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1.
Cell ; 184(10): 2796-2796.e1, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33989551

RESUMO

Microbes can play both pathogenic and commensal roles, and it is common to label them as either detrimental or beneficial. However, the lines between good and bad can be blurred. This graphical summary attempts to illustrate the complexity of host-microbe interactions, with outcomes for human health being highly context specific. To view this SnapShot, open or download the PDF.


Assuntos
Interações entre Hospedeiro e Microrganismos/fisiologia , Microbiota , Simbiose , Animais , Humanos
2.
Cell ; 171(3): 503-505, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-29053967

RESUMO

Inflammatory bowel disease is thought to arise from inappropriate inflammation to gut bacteria, yet mechanisms preventing these responses remain elusive. In this issue of Cell, Nanjundappa et al. report that Bacteroides share an epitope with a pancreas-specific peptide that induces protective CD8+ T cells, identifying molecular mimicry as a mechanism to enforce tolerance in the gut.


Assuntos
Colite , Microbioma Gastrointestinal , Amigos , Humanos , Intestinos , Mimetismo Molecular
3.
Immunity ; 55(6): 1051-1066.e4, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35649416

RESUMO

Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for detecting exposure and response to microbial protein products. We designed and constructed a library of 95,601 56-amino acid peptide tiles spanning 14,430 proteins with "toxin" or "virulence factor" keyword annotations. We used PhIP-Seq to profile the antibodies of ∼1,000 individuals against this "ToxScan" library. In addition to enumerating immunodominant antibody epitopes, we studied the age-dependent stability of the ToxScan profile and used a genome-wide association study to find that the MHC-II locus modulates bacterial epitope selection. We detected previously described anti-flagellin antibody responses in a Crohn's disease cohort and identified an association between anti-flagellin antibodies and juvenile dermatomyositis. PhIP-Seq with the ToxScan library is thus an effective tool for studying the environmental determinants of health and disease at cohort scale.


Assuntos
Bacteriófagos , Biblioteca de Peptídeos , Sequência de Aminoácidos , Anticorpos , Formação de Anticorpos , Bacteriófagos/genética , Estudo de Associação Genômica Ampla , Humanos , Epitopos Imunodominantes , Prevalência , Fatores de Virulência/genética
4.
Nature ; 596(7870): 114-118, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34262174

RESUMO

Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host. We find that potentially pathogenic Candida species induce and are targeted by intestinal immunoglobulin A (IgA) responses. Focused studies on Candida albicans reveal that the pathogenic hyphal morphotype, which is specialized for adhesion and invasion, is preferentially targeted and suppressed by intestinal IgA responses. IgA from mice and humans directly targets hyphal-enriched cell-surface adhesins. Although typically required for pathogenesis, C. albicans hyphae are less fit for gut colonization1,2 and we show that immune selection against hyphae improves the competitive fitness of C. albicans. C. albicans exacerbates intestinal colitis3 and we demonstrate that hyphae and an IgA-targeted adhesin exacerbate intestinal damage. Finally, using a clinically relevant vaccine to induce an adhesin-specific immune response protects mice from C. albicans-associated damage during colitis. Together, our findings show that adaptive immunity suppresses harmful fungal effectors, with benefits to both C. albicans and its host. Thus, IgA uniquely uncouples colonization from pathogenesis in commensal fungi to promote homeostasis.


Assuntos
Imunidade Adaptativa , Candida albicans/imunologia , Candida albicans/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Simbiose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Fungos/imunologia , Candida albicans/patogenicidade , Colite/imunologia , Colite/microbiologia , Colite/patologia , Feminino , Vacinas Fúngicas/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Hifas/imunologia , Imunoglobulina A/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
5.
Nature ; 594(7863): 413-417, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33981034

RESUMO

Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection1. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses1,2. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described3,4. Although the local environment shapes the differentiation of effector cells3-5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.


Assuntos
Células Dendríticas/imunologia , Microbioma Gastrointestinal/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Timo/imunologia , Envelhecimento/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , DNA Bacteriano/análise , Células Dendríticas/metabolismo , Escherichia coli/imunologia , Feminino , Masculino , Camundongos , Especificidade de Órgãos , Salmonella/imunologia , Simbiose/imunologia , Timo/metabolismo
6.
Immunity ; 46(6): 977-979, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28636967

RESUMO

Whereas strong evidence supports the notion that the microbiota promotes immune system maturation in multiple tissues, the identity of the specific microbes that elicit protective immunity to different infections is less clear. In a recent issue of Cell Host & Microbe, Thiemann et al. (2017) report the identification of specific gut bacteria that protect from Salmonella infection by priming host IFN-γ responses.


Assuntos
Microbioma Gastrointestinal , Interferon gama/metabolismo , Infecções por Salmonella/imunologia , Salmonella/imunologia , Simbiose , Animais , Biodiversidade , Modelos Animais de Doenças , Suscetibilidade a Doenças , Exposição Ambiental , Humanos , Imunidade Inata , Interferon gama/genética , Camundongos , Probióticos , Especificidade da Espécie
7.
J Immunol ; 210(7): 926-934, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36883849

RESUMO

The proinflammatory microRNA-155 (miR-155) is highly expressed in the serum and CNS lesions of patients with multiple sclerosis (MS). Global knockout (KO) of miR-155 in mice confers resistance to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), by reducing the encephalogenic potential of CNS-infiltrating Th17 T cells. However, cell-intrinsic roles for miR-155 during EAE have not been formally determined. In this study, we use single-cell RNA sequencing and cell-specific conditional miR-155 KOs to determine the importance of miR-155 expression in distinct immune cell populations. Time-course single-cell sequencing revealed reductions in T cells, macrophages, and dendritic cells (DCs) in global miR-155 KO mice compared with wild-type controls at day 21 after EAE induction. Deletion of miR-155 in T cells, driven by CD4 Cre, significantly reduced disease severity similar to global miR-155 KOs. CD11c Cre-mediated deletion of miR-155 in DCs also resulted in a modest yet significant reduction in the development of EAE, with both T cell- and DC-specific KOs showing a reduction in Th17 T cell infiltration into the CNS. Although miR-155 is highly expressed in infiltrating macrophages during EAE, deletion of miR-155 using LysM Cre did not impact disease severity. Taken together, these data show that although miR-155 is highly expressed in most infiltrating immune cells, miR-155 has distinct roles and requirements depending on the cell type, and we have demonstrated this using the gold standard conditional KO approach. This provides insights into which functionally relevant cell types should be targeted by the next generation of miRNA therapeutics.


Assuntos
Encefalomielite Autoimune Experimental , MicroRNAs , Esclerose Múltipla , Animais , Camundongos , Doenças Neuroinflamatórias , Células Th17/metabolismo , Encéfalo/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Annu Rev Microbiol ; 72: 399-422, 2018 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-29927706

RESUMO

Mammalian immune systems evolved within a diverse world dominated by microbes, making interactions between these two life-forms inevitable. Adaptive immunity protects against microbes through antigen-specific responses. In classical studies, these responses were investigated in the context of pathogenicity; however, we now know that they have significant effects on our resident microbes. In turn, microbes employ an arsenal of mechanisms to influence development and specificity of host immunity. Understanding these complex reactions will be necessary to develop microbiota-based strategies to prevent or treat disease. Here we review the literature detailing the cross talk between resident microbes with a focus on the specificity of host responses and the microbial molecules that influence them.


Assuntos
Imunidade Adaptativa , Interações Hospedeiro-Patógeno , Imunidade Inata , Mamíferos/imunologia , Mamíferos/microbiologia , Microbiota/imunologia , Animais , Humanos
9.
BMC Cancer ; 23(1): 300, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37013476

RESUMO

BACKGROUND: Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. METHODS: Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into 'highly active' and'not-highly active'(≥ / < 18 MET hrs/wk). BMI (kg/m2) was categorized into 'normal weight', 'overweight', and 'obese'. Patients were further classified into combined physical activity and BMI groups. Cox-proportional hazard models with Firth correction were computed to assess associations [hazard ratio (HR), 95% profile HR likelihood confidence interval (95% CI) between individual and combined physical activity and BMI groups with overall and disease-free survival in colorectal cancer patients. RESULTS: 'Not-highly active' compared to 'highly active' and 'overweight'/ 'obese' compared to 'normal weight' patients had a 40-50% increased risk of death or recurrence (HR: 1.41 (95% CI: 0.99-2.06), p = 0.03; HR: 1.49 (95% CI: 1.02-2.21) and HR: 1.51 (95% CI: 1.02-2.26), p = 0.04, respectively). 'Not-highly active' patients had worse disease-free survival outcomes, regardless of their BMI, compared to 'highly active/normal weight' patients. 'Not-highly active/obese' patients had a 3.66 times increased risk of death or recurrence compared to 'highly active/normal weight' patients (HR: 4.66 (95% CI: 1.75-9.10), p = 0.002). Lower activity thresholds yielded smaller effect sizes. CONCLUSION: Physical activity and BMI were individually associated with disease-free survival among colorectal cancer patients. Physical activity seems to improve survival outcomes in patients regardless of their BMI.


Assuntos
Neoplasias Colorretais , Obesidade , Humanos , Índice de Massa Corporal , Obesidade/complicações , Sobrepeso/complicações , Sobrepeso/epidemiologia , Exercício Físico , Fatores de Risco
10.
Immunity ; 41(4): 605-19, 2014 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25367574

RESUMO

Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.


Assuntos
Centro Germinativo/imunologia , Inflamação/imunologia , MicroRNAs/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Linfócitos B/imunologia , Antígenos CD4/biossíntese , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Antígeno 2 Relacionado a Fos/genética , Centro Germinativo/citologia , Imunidade Humoral , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Interferência de RNA , RNA Interferente Pequeno
11.
J Immunol ; 207(7): 1719-1724, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544814

RESUMO

Metabolic diseases are common worldwide and include diseases of overnutrition, such as obesity, or undernutrition, such as kwashiorkor. Both the immune system and the microbiota contribute to a variety of metabolic diseases; however, these two processes have largely been studied independently of one another in this context. The gastrointestinal system houses the greatest density of microbes but also houses one of the largest collections of immune molecules, especially Abs. The IgA isotype dominates the Ab landscape at mucosal sites, and a number of studies have demonstrated the importance of this Ab to the stability of the microbiota. In this article, we review the literature that demonstrates how homeostatic Ab responses control microbiota composition and function to influence metabolic disease. We propose that many metabolic diseases may arise from disruptions to homeostatic immune control of gut commensals and that further understanding this interaction can offer a novel opportunity for therapeutic interventions.


Assuntos
Disbiose/imunologia , Imunoglobulina A/metabolismo , Doenças Metabólicas/imunologia , Microbiota/imunologia , Mucosa/imunologia , Animais , Disbiose/microbiologia , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade nas Mucosas , Imunomodulação , Doenças Metabólicas/microbiologia , Mucosa/microbiologia
12.
J Immunol ; 204(8): 2064-2075, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32161096

RESUMO

Aging-related chronic inflammation is a risk factor for many human disorders through incompletely understood mechanisms. Aged mice deficient in microRNA (miRNA/miR)-146a succumb to life-shortening chronic inflammation. In this study, we report that miR-155 in T cells contributes to shortened lifespan of miR-146a-/- mice. Using single-cell RNA sequencing and flow cytometry, we found that miR-155 promotes the activation of effector T cell populations, including T follicular helper cells, and increases germinal center B cells and autoantibodies in mice aged over 15 months. Mechanistically, aerobic glycolysis genes are elevated in T cells during aging, and upon deletion of miR-146a, in a T cell miR-155-dependent manner. Finally, skewing T cell metabolism toward aerobic glycolysis by deleting mitochondrial pyruvate carrier recapitulates age-dependent T cell phenotypes observed in miR-146a-/- mice, revealing the sufficiency of metabolic reprogramming to influence immune cell functions during aging. Altogether, these data indicate that T cell-specific miRNAs play pivotal roles in regulating lifespan through their influences on inflammaging.


Assuntos
Modelos Animais de Doenças , Inflamação/genética , Longevidade/genética , MicroRNAs/genética , Linfócitos T/metabolismo , Fatores Etários , Animais , Feminino , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/imunologia , Linfócitos T/patologia
13.
PLoS Genet ; 15(2): e1007970, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30768595

RESUMO

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways. RNA-sequencing of adipose tissue macrophages demonstrated a role for miR-146a in regulating both inflammation and cellular metabolism, including the mTOR pathway, during obesity. Further, we demonstrate that miR-146a regulates inflammation, cellular respiration and glycolysis in macrophages through a mechanism involving its direct target Traf6. Finally, we found that administration of rapamycin, an inhibitor of mTOR, was able to rescue the obesity phenotype in miR-146a-/- mice. Altogether, our study provides evidence that miR-146a represses inflammation and diet-induced obesity and regulates metabolic processes at the cellular and organismal levels, demonstrating how the combination of diet and miRNA genetics influences obesity and diabetic phenotypes.


Assuntos
Inflamação/prevenção & controle , Doenças Metabólicas/prevenção & controle , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Inflamação/genética , Inflamação/metabolismo , Insulina/sangue , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Macrófagos/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , NF-kappa B/metabolismo , Obesidade/genética , Obesidade/metabolismo , Obesidade/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/genética
14.
Symbiosis ; 87(1): 45-58, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-37915425

RESUMO

Fungi are often overlooked in microbiome research and, as a result, little is known about the mammalian mycobiome. Although frequently detected in vertebrate guts and known to contribute to digestion in some herbivores, whether these eukaryotes are a persistent part of the mammalian gut microbiome remains contentious. To address this question, we sampled fungi from wild woodrats (Neotoma spp.) collected from 25 populations across the southwestern United States. For each animal, we collected a fecal sample in the wild, and then re-sampled the same individual after a month in captivity on a controlled diet. We characterized and quantified fungi using three techniques: ITS metabarcoding, shotgun metagenomics and qPCR. Wild individuals contained diverse fungal assemblages dominated by plant pathogens, widespread molds, and coprophilous taxa primarily in Ascomycota and Mucoromycota. Fungal abundance, diversity and composition differed between individuals, and was primarily influenced by animal geographic origin. Fungal abundance and diversity significantly declined in captivity, indicating that most fungi in wild hosts came from diet and environmental exposure. While this suggests that these mammals lack a persistent gut mycobiome, natural fungal exposure may still impact fungal dispersal and animal health.

15.
J Neuroinflammation ; 17(1): 291, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023618

RESUMO

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. METHODS: We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). RESULTS: We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. CONCLUSIONS: Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.


Assuntos
Sistema Nervoso Central/imunologia , Microbioma Gastrointestinal/imunologia , Lacticaseibacillus paracasei/imunologia , Leucócitos/imunologia , Animais , Sistema Nervoso Central/patologia , Feminino , Humanos , Leucócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
J Immunol ; 200(4): 1457-1470, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29330323

RESUMO

T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4+ and CD8+ T cells leads to arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non-Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. The microbial pattern recognition receptor TLR2 was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell-intrinsic expression of TLR2 contributed to IFN-γ production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. The IL-10-deficient mouse reveals a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broad application to immune pathogenesis.


Assuntos
Interleucina-10/deficiência , Doença de Lyme/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Feminino , Interleucina-10/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
17.
Proc Natl Acad Sci U S A ; 114(21): 5497-5502, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28487480

RESUMO

Symbiotic microbes impact the severity of a variety of diseases through regulation of T-cell development. However, little is known regarding the molecular mechanisms by which this is accomplished. Here we report that a secreted factor, Erdr1, is regulated by the microbiota to control T-cell apoptosis. Erdr1 expression was identified by transcriptome analysis to be elevated in splenic T cells from germfree and antibiotic-treated mice. Suppression of Erdr1 depends on detection of circulating microbial products by Toll-like receptors on T cells, and this regulation is conserved in human T cells. Erdr1 was found to function as an autocrine factor to induce apoptosis through caspase 3. Consistent with elevated levels of Erdr1, germfree mice have increased splenic T-cell apoptosis. RNA sequencing of Erdr1-overexpressing cells identified the up-regulation of genes involved in Fas-mediated cell death, and Erdr1 fails to induce apoptosis in Fas-deficient cells. Importantly, forced changes in Erdr1 expression levels dictate the survival of auto-reactive T cells and the clinical outcome of neuro-inflammatory autoimmune disease. Cellular survival is a fundamental feature regulating appropriate immune responses. We have identified a mechanism whereby the host integrates signals from the microbiota to control T-cell apoptosis, making regulation of Erdr1 a potential therapeutic target for autoimmune disease.


Assuntos
Apoptose , Proteínas de Membrana/fisiologia , Microbiota , Linfócitos T/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Encefalomielite Autoimune Experimental/metabolismo , Homeostase , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Receptor fas/metabolismo
18.
Blood ; 129(23): 3074-3086, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28432220

RESUMO

FLT3-ITD+ acute myeloid leukemia (AML) accounts for ∼25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD+ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we used a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon (IFN) response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD+ AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD+ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD+ AML samples using locked nucleic acid antisense inhibitors, results in an elevated IFN response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and that this involves a multitarget mechanism that includes repression of IFN signaling.


Assuntos
Interferons/biossíntese , MicroRNAs/genética , Transtornos Mieloproliferativos/etiologia , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , MicroRNAs/antagonistas & inibidores , Mutação , Células Progenitoras Mieloides/imunologia , Células Progenitoras Mieloides/patologia , Mielopoese/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Ensaio Tumoral de Célula-Tronco
19.
Immunity ; 33(4): 607-19, 2010 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-20888269

RESUMO

Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory disease. Consistent with a positive role for miR-155 in mediating inflammatory responses, Mir155(-/-) mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4(+) T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Encefalomielite Autoimune Experimental/etiologia , MicroRNAs/fisiologia , Animais , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Glicoproteínas/imunologia , Hipersensibilidade Tardia/imunologia , Interferon gama/fisiologia , Interleucina-17/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia
20.
J Immunol ; 199(10): 3559-3570, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28978688

RESUMO

Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. In this article, we demonstrate that Rab27a and Rab27b double-knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by wild-type (WT) hematopoietic cells or administration of exosomes produced by GM-CSF-expanded bone marrow cells. In addition, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT, but not miR-155-/-, cells, suggesting that uptake of miR-155-containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased after treatment with WT, but not miR-155-/-, exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.


Assuntos
Exossomos/metabolismo , Inflamação/imunologia , MicroRNAs/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTP/metabolismo , Doença Aguda , Animais , Proliferação de Células , Células Cultivadas , Doença Crônica , Citocinas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Tolerância Imunológica , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/patologia , Proteínas rab de Ligação ao GTP/genética , Proteínas rab27 de Ligação ao GTP/genética
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