-kappa B/genética , Motivos de Nucleótidos , Fenotipo , Unión Proteica , Transducción de Señal , Linfocitos T Reguladores/citología , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Transcriptoma
6.
Proc Natl Acad Sci U S A ; 120(46): e2312595120, 2023 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-37931099

RESUMEN

The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins were previously shown to inhibit both NF-κB and Ras activation through independent mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In this study, we have used two mouse models to establish the relevance of the κB-Ras proteins for tumorigenesis. Additionally, we have utilized a pan-cancer bioinformatics analysis to explore the role of the κB-Ras proteins in human cancers. Surprisingly, we find that the genes encoding κB-Ras 1 (NKIRAS1) and κB-Ras 2 (NKIRAS2) are rarely down-regulated in tumor samples with oncogenic Ras mutations. Reduced expression of human NKIRAS1 alone is associated with worse prognosis in at least four cancer types and linked to a network of genes implicated in tumorigenesis. Our findings provide direct evidence that loss of NKIRAS1 in human tumors that do not carry oncogenic RAS mutations is associated with worse clinical outcomes.


Asunto(s)
Carcinogénesis , Proteínas Portadoras , Genes Supresores de Tumor , Animales , Humanos , Ratones , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Genes ras , FN-kappa B/metabolismo , Proteínas ras/metabolismo , Proteínas Portadoras/genética
7.
Nature ; 559(7712): 114-119, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29950719

RESUMEN

Prolonged exposure to microbial products such as lipopolysaccharide can induce a form of innate immune memory that blunts subsequent responses to unrelated pathogens, known as lipopolysaccharide tolerance. Sepsis is a dysregulated systemic immune response to disseminated infection that has a high mortality rate. In some patients, sepsis results in a period of immunosuppression (known as 'immunoparalysis')1 characterized by reduced inflammatory cytokine output2, increased secondary infection3 and an increased risk of organ failure and mortality4. Lipopolysaccharide tolerance recapitulates several key features of sepsis-associated immunosuppression5. Although various epigenetic changes have previously been observed in tolerized macrophages6-8, the molecular basis of tolerance, immunoparalysis and other forms of innate immune memory has remained unclear. Here we perform a screen for tolerance-associated microRNAs and identify miR-221 and miR-222 as regulators of the functional reprogramming of macrophages during lipopolysaccharide tolerization. Prolonged stimulation with lipopolysaccharide in mice leads to increased expression of miR-221 and mir-222, both of which regulate brahma-related gene 1 (Brg1, also known as Smarca4). This increased expression causes the transcriptional silencing of a subset of inflammatory genes that depend on chromatin remodelling mediated by SWI/SNF (switch/sucrose non-fermentable) and STAT (signal transducer and activator of transcription), which in turn promotes tolerance. In patients with sepsis, increased expression of miR-221 and miR-222 correlates with immunoparalysis and increased organ damage. Our results show that specific microRNAs can regulate macrophage tolerization and may serve as biomarkers of immunoparalysis and poor prognosis in patients with sepsis.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Inmunidad Innata/inmunología , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , MicroARNs/genética , Animales , ADN Helicasas/metabolismo , Femenino , Células HEK293 , Humanos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Inmunidad Innata/genética , Inflamación/genética , Inflamación/inmunología , Mediadores de Inflamación/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Masculino , Ratones , Proteínas Nucleares/metabolismo , Células RAW 264.7 , Factores de Transcripción STAT/metabolismo , Sepsis/inmunología , Choque Séptico/inmunología , Factores de Transcripción/metabolismo
8.
Mol Cell ; 61(5): 644-645, 2016 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-26942667

RESUMEN

NLRP3 inflammasome activation is accompanied by induction of mitochondrial damage. In the current issue of Cell, Zhong et al. describe an intracellular mechanism orchestrated by NF-κB to remove inflammasome-activating damaged mitochondria and prevent pathologic inflammation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Choque Térmico/metabolismo , Inflamasomas/metabolismo , Mitocondrias/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Animales
9.
Nat Immunol ; 12(8): 695-708, 2011 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-21772278

RESUMEN

NF-κB transcription factors are critical regulators of immunity, stress responses, apoptosis and differentiation. A variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs. Consequently, NF-κB-dependent transcription is not only tightly controlled by positive and negative regulatory mechanisms but also closely coordinated with other signaling pathways. This intricate crosstalk is crucial to shaping the diverse biological functions of NF-κB into cell type- and context-specific responses.


Asunto(s)
FN-kappa B/fisiología , Animales , Comunicación Celular/fisiología , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal , Activación Transcripcional
10.
J Immunol ; 206(8): 1776-1783, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33789982

RESUMEN

Regulatory T (Treg) cells have an essential role in maintaining immune homeostasis, in part by suppressing effector T cell functions. Phosphoinositide-dependent kinase 1 (PDK1) is a pleiotropic kinase that acts as a key effector downstream of PI3K in many cell types. In T cells, PDK1 has been shown to be critical for activation of NF-κB and AKT signaling upon TCR ligation and is therefore essential for effector T cell activation, proliferation, and cytokine production. Using Treg cell-specific conditional deletion, we now demonstrate that PDK1 is also essential for Treg cell suppressive activity in vivo. Ablation of Pdk1 specifically in Treg cells led to systemic, lethal, scurfy-like inflammation in mice. Genome-wide analysis confirmed that PDK1 is essential for the regulation of key Treg cell signature gene expression and, further, suggested that PDK1 acts primarily to control Treg cell gene expression through regulation of the canonical NF-κB pathway. Consistent with these results, the scurfy-like phenotype of mice lacking PDK1 in Treg cells was rescued by enforced activation of NF-κB downstream of PDK1. Therefore, PDK1-mediated activation of the NF-κB signaling pathway is essential for regulation of Treg cell signature gene expression and suppressor function.


Asunto(s)
Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Trastornos Linfoproliferativos/genética , Linfocitos T Reguladores/inmunología , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Animales , Antígenos CD4/metabolismo , Proliferación Celular , Células Cultivadas , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Terapia de Inmunosupresión , Activación de Linfocitos , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Transducción de Señal , Transcriptoma
11.
Cell ; 132(3): 344-62, 2008 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-18267068

RESUMEN

The transcription factor NF-kappaB has served as a standard for inducible transcription factors for more than 20 years. The numerous stimuli that activate NF-kappaB, and the large number of genes regulated by NF-kappaB, ensure that this transcription factor is still the subject of intense research. Here, we attempt to synthesize some of the basic principles that have emerged from studies of NF-kappaB, and we aim to generate a more unified view of NF-kappaB regulation.


Asunto(s)
FN-kappa B/metabolismo , Transducción de Señal , Animales , Humanos , Quinasa I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , FN-kappa B/genética , Transcripción Genética
12.
Proc Natl Acad Sci U S A ; 117(16): 9022-9031, 2020 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-32284404

RESUMEN

The vast majority of type 1 diabetes (T1D) genetic association signals lie in noncoding regions of the human genome. Many have been predicted to affect the expression and secondary structure of long noncoding RNAs (lncRNAs), but the contribution of these lncRNAs to the pathogenesis of T1D remains to be clarified. Here, we performed a complete functional characterization of a lncRNA that harbors a single nucleotide polymorphism (SNP) associated with T1D, namely, Lnc13 Human pancreatic islets harboring the T1D-associated SNP risk genotype in Lnc13 (rs917997*CC) showed higher STAT1 expression than islets harboring the heterozygous genotype (rs917997*CT). Up-regulation of Lnc13 in pancreatic ß-cells increased activation of the proinflammatory STAT1 pathway, which correlated with increased production of chemokines in an allele-specific manner. In a mirror image, Lnc13 gene disruption in ß-cells partially counteracts polyinosinic-polycytidylic acid (PIC)-induced STAT1 and proinflammatory chemokine expression. Furthermore, we observed that PIC, a viral mimetic, induces Lnc13 translocation from the nucleus to the cytoplasm promoting the interaction of STAT1 mRNA with (poly[rC] binding protein 2) (PCBP2). Interestingly, Lnc13-PCBP2 interaction regulates the stability of the STAT1 mRNA, sustaining inflammation in ß-cells in an allele-specific manner. Our results show that the T1D-associated Lnc13 may contribute to the pathogenesis of T1D by increasing pancreatic ß-cell inflammation. These findings provide information on the molecular mechanisms by which disease-associated SNPs in lncRNAs influence disease pathogenesis and open the door to the development of diagnostic and therapeutic approaches based on lncRNA targeting.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Células Secretoras de Insulina/inmunología , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT1/genética , Regiones no Traducidas 3'/genética , Supervivencia Celular/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/virología , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/virología , Células Jurkat , Poli I-C/inmunología , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , Estabilidad del ARN/genética , ARN Mensajero/metabolismo , ARN Viral/inmunología , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Regulación hacia Arriba/inmunología
13.
Immunity ; 38(1): 119-30, 2013 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-23246311

RESUMEN

Toll-like receptor 11 (TLR11) recognizes T. gondii profilin (TgPRF) and is required for interleukin-12 production and induction of immune responses that limit cyst burden in Toxoplasma gondii-infected mice. However, TLR11 only modestly affects survival of T. gondii-challenged mice. We report that TLR12, a previously uncharacterized TLR, also recognized TgPRF. TLR12 was sufficient for recognition of TgPRF by plasmacytoid dendritic cells (pDCs), whereas TLR11 and TLR12 were both required in macrophages and conventional DCs. In contrast to TLR11, TLR12-deficient mice succumb rapidly to T. gondii infection. TLR12-dependent induction of IL-12 and IFN-α in pDCs led to production of IFN-γ by NK cells. Consistent with this observation, the partial resistance of Tlr11(-/-) mice is lost upon pDC or NK cell depletion. Thus, TLR12 is critical for the innate immune response to T. gondii, and this TLR may promote host resistance by triggering pDC and NK cell function.


Asunto(s)
Interacciones Huésped-Patógeno/inmunología , Profilinas/metabolismo , Receptores Toll-Like/metabolismo , Toxoplasma/inmunología , Toxoplasmosis Animal/inmunología , Toxoplasmosis Animal/metabolismo , Secuencia de Aminoácidos , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Predisposición Genética a la Enfermedad , Inmunidad Innata , Interferón-alfa/biosíntesis , Interferón gamma/biosíntesis , Interleucina-12/biosíntesis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , FN-kappa B/metabolismo , Profilinas/inmunología , Unión Proteica , Multimerización de Proteína , Alineación de Secuencia , Receptores Toll-Like/química , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Toxoplasmosis Animal/genética
14.
Heredity (Edinb) ; 129(6): 346-355, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36319737

RESUMEN

Cat domestication likely initiated as a symbiotic relationship between wildcats (Felis silvestris subspecies) and the peoples of developing agrarian societies in the Fertile Crescent. As humans transitioned from hunter-gatherers to farmers ~12,000 years ago, bold wildcats likely capitalized on increased prey density (i.e., rodents). Humans benefited from the cats' predation on these vermin. To refine the site(s) of cat domestication, over 1000 random-bred cats of primarily Eurasian descent were genotyped for single-nucleotide variants and short tandem repeats. The overall cat population structure suggested a single worldwide population with significant isolation by the distance of peripheral subpopulations. The cat population heterozygosity decreased as genetic distance from the proposed cat progenitor's (F.s. lybica) natural habitat increased. Domestic cat origins are focused in the eastern Mediterranean Basin, spreading to nearby islands, and southernly via the Levantine coast into the Nile Valley. Cat population diversity supports the migration patterns of humans and other symbiotic species.


Asunto(s)
Domesticación , Repeticiones de Microsatélite , Animales , Gatos/genética , Genotipo , Medio Oriente
15.
Adv Exp Med Biol ; 1363: 147-160, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35220569

RESUMEN

Genome wide association studies (GWAS) have identified many loci contributing to genetic variation of complex traits. Immune mediated disorders are complex diseases for which hundreds of risk alleles have been identified by GWAS. However, the intergenic location of most of the signals has make it difficult to decipher their implication in disease pathogenesis. A significant number of immune disease-associated SNPs are located within long noncoding RNAs (lncRNAs). LncRNAs have gained importance due to their involvement in the regulation of a wide range of biological processes, including immune responses. GWAS SNPs located within lncRNAs can affect their regulatory capacity by modifying their secondary structure, altering their expression levels or regulating the transcription of different isoforms. In this review we discuss the functional implications of immune-related lncRNAs harboring disease associated SNPs on various disease conditions.


Asunto(s)
Estudio de Asociación del Genoma Completo , ARN Largo no Codificante , Alelos , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
16.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-36555493

RESUMEN

Long-read sequencing (LRS) has been adopted to meet a wide variety of research needs, ranging from the construction of novel transcriptome annotations to the rapid identification of emerging virus variants. Amongst other advantages, LRS preserves more information about RNA at the transcript level than conventional high-throughput sequencing, including far more accurate and quantitative records of splicing patterns. New studies with LRS datasets are being published at an exponential rate, generating a vast reservoir of information that can be leveraged to address a host of different research questions. However, mining such publicly available data in a tailored fashion is currently not easy, as the available software tools typically require familiarity with the command-line interface, which constitutes a significant obstacle to many researchers. Additionally, different research groups utilize different software packages to perform LRS analysis, which often prevents a direct comparison of published results across different studies. To address these challenges, we have developed the Long-Read Analysis Pipeline for Transcriptomics (L-RAPiT), a user-friendly, free pipeline requiring no dedicated computational resources or bioinformatics expertise. L-RAPiT can be implemented directly through Google Colaboratory, a system based on the open-source Jupyter notebook environment, and allows for the direct analysis of transcriptomic reads from Oxford Nanopore and PacBio LRS machines. This new pipeline enables the rapid, convenient, and standardized analysis of publicly available or newly generated LRS datasets.


Asunto(s)
Nube Computacional , ARN , ARN/genética , Perfilación de la Expresión Génica/métodos , Biología Computacional/métodos , Programas Informáticos , Análisis de Secuencia de ARN , Secuenciación de Nucleótidos de Alto Rendimiento/métodos
17.
Nat Immunol ; 10(2): 158-66, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19122654

RESUMEN

In addition to ligation of the T cell antigen receptor (TCR), activation of the CD28 coreceptor by the costimulatory molecule B7 is required for induction of the transcription factor NF-kappaB and robust T cell activation, although the contribution of CD28 to this process remains incompletely understood. We show here that phosphoinositide-dependent kinase 1 (PDK1) is essential for integrating the TCR and CD28 signals. After we deleted PDK1 from T cells, TCR-CD28 signals were unable to induce activation of NF-kappaB or phosphorylation of protein kinase C-theta, although T cell survival and pathways dependent on the kinases p38 and Jnk or the transcription factor NFAT were unaffected. CD28 facilitated NF-kappaB activation by regulating recruitment and phosphorylation of PDK1, which are necessary for efficient binding of PDK1 to protein kinase C-theta and the adaptor CARMA1 and thus for NF-kappaB induction.


Asunto(s)
Antígenos CD28/inmunología , Activación de Linfocitos/inmunología , FN-kappa B/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Animales , Proteínas Adaptadoras de Señalización CARD/inmunología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Antígenos CD28/metabolismo , Supervivencia Celular , Ensayo de Cambio de Movilidad Electroforética , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunoprecipitación , Ratones , Ratones Transgénicos , Microscopía Fluorescente , FN-kappa B/metabolismo , Fosforilación , Proteína Quinasa C-delta/inmunología , Proteína Quinasa C-delta/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Linfocitos T/metabolismo
18.
Immunology ; 160(1): 64-77, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32064589

RESUMEN

Sterile inflammation contributes to many pathological states associated with mitochondrial injury. Mitochondrial injury disrupts calcium homeostasis and results in the release of CpG-rich mitochondrial DNA. The role of CpG-stimulated TLR9 innate immune signalling and sterile inflammation is well studied; however, how calcium dyshomeostasis affects this signalling is unknown. Therefore, we interrogated the relationship beτween intracellular calcium and CpG-induced TLR9 signalling in murine macrophages. We found that CpG-ODN-induced NFκB-dependent IL1α and IL1ß expression was significantly attenuated by both calcium chelation and calcineurin inhibition, a finding mediated by inhibition of degradation of the NFκB inhibitory protein IκBß. In contrast, calcium ionophore exposure increased CpG-induced IκBß degradation and IL1α and IL1ß expression. These results demonstrate that through its effect on IκBß degradation, increased intracellular Ca2+ drives a pro-inflammatory TLR9-mediated innate immune response. These results have implications for the study of innate immune signalling downstream of mitochondrial stress and injury.


Asunto(s)
Señalización del Calcio/inmunología , Calcio/metabolismo , Proteínas I-kappa B/metabolismo , Inmunidad Innata , Receptor Toll-Like 9/metabolismo , Animales , Inhibidores de la Calcineurina/farmacología , Señalización del Calcio/efectos de los fármacos , Quelantes/farmacología , Proteínas I-kappa B/antagonistas & inhibidores , Proteínas I-kappa B/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Macrófagos , Masculino , Ratones , Ratones Noqueados , Oligodesoxirribonucleótidos/inmunología , Cultivo Primario de Células , Proteolisis/efectos de los fármacos , Células RAW 264.7
20.
J Immunol ; 200(7): 2362-2371, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29459403

RESUMEN

CD4+Foxp3+ regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-κB family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-κB pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2, in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2-deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-κB signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity.


Asunto(s)
Tolerancia Inmunológica/inmunología , Subunidad p52 de NF-kappa B/genética , Proteínas Nucleares/genética , Linfocitos T Reguladores/inmunología , Factor de Transcripción ReIB/genética , Animales , Autoinmunidad/inmunología , Diferenciación Celular , Células Cultivadas , Endonucleasas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subunidad p52 de NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-rel/metabolismo , Linfocitos T Reguladores/citología , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIB/metabolismo
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