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1.
Immunol Rev ; 311(1): 50-74, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35672656

RESUMO

Fungal infections in the central nervous system (CNS) cause high morbidity and mortality. The frequency of CNS mycosis has increased over the last two decades as more individuals go through immunocompromised conditions for various reasons. Nevertheless, options for clinical interventions for CNS mycoses are still limited. Thus, there is an urgent need to understand the host-pathogen interaction mechanisms in CNS mycoses for developing novel treatments. Although the CNS has been regarded as an immune-privileged site, recent studies demonstrate the critical involvement of immune responses elicited by CNS-resident and CNS-infiltrated cells during fungal infections. In this review, we discuss mechanisms of fungal invasion in the CNS, fungal pathogen detection by CNS-resident cells (microglia, astrocytes, oligodendrocytes, neurons), roles of CNS-infiltrated leukocytes, and host immune responses. We consider that understanding host immune responses in the CNS is crucial for endeavors to develop treatments for CNS mycosis.


Assuntos
Sistema Nervoso Central , Micoses , Interações Hospedeiro-Patógeno , Humanos , Imunidade
2.
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
3.
Infect Immun ; 88(9)2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32540868

RESUMO

C-type lectin receptors (CLRs) play key roles in antifungal defense. CLR-induced NF-κB is central to CLR functions in immunity, and thus, molecules that control the amplitude of CLR-induced NF-κB could profoundly influence host defense against fungal pathogens. However, little is known about the mechanisms that negatively regulate CLR-induced NF-κB, and molecules which act on the CLR family broadly and which directly regulate acute CLR-signaling cascades remain unidentified. Here, we identify the ubiquitin-editing enzyme A20 as a negative regulator of acute NF-κB activation downstream of multiple CLR pathways. Absence of A20 suppression results in exaggerated CLR responses in cells which are A20 deficient and also cells which are A20 haplosufficient, including multiple primary immune cells. Loss of a single allele of A20 results in enhanced defense against systemic Candida albicans infection and prolonged host survival. Thus, A20 restricts CLR-induced innate immune responses in vivo and is a suppressor of host defense against systemic fungal infection.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Lectinas Tipo C/imunologia , Processamento de Proteína Pós-Traducional , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/microbiologia , Candida albicans/patogenicidade , Candidíase/genética , Candidíase/microbiologia , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Feminino , Feto , Interações entre Hospedeiro e Microrganismos/genética , Imunidade Inata , Lectinas Tipo C/genética , Fígado/imunologia , Fígado/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Cultura Primária de Células , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/deficiência , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Ubiquitina/genética , Ubiquitina/imunologia , Ubiquitinação
4.
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
5.
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
6.
Cell Stem Cell ; 30(8): 1054-1071.e8, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37541211

RESUMO

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.


Assuntos
Lesões Encefálicas , Nascimento Prematuro , Substância Branca , Feminino , Humanos , Animais , Camundongos , Recém-Nascido , Substância Branca/metabolismo , Leite Humano/metabolismo , Proteínas Hedgehog/metabolismo , Ventrículos Cerebrais/metabolismo , Oligodendroglia/fisiologia
7.
Front Immunol ; 12: 670574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995406

RESUMO

Neutrophils are critical as the first-line defense against fungal pathogens. Yet, previous studies indicate that neutrophil function is complex during Cryptococcus neoformans (Cn) infection. To better understand the role of neutrophils in acute pulmonary cryptococcosis, we analyzed neutrophil heterogeneity by single-cell transcriptional analysis of immune cells in the lung of Cn-infected mice from a published dataset. We identified neutrophils by reference-based annotation and identified two distinct neutrophil subsets generated during acute Cn infection: A subset with an oxidative stress signature (Ox-PMN) and another with enhanced cytokine gene expression (Cyt-PMN). Based on gene regulatory network and ligand-receptor analysis, we hypothesize that Ox-PMNs interact with the fungus and generate ROS, while Cyt-PMNs are longer-lived neutrophils that indirectly respond to Cn-derived ligands and cytokines to modulate cell-cell communication with dendritic cells and alveolar macrophages. Based on the data, we hypothesized that, during in vivo fungal infection, there is a division of labor in which each activated neutrophil becomes either Ox-PMN or Cyt-PMN.


Assuntos
Criptococose/imunologia , Pneumopatias Fúngicas/imunologia , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Animais , Criptococose/metabolismo , Cryptococcus neoformans/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Pneumopatias Fúngicas/metabolismo , Camundongos , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/imunologia , Análise de Célula Única
8.
Front Immunol ; 12: 661290, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995384

RESUMO

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.


Assuntos
Colo/imunologia , Células Dendríticas/imunologia , Macrófagos/imunologia , Fagócitos/imunologia , Células Th17/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígeno CD24/imunologia , Antígeno CD24/metabolismo , Colo/citologia , Colo/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Expressão Gênica/imunologia , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Intestino Delgado/imunologia , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Camundongos da Linhagem 129 , Camundongos Knockout , Camundongos Transgênicos , Fagócitos/metabolismo , Receptor da Anafilatoxina C5a/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Células Th17/metabolismo
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