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1.
Nat Commun ; 9(1): 3338, 2018 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-30115909

RESUMEN

Li-Fan Lu and Alexander Y. Rudensky, who supplied miR-146a floxed mice used in this study, were inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article. The generation of the floxed mice has been described in detail by Cho and Lee et al.1.

2.
Nat Commun ; 8(1): 851, 2017 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-29021573

RESUMEN

The innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-κB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-κB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-κB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-κB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-κB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity.MicroRNAs (miR) are important regulators of gene transcription, with miR-155 and miR-146a both implicated in macrophage activation. Here the authors show that NF-κB signalling, miR-155 and miR-146a form a complex network of cross-regulations to control gene transcription in macrophages for modulating inflammatory responses.


Asunto(s)
Macrófagos/metabolismo , MicroARNs/metabolismo , FN-kappa B/metabolismo , Animales , Células HEK293 , Humanos , Macrófagos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo
3.
J Exp Med ; 212(10): 1679-92, 2015 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-26371188

RESUMEN

MicroRNAs have emerged as key regulators of B cell fate decisions and immune function. Deregulation of several microRNAs in B cells leads to the development of autoimmune disease and cancer in mice. We demonstrate that the microRNA-212/132 cluster (miR-212/132) is induced in B cells in response to B cell receptor signaling. Enforced expression of miR-132 results in a block in early B cell development at the prepro-B cell to pro-B cell transition and induces apoptosis in primary bone marrow B cells. Importantly, loss of miR-212/132 results in accelerated B cell recovery after antibody-mediated B cell depletion. We find that Sox4 is a target of miR-132 in B cells. Co-expression of SOX4 with miR-132 rescues the defect in B cell development from overexpression of miR-132 alone, thus suggesting that miR-132 may regulate B lymphopoiesis through Sox4. In addition, we show that the expression of miR-132 can inhibit cancer development in cells that are prone to B cell cancers, such as B cells expressing the c-Myc oncogene. We have thus uncovered miR-132 as a novel contributor to B cell development.


Asunto(s)
Linfocitos B/fisiología , MicroARNs/genética , Factores de Transcripción SOXC/genética , Regiones no Traducidas 3' , Animales , Apoptosis/genética , Linfocitos B/patología , Supervivencia Celular , Regulación de la Expresión Génica , Células HEK293 , Humanos , Leucemia de Células B/genética , Leucemia Experimental/genética , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/metabolismo , Familia de Multigenes , Factores de Transcripción SOXC/metabolismo
4.
Elife ; 2: e00537, 2013 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-23705069

RESUMEN

During inflammation and infection, hematopoietic stem and progenitor cells are stimulated to proliferate and differentiate into mature immune cells, especially of the myeloid lineage. MicroRNA-146a (miR-146a) is a critical negative regulator of inflammation. Deletion of miR-146a produces effects that appear as dysregulated inflammatory hematopoiesis, leading to a decline in the number and quality of hematopoietic stem cells (HSCs), excessive myeloproliferation, and, ultimately, to HSC exhaustion and hematopoietic neoplasms. At the cellular level, the defects are attributable to both an intrinsic problem in the miR-146a-deficient HSCs and extrinsic effects of lymphocytes and nonhematopoietic cells. At the molecular level, this involves a molecular axis consisting of miR-146a, signaling protein TRAF6, transcriptional factor NF-κB, and cytokine IL-6. This study has identified miR-146a to be a critical regulator of HSC homeostasis during chronic inflammation in mice and provided a molecular connection between chronic inflammation and the development of bone marrow failure and myeloproliferative neoplasms. DOI:http://dx.doi.org/10.7554/eLife.00537.001.


Asunto(s)
Senescencia Celular/genética , Células Madre Hematopoyéticas/citología , MicroARNs/genética , Animales , Homeostasis , Inflamación/metabolismo , Interleucina-6/metabolismo , Ratones , Ratones Mutantes , FN-kappa B/metabolismo
5.
Blood ; 120(12): 2428-37, 2012 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-22791292

RESUMEN

APCs are essential for innate and adaptive immunity as well as self-immune tolerance. Here, we show that the Cap'n'collar member Bach1 regulates the generation of APCs, specifically macrophages and dendritic cells, in mice. The impaired APC development in Bach1(-/-) mice was accompanied by defects in downstream T-cell responses and partial protection from experimental autoimmune encephalomyelitis. Genomewide analyses identified a panel of Bach1 target genes and ablation of the direct Bach1 target gene HO-1 exacerbated the impaired APC development observed in Bach1(-/-) mice. This was attributed to the impaired ability of HO-1(-/-)Bach1(-/-) double mutants to produce upstream APC progenitor cells, including common myeloid progenitor (CMP)-Flk2(+). By contrast, we observed an increase in hematopoietic stem-progenitor cells (HSPCs) in these mice, suggesting a developmental block in the progression of HSPCs to CMP-Flk2(+) and subsequently APCs.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Autoinmunidad/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/fisiología , Encefalomielitis Autoinmune Experimental/etiología , Células Madre Hematopoyéticas/inmunología , Hemo-Oxigenasa 1/fisiología , Inmunidad Celular/inmunología , Proteínas de la Membrana/fisiología , Animales , Biomarcadores/metabolismo , Western Blotting , Encefalomielitis Autoinmune Experimental/patología , Femenino , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/citología , Inmunización , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
6.
J Exp Med ; 208(6): 1189-201, 2011 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-21555486

RESUMEN

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.


Asunto(s)
Autoinmunidad , MicroARNs/genética , Neoplasias/inmunología , Regiones no Traducidas 3' , Animales , Proliferación Celular , Transformación Celular Neoplásica , Femenino , Humanos , Inflamación , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Lipopolisacáridos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias/genética , Procesamiento Postranscripcional del ARN , Factor 6 Asociado a Receptor de TNF/metabolismo , Regulación hacia Arriba
7.
Immunity ; 33(1): 48-59, 2010 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-20598588

RESUMEN

MicroRNAs (miRNAs) can influence lineage choice or affect critical developmental checkpoints during hematopoiesis. We examined the role of the p53-induced microRNA miR-34a in hematopoiesis by gain-of-function analysis in murine bone marrow. Constitutive expression of miR-34a led to a block in B cell development at the pro-B-cell-to-pre-B-cell transition, leading to a reduction in mature B cells. This block appeared to be mediated primarily by inhibited expression of the transcription factor Foxp1. Foxp1 was a direct target of miR-34a in a 3'-untranslated region (UTR)-dependent fashion. Knockdown of Foxp1 by siRNA recapitulated the B cell developmental phenotype induced by miR-34a, whereas cotransduction of Foxp1 lacking its 3' UTR with miR-34a rescued B cell maturation. Knockdown of miR-34a resulted in increased amounts of Foxp1 and mature B cells. These findings identify a role for miR-34a in connecting the p53 network with suppression of Foxp1, a known B cell oncogene.


Asunto(s)
Linfocitos B/metabolismo , Médula Ósea/metabolismo , Factores de Transcripción Forkhead/metabolismo , Células Precursoras de Linfocitos B/metabolismo , Proteínas Represoras/metabolismo , Regiones no Traducidas 3' , Animales , Linfocitos B/patología , Médula Ósea/patología , Línea Celular , Clonación Molecular , Factores de Transcripción Forkhead/genética , Hematopoyesis , Humanos , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Células Precursoras de Linfocitos B/patología , Quimera por Radiación , Proteínas Represoras/genética , Proteína p53 Supresora de Tumor/metabolismo
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