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1.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
3.
Nat Commun ; 10(1): 3031, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292453

RESUMO

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Assuntos
Acetatos/sangue , Feto/imunologia , Pré-Eclâmpsia/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T Reguladores/imunologia , Acetatos/administração & dosagem , Acetatos/imunologia , Acetatos/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Desenvolvimento Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Feto/citologia , Feto/diagnóstico por imagem , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Estudos Longitudinais , Troca Materno-Fetal/imunologia , Camundongos , Tamanho do Órgão/imunologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Estudos Prospectivos , Timo/citologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
4.
Nat Commun ; 10(1): 2220, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101805

RESUMO

Both medullary thymic epithelial cells (mTEC) and dendritic cells (DC) present tissue-restricted antigens (TRA) to thymocytes to induce central tolerance, but the relative contributions of these antigen-presenting cell (APC) subsets remain unresolved. Here we developed a two-photon microscopy approach to observe thymocytes interacting with intact APCs presenting TRAs. We find that mTECs and DCs cooperate extensively to induce tolerance, with their relative contributions regulated by the cellular form of the TRA and the class of major histocompatibility complex (MHC) on which antigen is presented. Even when TRA expression is restricted to mTECs, DCs still present self-antigens at least as frequently as mTECs. Notably, the DC subset cDC2 efficiently acquires secreted mTEC-derived TRAs for cross-presentation on MHC-I. By directly imaging interactions between thymocytes and APCs, while monitoring intracellular signaling, this study reveals that distinct DC subsets and AIRE+ mTECs contribute substantially to presentation of diverse self-antigens for establishing central tolerance.


Assuntos
Tolerância Central/imunologia , Células Dendríticas/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Transplante de Medula Óssea , Separação Celular/métodos , Células Dendríticas/metabolismo , Células Epiteliais/imunologia , Feminino , Citometria de Fluxo/métodos , Microscopia Intravital/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Linfócitos T Reguladores/imunologia , Timócitos/metabolismo , Timo/citologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Quimeras de Transplante/imunologia
5.
Mol Immunol ; 111: 162-171, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063937

RESUMO

B cells have been reported to have a suppressive function in autoimmune diseases, which appears to require an increase of CD11b expression on B cells. However, little is known how CD11b is induced in B cells to play the function. In this study, we found that the high expression of CD11b in B cells occurred not only in the mucosal immune organs, but also in systemically immune organs such as the spleen during dextran sulfate sodium (DSS)-induced colitis. Since the inflammatory lesions in mouse models of inflammatory bowel disease (IBD) were revealed to be significantly hypoxic or even anoxic, the B cells from colitic mice Peyer's patches (PP) were investigated to express higher levels of hypoxia-inducible factor-1α (HIF-1α) than naïve B cells from wildtype (WT) mice. HIF-1α siRNA transfection or HIF-1α protein inhibition led to decreased CD11b expression at both the mRNA and protein levels in vitro. B cells with HIF-1α specific knockdown were then adoptively transferred to Rag-1-/- mice. The result displayed that CD11b expression was decreased in B cells and an exacerbated colitis occurred. The bio-informatics promoter analysis and ChIP assay showed that HIF-1α was the critical transcription factor for CD11b and cooperatively formed a complex with the p-STAT3 homodimers to bind onto hypoxia-responsive element (HRE) regions, which was guaranteed by MEK/ERK pathway activation and IL-10 secretion. In conclusion, our study demonstrated the key function of the hypoxia-associated transcription factor HIF-1α together with p-STAT3 in driving CD11b transcription in B cells and controlling B cell's protective activity in experimental inflammatory bowel disease (IBD).


Assuntos
Linfócitos B/imunologia , Antígeno CD11b/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Doenças Inflamatórias Intestinais/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Animais , Colite/imunologia , Colo/imunologia , Regulação da Expressão Gênica/imunologia , Proteínas de Homeodomínio/imunologia , Imunossupressão/métodos , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/imunologia , RNA Mensageiro/imunologia , Baço/imunologia , Fatores de Transcrição/imunologia
6.
Nat Commun ; 10(1): 2157, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089138

RESUMO

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8+ T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155-Phf19-PRC2 as a pivotal axis regulating CD8+ T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma Experimental/imunologia , MicroRNAs/metabolismo , Neoplasias Cutâneas/imunologia , Fatores de Transcrição/metabolismo , Transferência Adotiva/métodos , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Epigênese Genética/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Complexo Repressor Polycomb 2/imunologia , Complexo Repressor Polycomb 2/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
7.
Mol Immunol ; 112: 115-122, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31082645

RESUMO

Mycobacterium tuberculosis (M. tuberculosis) persistent infection might cause the dysfunction of hematopoiesis. To investigate whether M. tuberculosis persistent antigen stimulation impairs the proliferation and differentiation of hematopoietic stem and progenitor cells characterized as lineage- c-Kit+ (LK cells), C57BL/6 mice were primed with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and boosted with a cocktail of M. tuberculosis antigens ESAT6, CFP10 and Mtb10.4-HspX (MH) along with adjuvant N, N'-dimethyl-N, N'-dioctadecylammonium bromide (DDA) plus polyinosinic-polycytidylic acid (Poly I:C) weekly for 12 or 22 weeks. The cytokine production by splenic T cells, proliferation of LK cells and transcriptional events during differentiation of bone marrow (BM) c-Kit+ cells were investigated. Meanwhile, the mice were treated with interleukin 2 (IL-2) and the therapeutic effects were analyzed. We found that antigen specific interferon-γ (IFN-γ) production by splenic CD4+ T cells increased following antigen stimulation for 12 weeks, but it declined after continuous stimulation for 22 weeks. The long-term exposure of mice to M. tuberculosis antigen compromised the proliferation of LK cells. Moreover, the expression of transcription factors in the c-Kit+ cells was adjusted, with up-regulation of IRF8 and Batf2 involved in myeloid differentiation and down-regulation of NOTCH1 and GATA2 participated in T-cell lineage commitment. The concentrations of IFN-γ in BM of the persistent antigen group were higher than that in sham control at the 12th week, while the concentrations of IL-2 in BM of the persistent antigen group were lower compared with the transient antigen stimulation control. Following IL-2 treatment, the concentrations of IL-2 in BM increased while IFN-γ got declined. IL-2 treatment could restore the expression levels of those transcription factors and the proliferating activity of LK cells impaired by persistent antigen stimulation. Our results indicate that M. tuberculosis antigen persistent stimulation decreases the proliferating activity of LK cells, promotes myelopoietic differentiation, and represses lymphopoietic differentiation as a consequence of elevated IFN-γ production. IL-2 supplementation contributes to maintaining the homeostasis of hemopoiesis.


Assuntos
Antígenos de Bactérias/imunologia , Medula Óssea/imunologia , Proliferação de Células/fisiologia , Mycobacterium tuberculosis/imunologia , Transcrição Genética/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/imunologia , Medula Óssea/microbiologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Interferon gama/imunologia , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Fatores de Transcrição/imunologia
8.
Mol Immunol ; 111: 209-219, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31096062

RESUMO

We have previously reported Israa, immune-system-released activating agent, as a novel gene nested in intron 8 of the mouse Zmiz1 gene. We have also shown that Israa encodes for a novel FYN-binding protein and might be involved in the regulation of T-cell activation. In this report, we demonstrate that Israa gene product regulates the expression of a pool of genes involved in T-cell activation and signaling. Real time PCR and GFP knock-in expression analysis showed that Israa is transcribed and expressed in the spleen mainly by CD3+CD8+ cells as well as in the thymus by CD3+ (DP and DN), CD4+SP and CD8+SP cells at different developmental stages. We also showed that Israa is downregulated in T-cells following activation of T-cell receptor. Using yeast two-hybrid analysis, we identified ELF1, a transcription factor involved in T-cell regulation, as an ISRAA-binding partner. Transcriptomic analysis of an EL4 cell line overexpressing ISRAA revealed differential expression of several genes involved in T-cell signaling, activation and development. Among these genes, Prkcb, Mib2, Fos, Ndfip2, Cxxc5, B2m, Gata3 and Cd247 were upregulated whereas Itk, Socs3, Tigit, Ifng, Il2ra and FoxJ1 were downregulated. Our findings support the existence in mouse of a novel FYN-related T-cell regulation pathway involving the product of an intron-nested gene.


Assuntos
Íntrons/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfocinas/imunologia , Genes Inseridos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Regulação para Baixo/imunologia , Feminino , Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Transcrição/imunologia , Regulação para Cima/imunologia
9.
Vet Microbiol ; 232: 128-136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31030836

RESUMO

The interleukin-1 (IL-1) family of cytokines, particularly IL-1α and IL-1ß, are potent regulators of innate immunity that play key roles in host defense against infection, hence we evaluated the role of these cytokines in the control of brucellosis within RAW 264.7 cells. Marked expression and secretion of IL-1α and IL-1ß were observed during Brucella infection in macrophages. Blocking of IL-1α and IL-1ß reduced induction of IL-10, IL-1ß and TNF, and IL-6 and TNF, respectively. However, interference of IL-1α and not IL-1ß signaling notably augmented susceptibility of macrophages to Brucella infection which indicates that IL-1α is required for a downstream signaling cascade of innate immunity for efficient clearance of Brucella. This protection requires binding to interleukin-1 receptor (IL-1R) mediated by myeloid differentiation factor 88 (MyD88) signaling and associated with increased lysosomal-mediated killing and nitric oxide (NO) production. Expression of pro-inflammatory cytokines was observed to be mediated via NF-κB-p50, HIF-1α and CEBPA, but negatively controlled by CEBPB while transcription of some important phagolysosomal genes was regulated via CEBPA and c-Jun which indicates the important role of these transcription factors in the control of Brucella infection in macrophages via IL-1α signaling pathway.


Assuntos
Brucella abortus/patogenicidade , Interleucina-1alfa/imunologia , Macrófagos/imunologia , Óxido Nítrico/imunologia , Animais , Imunidade Inata , Interleucina-1alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/microbiologia , Camundongos , Viabilidade Microbiana , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Células RAW 264.7 , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
10.
Fish Shellfish Immunol ; 89: 420-427, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974221

RESUMO

As an important pathogen in aquaculture, Pseudomonas plecoglossicida has caused heavy losses. It was determined with RNA-seq that the expression of a LysR-type transcriptional regulator gene (L321_20267) of P. plecoglossicida at 18 °C was significantly higher than that at 28 °C, which was verified by quantitative real-time PCR (qRT-PCR). RNAi significantly reduced the content of L321_20267 mRNA in P. plecoglossicida, with a maximal decrease of 90.63%. Compared with the wild-type strain, infection with the L321_20267-RNAi strain resulted in a 50% reduction in mortality and an onset time delay of Epinephelus coioides, as well as alleviation of the symptoms in E. coioides spleens. Compared with the wild-type strain of P. plecoglossicida, the L321_20267-RNAi strain resulted in a significant change in the spleen transcriptome of infected E. coioides. The results of GO and KEGG analysis showed that genes of serine hydrolase activity, the antigen processing and presentation pathway, the B cell receptor signalling pathway and the chemokine signalling pathway were most affected by the L321_20267 gene of P. plecoglossicida. Meanwhile, the immune genes were related to different numbers of miRNAs and lncRNAs, and some miRNAs were related to more than one gene. The results indicated that 1. L321_20267 is a virulence gene of P. plecoglossicida; 2. the upregulation of the immune pathways facilitated E. coioides to remove the L321_20267-RNAi strain compared with the wild-type strain of P. plecoglossicida; and 3. the immune genes were regulated by miRNA and lncRNA in a complex manner.


Assuntos
Proteínas de Bactérias/imunologia , Bass/imunologia , Imunidade Inata , Pseudomonas/fisiologia , Fatores de Transcrição/imunologia , Animais , Genes Bacterianos/imunologia , Pseudomonas/genética
11.
Mol Immunol ; 111: 43-52, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959420

RESUMO

Salmonella enterica serovar Typhimurium (S. Typhimurium) changes the structure of its lipopolysaccharide (LPS) in response to the environment. The two main LPS variants found in S. Typhimurium correspond to LPS with a hepta-acylated lipid A (LPS 430) and LPS with modified phosphate groups on its lipid A (LPS 435). We have previously shown that these modified LPS have a lower capacity than wild type (WT) LPS to induce the production of pro-inflammatory cytokines in mice. Nevertheless, it is not know if LPS 430 and LPS 435 could also subvert the innate immune responses in human cells. In this study, we found that LPS 430 and LPS 435 were less efficient than WT LPS to induce the production of pro-inflammatory cytokines by human monocytes, in addition we found a decreased dimerization of the TLR4/MD-2 complex in response to LPS 430, suggesting that structurally modified LPS are sensed differently than WT LPS by this receptor; however, LPS 430 and 435 induced similar activation of the transcription factors NF-κB p65, IRF3, p38 and ERK1/2 than WT LPS. Microarray analysis of LPS 430- and LPS 435-activated monocytes revealed a gene transcription profile with differences only in the expression levels of microRNA genes compared to the profile induced by WT LPS, suggesting that the lipid A modifications present in LPS 430 and LPS 435 have a moderate effect on the activation of the human TLR4/MD-2 complex. Our results are relevant to understand LPS modulation of immune responses and this knowledge could be useful for the development of novel adjuvants and immunomodulators.


Assuntos
Citocinas/imunologia , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Antígeno 96 de Linfócito/imunologia , Monócitos/imunologia , Salmonella typhimurium/imunologia , Receptor 4 Toll-Like/imunologia , Acilação/imunologia , Dimerização , Humanos , Inflamação/microbiologia , Lipídeo A/imunologia , Monócitos/microbiologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Transdução de Sinais/imunologia , Fatores de Transcrição/imunologia , Transcrição Genética/imunologia
12.
Infect Immun ; 87(5)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833335

RESUMO

Numerous factors have, to date, been identified as playing a role in the regulation of Agr activity in Staphylococcus aureus, including transcription factors, antisense RNAs, and host elements. Herein we investigated the product of SAUSA300_1984 (termed MroQ), a transmembrane Abi-domain/M79 protease-family protein, as a novel effector of this system. Using a USA300 mroQ mutant, we observed a drastic reduction in proteolysis, hemolysis, and pigmentation that was fully complementable. This appears to result from diminished agr activity, as transcriptional analysis revealed significant decreases in expression of both RNAII and RNAIII in the mroQ mutant. Such effects appear to be direct, rather than indirect, as known agr effectors demonstrated limited alterations in their activity upon mroQ disruption. A comparison of RNA sequencing data sets for both mroQ and agr mutants revealed a profound overlap in their regulomes, with the majority of factors affected being known virulence determinants. Importantly, the preponderance of alterations in expression were more striking in the agr mutant, indicating that MroQ is necessary, but not sufficient, for Agr function. Mechanism profiling revealed that putative residues for metalloprotease activity within MroQ are required for its Agr-controlling effect; however, this was not wielded at the level of AgrD processing. Virulence assessment demonstrated that both mroQ and agr mutants exhibited increased formation of renal abscesses but decreased skin abscess formation alongside diminished dermonecrosis. Collectively, we present the characterization of a novel agr effector in S. aureus which would appear to be a direct regulator, potentially functioning via interaction with the AgrC histidine kinase.


Assuntos
Proteínas de Bactérias/imunologia , Regulação Bacteriana da Expressão Gênica/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Fatores de Transcrição/imunologia , Fatores de Virulência/imunologia , Animais , Proteínas de Bactérias/genética , Feminino , Regulação Bacteriana da Expressão Gênica/genética , Humanos , Camundongos , Modelos Animais , Infecções Estafilocócicas/genética , Staphylococcus aureus/genética , Fatores de Transcrição/genética , Fatores de Virulência/genética
13.
Cell Host Microbe ; 25(4): 602-616.e7, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30902577

RESUMO

Establishing the balance between positive and negative innate immune mechanisms is crucial for maintaining homeostasis. Here we uncover the regulatory crosstalk between two previously unlinked innate immune receptor families: RIG-I, an anti-viral cytosolic receptor activated type I interferon production, and NLR (nucleotide-binding domain, leucine repeat domain-containing protein). We show that NLRP12 dampens RIG-I-mediated immune signaling against RNA viruses by controlling RIG-I's association with its adaptor MAVS. The nucleotide-binding domain of NLRP12 interacts with the ubiquitin ligase TRIM25 to prevent TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. NLRP12 also enhances RNF125-mediated, Lys48-linked degradative ubiquitination of RIG-I. Vesicular stomatitis virus (VSV) infection downregulates NLRP12 expression to allow RIG-I activation. Myeloid-cell-specific Nlrp12-deficient mice display a heightened interferon and TNF response and are more resistant to VSV infection. These results indicate that NLRP12 functions as a checkpoint for anti-viral RIG-I activation.


Assuntos
Proteína DEAD-box 58/imunologia , Proteínas de Ligação a DNA/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Fatores de Transcrição/imunologia , Animais , Proteína DEAD-box 58/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Interferons/genética , Interferons/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Fatores de Transcrição/genética , Ubiquitinação
14.
Plant Mol Biol ; 99(4-5): 299-316, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30706286

RESUMO

KEY MESSAGE: Transcriptomic analysis resulted in the upregulation of the genes related to common defense mechanisms for black spot and the downregulation of the genes related to photosynthesis and cell wall modification for powdery mildew. Plant pathogenic fungi successfully colonize their hosts by manipulating the host defense mechanisms, which is accompanied by major transcriptome changes in the host. To characterize compatible plant pathogen interactions at early stages of infection by the obligate biotrophic fungus Podosphaera pannosa, which causes powdery mildew, and the hemibiotrophic fungus Diplocarpon rosae, which causes black spot, we analyzed changes in the leaf transcriptome after the inoculation of detached rose leaves with each pathogen. In addition, we analyzed differences in the transcriptomic changes inflicted by both pathogens as a first step to characterize specific infection strategies. Transcriptomic changes were analyzed using next-generation sequencing based on the massive analysis of cDNA ends approach, which was validated using high-throughput qPCR. We identified a large number of differentially regulated genes. A common set of the differentially regulated genes comprised of pathogenesis-related (PR) genes, such as of PR10 homologs, chitinases and defense-related transcription factors, such as various WRKY genes, indicating a conserved but insufficient PTI [pathogen associated molecular pattern (PAMP) triggered immunity] reaction. Surprisingly, most of the differentially regulated genes were specific to the interactions with either P. pannosa or D. rosae. Specific regulation in response to D. rosae was detected for genes from the phenylpropanoid and flavonoid pathways and for individual PR genes, such as paralogs of PR1 and PR5, and other factors of the salicylic acid signaling pathway. Differently, inoculation with P. pannosa leads in addition to the general pathogen response to a downregulation of genes related to photosynthesis and cell wall modification.


Assuntos
Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Folhas de Planta/genética , Folhas de Planta/imunologia , Rosa/genética , Rosa/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Proteínas de Arabidopsis , Ascomicetos/patogenicidade , Quitinases/genética , Flavonoides/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/imunologia , Genes de Plantas/genética , Genes de Plantas/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade , Padrões Moleculares Associados a Patógenos/metabolismo , Doenças das Plantas/imunologia , Reguladores de Crescimento de Planta/genética , Reguladores de Crescimento de Planta/imunologia , Folhas de Planta/metabolismo , Folhas de Planta/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Rosa/metabolismo , Ácido Salicílico , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
15.
Dev Comp Immunol ; 95: 19-27, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30708026

RESUMO

The miR-317 has been revealed to involve in the reproductive response and the larval ovary morphogenesis of Drosophila. However, whether the miR-317 can also regulate Drosophila innate immune responses, which remains unclear to date. Here we have verified that miR-317 can directly target the 3'UTR of Dif-Rc to down-regulate the expression levels of AMP Drs to negatively control Drosophila Toll immune response in vivo and vitro. Specially, the Dif is an important transcription factor of Toll pathway with four transcripts (Dif-Ra, Dif-Rb, Dif-Rc and Dif-Rd). Our results show that miR-317 only targets to Dif-Rc, but not Dif-Ra/b/d, implying that miRNAs can regulate different isoforms of an alternative splicing gene to fine tune immune responses and maintain homeostasis in post-transcriptional level. Furthermore, we have demonstrated that the miR-317 sponge can restore the expression levels of Drs and Dif-Rc at mRNA and protein levels. Remarkably, during Gram-positive bacterial infection, the overexpressed miR-317 flies have poor survival outcome, whereas the knockout miR-317 flies have favorable survival compared to the control group, respectively, suggesting that the miR-317 might play a key role in Drosophila survival. Taken together, our current works not only reveal an innate immune function and a novel regulation pattern of miR-317, but also provide a new insight into the underlying molecular mechanisms of immunity disorder influencing on Drosophila survival.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , MicroRNAs/metabolismo , Receptores Toll-Like/metabolismo , Fatores de Transcrição/genética , Processamento Alternativo , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/imunologia , Proteínas de Drosophila/imunologia , Drosophila melanogaster/microbiologia , Regulação da Expressão Gênica/imunologia , Infecções por Bactérias Gram-Positivas/mortalidade , Imunidade Inata/genética , Masculino , MicroRNAs/genética , MicroRNAs/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Fatores de Transcrição/imunologia
16.
Fish Shellfish Immunol ; 87: 297-306, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30682407

RESUMO

Relish is a transcription factor and forms an important part of the immune deficiency signaling pathway. In the current study, a Relish homolog was cloned from the hemolymph of Scylla paramamosain using RT-PCR and RACE. The full length cDNA of Relish consists of 4263 base pairs (bp), including a 3552 bp open reading frame encoding a 1184 amino acid protein. The data showed that Relish was highly expressed in the gonad and digestive organs of S. paramamosain. Furthermore, the expression of Relish was up-regulated by infection with white spot syndrome virus (WSSV) or Vibrio alginolyticus. When Relish was knocked down, immune genes such as Janus Kinase, signal transducer and activator of transcription, crustin antimicrobial peptide, prophenoloxidase, C-type-lectin and myosin-II-essential-light-chain-like-protein were significantly down-regulated (P < 0.01), and Toll-like receptor was significantly up-regulated (P < 0.01) in hemocytes. The mortality of WSSV-infected or V. alginolyticus-infected crabs was enhanced following Relish knockdown. Thus, Relish is very important in the progression of WSSV and V. alginolyticus infection. It was found that Relish knockdown caused the highest level of apoptosis in the disease-free group, and higher levels of apoptosis in the WSSV group and V. alginolyticus group compared with that in the control group. Knockdown of Relish influenced the activity of phenoloxidase (PO) and superoxide dismutase (SOD), and total hemocyte count (THC) following WSSV or V. alginolyticus infection, indicating that Relish plays a regulatory role in the immune response to WSSV or V. alginolyticus infection in crabs. Thus, we conclude that Relish may anticipate host defense mechanisms against pathogen infection by affecting apoptosis, THC, PO activity and SOD activity.


Assuntos
Braquiúros/genética , Braquiúros/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Perfilação da Expressão Gênica , Filogenia , Alinhamento de Sequência , Fatores de Transcrição/química , Vibrio alginolyticus/fisiologia , Vírus da Síndrome da Mancha Branca 1/fisiologia
17.
Biochem Biophys Res Commun ; 509(3): 700-706, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30611571

RESUMO

Nuclear factor-κB (NF-κB) is a crucial transcription factor family involved in the regulation of immune and inflammatory responses and cell survival. The linear ubiquitin chain assembly complex (LUBAC), composed of the HOIL-1L, HOIP, and SHARPIN subunits, specifically generates Met1-linked linear ubiquitin chains through the ubiquitin ligase activity in HOIP, and activates the NF-κB pathway. We recently identified a chemical inhibitor of LUBAC, which we named HOIPIN-1 (HOIP inhibitor-1). To improve the potency of HOIPIN-1, we synthesized 7 derivatives (HOIPIN-2∼8), and analyzed their effects on LUBAC and NF-κB activation. Among them, HOIPIN-8 suppressed the linear ubiquitination activity by recombinant LUBAC at an IC50 value of 11 nM, corresponding to a 255-fold increase over that of HOIPIN-1. Furthermore, as compared with HOIPIN-1, HOIPIN-8 showed 10-fold and 4-fold enhanced inhibitory activities on LUBAC- and TNF-α-induced NF-κB activation respectively, without cytotoxicity. These results indicated that HOIPIN-8 is a powerful tool to explore the physiological functions of LUBAC.


Assuntos
Anti-Inflamatórios/farmacologia , NF-kappa B/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Células A549 , Anti-Inflamatórios/química , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Células HEK293 , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Fatores de Transcrição/imunologia , Ubiquitina/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação/efeitos dos fármacos
18.
Nat Immunol ; 20(3): 288-300, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692620

RESUMO

Although tissue-resident memory T cells (TRM cells) have been shown to regulate host protection in infectious disorders, their function in inflammatory bowel disease (IBD) remains to be investigated. Here we characterized TRM cells in human IBD and in experimental models of intestinal inflammation. Pro-inflammatory TRM cells accumulated in the mucosa of patients with IBD, and the presence of CD4+CD69+CD103+ TRM cells was predictive of the development of flares. In vivo, functional impairment of TRM cells in mice with double knockout of the TRM-cell-associated transcription factors Hobit and Blimp-1 attenuated disease in several models of colitis, due to impaired cross-talk between the adaptive and innate immune system. Finally, depletion of TRM cells led to a suppression of colitis activity. Together, our data demonstrate a central role for TRM cells in the pathogenesis of chronic intestinal inflammation and suggest that these cells could be targets for future therapeutic approaches in IBD.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colite/imunologia , Memória Imunológica/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Fatores de Transcrição/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Doença Crônica , Colite/genética , Colite/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Memória Imunológica/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo/deficiência , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
19.
J Nanobiotechnology ; 17(1): 6, 2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30660182

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) infection remains a global public health issue, especially in Asia. Due to the emergence of antibiotic-resistant strains and the complexity of H. pylori infection, conventional vaccination is the best way to control the disease. Our previous study found that the N-acetyl-neuroaminyllactose-binding hemagglutinin protein (HpaA) is an effective protective antigen for vaccination against H. pylori infection, and intranasal immunization with the immunodominant HpaA epitope peptide (HpaA 154-171, P22, MEGVLIPAGFIKVTILEP) in conjunction with a CpG adjuvant decreased bacterial colonization in H. pylori-infected mice. However, to confer more robust and effective protection against H. pylori infection, an optimized delivery system is needed to enhance the P22-specific memory T cell response. RESULTS: In this study, an intranasal nanoemulsion (NE) delivery system offering high vaccine efficacy without obvious cytotoxicity was designed and produced. We found that this highly stable system significantly prolonged the nasal residence time and enhanced the cellular uptake of the epitope peptide, which powerfully boosted the specific Th1 responses of the NE-P22 vaccine, thus reducing bacterial colonization without CpG. Furthermore, the protection efficacy was further enhanced by combining the NE-P22 vaccine with CpG. CONCLUSION: This epitope-loaded nanoemulsion delivery system was shown to extend antigen release and elicit potent Th1 response, it is an applicable delivery system for intranasal vaccine against H. pylori.


Assuntos
Portadores de Fármacos , Epitopos , Infecções por Helicobacter , Helicobacter pylori/imunologia , Fatores de Transcrição/imunologia , Administração Intranasal , Animais , Antígenos de Bactérias/imunologia , Sistemas de Liberação de Medicamentos , Emulsões , Epitopos/administração & dosagem , Epitopos/imunologia , Feminino , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas , Vacinas
20.
Mol Plant Microbe Interact ; 32(6): 673-684, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30598046

RESUMO

Mitogen-activated protein kinase (MAPK) cascades serve as unified signaling modules in plant development and defense response. Previous reports demonstrated an essential role of Arabidopsis GLIP1, a member of the GDSL-like-motif lipase family, in both local and systemic resistance. GLIP1 expression is highly induced by pathogen attack. However, the one or more signaling pathways involved are unknown. Here, we report that two pathogen-responsive MAPKs, MPK3 and MPK6, are implicated in regulating gene expression of GLIP1 as well as GLIP3 and GLIP4. After gain-of-function activation, MPK3 and MPK6 can strongly induce the expression of GLIP1, GLIP3, and GLIP4. Both GLIP1 and GLIP3 contribute to the plant resistance to Botrytis cinerea. WRKY33, a MPK3/MPK6 substrate, is essential for the MPK3/MPK6-dependent GLIP1 induction. In addition, WRKY2 and WRKY34, two close homologs of WRKY33, have a minor effect in MPK3/MPK6-regulated GLIP1 expression in B. cinerea-infected plants. Chromatin immunoprecipitation-quantitative polymerase chain reaction analysis demonstrated that the GLIP1 gene is a direct target of WRKY33. In addition, we demonstrated that MPK3/MPK6-induced GLIP1 expression is independent of ethylene and jasmonic acid, two important hormones in plant defense. Our results provide insights into the regulation of the GLIP family at the transcriptional level in plant immunity.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Hidrolases de Éster Carboxílico , Resistência à Doença , Regulação da Expressão Gênica de Plantas , Proteínas Quinases Ativadas por Mitógeno , Fatores de Transcrição , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/imunologia , Arabidopsis/microbiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/imunologia , Botrytis/fisiologia , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/imunologia , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Fatores de Transcrição/imunologia
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