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1.
Immunity ; 51(3): 479-490.e6, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31402259

RESUMO

Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.


Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , MicroRNAs/imunologia , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Células NIH 3T3 , Receptores de Interleucina-15/imunologia , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Fator de Crescimento Transformador beta/imunologia
2.
Proc Natl Acad Sci U S A ; 121(27): e2315944121, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38917002

RESUMO

Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered C15ORF48/miR-147 as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. C15ORF48/miR-147 encodes two molecular products, C15ORF48 protein and miR-147-3p microRNA, which are predominantly expressed in the intestinal epithelium. C15ORF48/miR-147 ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR-147-3p work together to suppress colonocyte metabolism and inflammation by silencing NDUFA4, a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C-terminal α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. NDUFA4 silencing hinders NF-κB signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the C15ORF48/miR-147-NDUFA4 molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation.


Assuntos
Metabolismo Energético , Microbioma Gastrointestinal , Inflamação , MicroRNAs , Animais , Humanos , Camundongos , Colite/metabolismo , Colite/microbiologia , Colite/genética , Colite/induzido quimicamente , Disbiose/metabolismo , Disbiose/microbiologia , Metabolismo Energético/genética , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais
3.
PLoS Biol ; 20(2): e3001552, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35180231

RESUMO

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.


Assuntos
Autoimunidade/imunologia , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Animais , Autoimunidade/genética , Transplante de Medula Óssea/métodos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica/métodos , Doença Enxerto-Hospedeiro/imunologia , Homeostase/genética , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , RNA-Seq/métodos , Transdução de Sinais/genética , Linfócitos T Reguladores/metabolismo
4.
Cell ; 142(6): 914-29, 2010 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-20850013

RESUMO

Foxp3(+) regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNγ-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFNγ receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity.


Assuntos
MicroRNAs/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Interferon gama/imunologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Fator de Transcrição STAT1/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia
5.
Blood ; 135(3): 167-180, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31805184

RESUMO

NF-κB is a key regulator of inflammation and cancer progression, with an important role in leukemogenesis. Despite its therapeutic potential, targeting NF-κB using pharmacologic inhibitors has proven challenging. Here, we describe a myeloid cell-selective NF-κB inhibitor using an miR-146a mimic oligonucleotide conjugated to a scavenger receptor/Toll-like receptor 9 agonist (C-miR146a). Unlike an unconjugated miR146a, C-miR146a was rapidly internalized and delivered to the cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets (IRAK1 and TRAF6), thereby blocking activation of NF-κB in target cells. IV injections of C-miR146a mimic to miR-146a-deficient mice prevented excessive NF-κB activation in myeloid cells, and thus alleviated myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome. Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in a xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR-146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using The Cancer Genome Atlas acute myeloid leukemia data set, we found an inverse correlation of miR-146a levels with NF-κB-related genes and with patient survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60, and MV4-11 leukemia cells in vitro. The repeated IV administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results show the potential of using myeloid cell-targeted miR-146a mimics for the treatment of inflammatory and myeloproliferative disorders.


Assuntos
Síndrome da Liberação de Citocina/prevenção & controle , Inflamação/prevenção & controle , Leucemia Mieloide Aguda/prevenção & controle , MicroRNAs/genética , Células Progenitoras Mieloides/patologia , NF-kappa B/metabolismo , Animais , Apoptose , Proliferação de Células , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Células Progenitoras Mieloides/metabolismo , NF-kappa B/genética , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Immunol ; 9(8): 839-45, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18645592

RESUMO

Decades of research went into understanding immune cell development and function without awareness that consideration of a key element, microRNA (miRNA), was lacking. The discovery of miRNAs as regulators of developmental events in model organisms suggested to many investigators that miRNA might be involved in the immune system. In the past few years, widespread examination of this possibility has produced notable results. Results have shown that miRNAs affect mammalian immune cell differentiation, the outcome of immune responses to infection and the development of diseases of immunological origin. Some miRNAs repress expression of target proteins with well established functions in hematopoiesis. Here we bring together much of this work, which has so far only scratched the surface of this very fertile field of investigation, and show how the results illuminate many historic questions about hematopoiesis and immune function.


Assuntos
Diferenciação Celular , Hematopoese/fisiologia , Imunidade/fisiologia , Inflamação/genética , MicroRNAs/fisiologia , Animais , Linhagem da Célula , Humanos , Imunidade/genética , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Proc Natl Acad Sci U S A ; 114(34): E7140-E7149, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28784800

RESUMO

microRNA-146a (miR-146a) has been previously implicated as an essential molecular brake, preventing immune overreaction and malignant transformation by attenuating NF-κB signaling, putatively via repression of the Traf6 and Irak1 genes. The exact contribution of miR-146a-mediated silencing of these genes to the control of immune activation is currently unknown. Therefore, we defined the role of the miR-146a-Traf6 signaling axis in the regulation of immune homeostasis using a genetic epistasis analysis in miR-146a-/- mice. We have uncovered a surprising separation of functions at the level of miR-146a targets. Lowering the Traf6 gene dose and consequent attenuation of NF-κB activation rescued several significant miR-146a-/- phenotypes, such as splenomegaly, aberrant myeloproliferation, and excessive inflammatory responses. In contrast, decreasing Traf6 expression had no effect on the development of the progressive bone marrow failure phenotype, as well as lymphomagenesis in miR-146a-/- mice, indicating that miR-146a controls these biological processes through different molecular mechanisms.


Assuntos
Autoimunidade , Células-Tronco Hematopoéticas/citologia , Inflamação/imunologia , MicroRNAs/imunologia , Mielopoese , Neoplasias/imunologia , Fator 6 Associado a Receptor de TNF/imunologia , Animais , Feminino , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/imunologia , Homeostase , Humanos , Inflamação/genética , Inflamação/fisiopatologia , Masculino , Camundongos , MicroRNAs/genética , Células Mieloides/citologia , Células Mieloides/imunologia , Neoplasias/genética , Neoplasias/fisiopatologia , Fator 6 Associado a Receptor de TNF/genética
8.
Proc Natl Acad Sci U S A ; 114(15): 3927-3932, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28356515

RESUMO

miRNAs play critical roles in various biological processes by targeting specific mRNAs. Current approaches to identifying miRNA targets are insufficient for elucidation of a miRNA regulatory network. Here, we created a cell-based screening system using a luciferase reporter library composed of 4,891 full-length cDNAs, each of which was integrated into the 3' UTR of a luciferase gene. Using this reporter library system, we conducted a screening for targets of miR-34a, a tumor-suppressor miRNA. We identified both previously characterized and previously uncharacterized targets. miR-34a overexpression in MDA-MB-231 breast cancer cells repressed the expression of these previously unrecognized targets. Among these targets, GFRA3 is crucial for MDA-MB-231 cell growth, and its expression correlated with the overall survival of patients with breast cancer. Furthermore, GFRA3 was found to be directly regulated by miR-34a via its coding region. These data show that this system is useful for elucidating miRNA functions and networks.


Assuntos
Neoplasias da Mama/genética , Biblioteca Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , MicroRNAs/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , MicroRNAs/metabolismo , RNA Helicases/genética , Transativadores/genética
9.
Blood ; 125(24): 3720-30, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-25931583

RESUMO

MicroRNAs (miRNAs) are a class of powerful posttranscriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with a targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, whereas the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of B-cell-activating factor (BAFF) receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B-cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B-cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis, and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.


Assuntos
Linfócitos B/patologia , Deleção de Genes , Síndromes de Imunodeficiência/genética , Transtornos Imunoproliferativos/genética , Linfopoese , MicroRNAs/genética , Animais , Receptor do Fator Ativador de Células B/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Imunidade Celular , Imunidade Humoral , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Transtornos Imunoproliferativos/imunologia , Transtornos Imunoproliferativos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/imunologia
10.
Immunol Rev ; 246(1): 205-20, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22435557

RESUMO

Since its discovery 25 years ago, nuclear factor-κB (NF-κB) has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory. Activation of NF-κB initiates an elaborate genetic program. Some of the NF-κB-driven genes do not encode proteins but rather are precursors to microRNAs. These microRNAs play important roles in the regulation of the inflammatory process, some being inhibitory and others activating. Here, we discuss both the regulation of their expression and the function of some of these non-coding RNA genes. We also include a personal discussion of how NF-κB was first discovered.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Animais , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Transdução de Sinais
11.
J Allergy Clin Immunol ; 134(4): 836-847.e11, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24996260

RESUMO

BACKGROUND: Chronic skin inflammation in atopic dermatitis (AD) is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. microRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. OBJECTIVE: The aim of this study was to investigate the role of miR-146a in skin inflammation in AD. METHODS: RNA and protein expression was analyzed using miRNA and mRNA arrays, RT-quantitative PCR, Western blotting, and immunonohistochemistry. Transfection of miR-146a precursors and inhibitors into human primary keratinocytes, luciferase assays, and MC903-dependent mouse model of AD were used to study miR-146a function. RESULTS: We show that miR-146a expression is increased in keratinocytes and chronic lesional skin of patients with AD. miR-146a inhibited the expression of numerous proinflammatory factors, including IFN-γ-inducible and AD-associated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-γ, TNF-α, or IL-1ß. In a mouse model of AD, miR-146a-deficient mice developed stronger inflammation characterized by increased accumulation of infiltrating cells in the dermis, elevated expression of IFN-γ, CCL5, CCL8, and UBD in the skin, and IFN-γ, IL-1ß, and UBD in draining lymph nodes. Both tissue culture and in vivo experiments in mice demonstrated that miR-146a-mediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain-containing protein 10 and IL-1 receptor-associated kinase 1. In addition, human CCL5 was determined as a novel, direct target of miR-146a. CONCLUSION: Our data demonstrate that miR-146a controls nuclear factor kappa B-dependent inflammatory responses in keratinocytes and chronic skin inflammation in AD.


Assuntos
Dermatite Atópica/genética , Queratinócitos/imunologia , MicroRNAs/fisiologia , NF-kappa B/metabolismo , Interferência de RNA , Pele/imunologia , Animais , Calcitriol/administração & dosagem , Calcitriol/análogos & derivados , Movimento Celular/genética , Células Cultivadas , Doença Crônica , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/imunologia , Modelos Animais de Doenças , Humanos , Imunidade Inata , Terapia de Imunossupressão , Inflamação/genética , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , NF-kappa B/genética , Interferência de RNA/imunologia , Transdução de Sinais/genética , Pele/patologia , Regulação para Cima
12.
Proc Natl Acad Sci U S A ; 108(22): 9184-9, 2011 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-21576471

RESUMO

MicroRNA miR-146a has been implicated as a negative feedback regulator of NF-κB activation. Knockout of the miR-146a gene in C57BL/6 mice leads to histologically and immunophenotypically defined myeloid sarcomas and some lymphomas. The sarcomas are transplantable to immunologically compromised hosts, showing that they are true malignancies. The animals also exhibit chronic myeloproliferation in their bone marrow. Spleen and marrow cells show increased transcription of NF-κB-regulated genes and tumors have higher nuclear p65. Genetic ablation of NF-κB p50 suppresses the myeloproliferation, showing that dysregulation of NF-κB is responsible for the myeloproliferative disease.


Assuntos
MicroRNAs/metabolismo , Transtornos Mieloproliferativos/metabolismo , NF-kappa B/metabolismo , Animais , Células da Medula Óssea/citologia , Genótipo , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Genéticos , Transplante de Neoplasias , Neoplasias/metabolismo , Mielofibrose Primária/patologia , Baço/metabolismo , Transcrição Gênica
13.
Cells ; 11(13)2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35805086

RESUMO

The miR-146 family consists of two microRNAs (miRNAs), miR-146a and miR-146b, which are both known to suppress a variety of immune responses. Here in this study, we show that miR-146b is abundantly expressed in neuronal cells, while miR-146a is mainly expressed in microglia and astroglia of adult mice. Accordingly, miR-146b deficient (Mir146b-/-) mice exhibited anxiety-like behaviors and enhanced cognition. Characterization of cellular composition of Mir146b-/- mice using flow cytometry revealed an increased number of neurons and a decreased abundancy of astroglia in the hippocampus and frontal cortex, whereas microglia abundancy remained unchanged. Immunohistochemistry showed a higher density of neurons in the frontal cortex of Mir146b-/- mice, enhanced hippocampal neurogenesis as evidenced by an increased proliferation, and survival of newly generated cells with enhanced maturation into neuronal phenotype. No microglial activation or signs of neuroinflammation were observed in Mir146b-/- mice. Further analysis demonstrated that miR-146b deficiency is associated with elevated expression of glial cell line-derived neurotrophic factor (Gdnf) mRNA in the hippocampus, which might be at least in part responsible for the observed neuronal expansion and the behavioral phenotype. This hypothesis is partially supported by the positive correlation between performance of mice in the object recognition test and Gdnf mRNA expression in Mir146b-/- mice. Together, these results show the distinct function of miR-146b in controlling behaviors and provide new insights in understanding cell-specific function of miR-146b in the neuronal and astroglial organization of the mouse brain.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial , MicroRNAs , Animais , Cognição , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neurogênese , RNA Mensageiro
14.
Front Immunol ; 13: 996415, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389659

RESUMO

The miR-146 family consists of two microRNAs (miRNAs), miR-146a and miR-146b (miR-146a/b), both of which are known to suppress immune responses in a variety of conditions. Here, we studied how constitutive deficiency of miR-146b (Mir146b-/-) affects lipopolysaccharide (LPS)-induced neuroinflammation in mice. Our experiments demonstrated that miR-146b deficiency results in the attenuation of LPS-induced neuroinflammation, as it was evidenced by the reduction of sickness behavior, a decrease in the inflammatory status of microglia, and the loss of morphological signs of microglial activation in the hippocampus. Gene expression analysis revealed that LPS-induced upregulation of hippocampal pro-inflammatory cytokines is attenuated in Mir146b-/- mice, compared to wild-type (WT) mice. In addition, reduced expression of the NF-κB nuclear protein p65, reduced miR-146 family target TLR4 expression and relatively stronger upregulation of miR-146a was found in Mir146b-/- mice as compared to WT mice upon LPS challenge. Compensatory upregulation of miR-146a can explain the attenuation of the LPS-induced neuroinflammation. This was supported by experiments conducted with miR-146a/b deficient mice (Mir146a/b-/-), which demonstrated that additional deletion of the miR-146a led to the restoration of LPS-induced sickness behavior and proinflammatory cytokines. Our experiments also showed that the observed upregulation of miR-146a in Mir146b-/- mice is due to the overexpression of a miR-146a transcription inducer, interferon regulatory factor 7 (Irf7). Altogether, our results show the existence of crosstalk between miR-146a and mir-146b in the regulation of LPS-induced neuroinflammation.


Assuntos
Lipopolissacarídeos , MicroRNAs , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Inflamação/genética , MicroRNAs/metabolismo , Regulação para Cima , Citocinas/metabolismo
15.
Clin Transl Med ; 11(6): e427, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34185416

RESUMO

Rhinovirus (RV) infections are associated with asthma exacerbations. MicroRNA-146a and microRNA-146b (miR-146a/b) are anti-inflammatory miRNAs that suppress signaling through the nuclear factor kappa B (NF-κB) pathway and inhibit pro-inflammatory chemokine production in primary human bronchial epithelial cells (HBECs). In the current study, we aimed to explore whether miR-146a/b could regulate cellular responses to RVs in HBECs and airways during RV-induced asthma exacerbation. We demonstrated that expression of miR-146a/b and pro-inflammatory chemokines was increased in HBECs and mouse airways during RV infection. However, transfection with cell-penetrating peptide (CPP)-miR-146a nanocomplexes before infection with RV significantly reduced the expression of the pro-inflammatory chemokines CCL5, IL-8 and CXCL1, increased interferon-λ production, and attenuated infection with the green fluorescent protein (GFP)-expressing RV-A16 in HBECs. Concordantly, compared to wild-type (wt) mice, Mir146a/b-/- mice exhibited more severe airway neutrophilia and increased T helper (Th)1 and Th17 cell infiltration in response to RV-A1b infection and a stronger Th17 response with a less prominent Th2 response in house dust mite extract (HDM)-induced allergic airway inflammation and RV-induced exacerbation models. Interestingly, intranasal administration of CPP-miR-146a nanocomplexes reduced HDM-induced allergic airway inflammation without a significant effect on the Th2/Th1/Th17 balance in wild-type mice. In conclusion, the overexpression of miR-146a has a strong anti-inflammatory effect on RV infection in HBECs and a mouse model of allergic airway inflammation, while a lack of miR-146a/b leads to attenuated type 2 cell responses in mouse models of allergic airway inflammation and RV-induced exacerbation of allergic airway inflammation. Furthermore, our data indicate that the application of CPP-miR-146a nanocomplexes has therapeutic potential for targeting airway inflammation.


Assuntos
Asma/patologia , Hipersensibilidade/patologia , Inflamação/patologia , MicroRNAs/genética , Infecções por Picornaviridae/complicações , Células Th2/imunologia , Adulto , Alérgenos , Animais , Asma/etiologia , Asma/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Infecções por Picornaviridae/virologia , Rhinovirus/fisiologia
16.
Curr Stem Cell Rep ; 4(2): 158-165, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30364527

RESUMO

PURPOSE OF REVIEW: Hematopoiesis is an ordered developmental process that requires dynamic regulation to warrant proper response to physiological challenges and prevent malignancies. Long noncoding RNAs are emerging as key, multi-faceted regulators of gene expression. This review explores the function of lncRNAs in the control of HSC homeostasis and hematopoietic differentiation. RECENT FINDINGS: Multiple lncRNAs have been implicated in maintaining HSC stemness and enabling progenitors to carry out the correct programs of lineage differentiation. Specific lncRNAs have been identified that regulate the differentiation of multipotent progenitors into terminally differentiated blood cells. These lncRNAs predominantly act by assisting master regulators that drive specific differentiation programs, either by enhancing or repressing the transcription of particular genomic loci. SUMMARY: Long noncoding RNAs contribute to the correct differentiation and maturation of various hematopoietic lineages by assisting with the activation of transcriptional programs in a time- and cell-dependent manner.

17.
J Clin Invest ; 127(10): 3702-3716, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28872459

RESUMO

Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a-deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a-deficient mice with 2D2 T cell receptor-Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a-deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL-6- and IL-21-induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL-6- and IL-21-induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases.


Assuntos
Autoimunidade , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , MicroRNAs/imunologia , Esclerose Múltipla/imunologia , Células Th17/imunologia , Animais , Comunicação Autócrina/genética , Comunicação Autócrina/imunologia , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/genética , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Esclerose Múltipla/genética , Glicoproteína Mielina-Oligodendrócito/genética , Glicoproteína Mielina-Oligodendrócito/imunologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Células Th17/patologia
18.
Cancer Cell ; 25(4): 501-15, 2014 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-24735924

RESUMO

Cancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Endotélio Vascular/patologia , MicroRNAs/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Endotélio Vascular/metabolismo , Feminino , Humanos , MicroRNAs/genética , Metástase Neoplásica
19.
J Exp Med ; 209(9): 1655-70, 2012 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-22891274

RESUMO

T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-κB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-κB is associated with T cell-mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-κB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-κB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-κB activity, at least partly through repressing the NF-κB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-κB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.


Assuntos
MicroRNAs/genética , Linfócitos T/fisiologia , Animais , Antígenos/imunologia , Antígenos/farmacologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação da Expressão Gênica , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator 6 Associado a Receptor de TNF/metabolismo
20.
J Exp Med ; 208(6): 1189-201, 2011 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-21555486

RESUMO

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.


Assuntos
Autoimunidade , MicroRNAs/genética , Neoplasias/imunologia , Regiões 3' não Traduzidas , Animais , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Humanos , Inflamação , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias/genética , Processamento Pós-Transcricional do RNA , Fator 6 Associado a Receptor de TNF/metabolismo , Regulação para Cima
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