Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.400
Filtrar
1.
Int Immunopharmacol ; 95: 107408, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33915488

RESUMO

OBJECTIVE: Sepsis, as a disease affecting the microcirculation and tissue perfusion, results in tissue hypoxia and multiple organ dysfunctions. Bone mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) have been demonstrated to transfer trivial molecules (proteins/peptides, mRNA, microRNA and lipids) to alleviate sepsis. We sought to define the function of microRNA (miR)-17 carried in BMSC-EVs in sepsis. METHODS: The purity of the extracted BMSCs was identified and confirmed by detection of the surface markers by flow cytometry, followed by osteoblastic, adipogenic, and chondrocyte differentiation experiments. Subsequently, EVs were collected from the medium of BMSCs. The uptake of PKH-67-labeled BMSC-EVs or EVs carrying cy3-miR-17 by RAW264.7 cells was observed under laser confocal microscopy. Furthermore, a series of gain- and loss-of-function approaches were conducted to test the effects of LPS, miR-17 and BRD4 on the inflammatory factors (IL-1ß, IL-6 and TNF-α), number of M1 macrophages and M2 macrophages, inflammatory-related signal pathway factors (EZH2, c-MYC and TRAIL), macrophage proliferation, and apoptosis in sepsis. The survival rates were measured in vivo. RESULTS: BMSC-EVs was internalized by the RAW264.7 cells. BDR4 was verified as a target of miR-17, while the expression pattern of miR-17 was upregulated in BMSC-EVs. MiR-17 carried by BMSC-EVs inhibited LPS-induced inflammation and apoptosis of RAW264.7 cells, but improved the viability of RAW264.7 cells. Next, in vitro experiments supported that miR-17 inhibited LPS-induced inflammation in RAW264.7 cells through BRD4/EZH2/TRAIL axis. BRD4 overexpression reversed the effects of miR-17. Moreover, the therapeutic function of BMSC-EVs carried miR-17 was verified by in vivo experiments. CONCLUSIONS: MiR-17 derived from BMSCs-EVs regulates BRD4-mediated EZH2/TRAIL axis to essentially inhibit LPS-induced macrophages inflammation.


Assuntos
Vesículas Extracelulares , Macrófagos/imunologia , Células-Tronco Mesenquimais , MicroRNAs , Sepse/imunologia , Animais , Apoptose , Células Cultivadas , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Humanos , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Fatores de Transcrição/imunologia
2.
Mol Cell ; 81(11): 2477-2493.e10, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33891860

RESUMO

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1+ progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Imunidade Celular , Coriomeningite Linfocítica/genética , Neoplasias/genética , Fatores de Transcrição/genética , Doença Aguda , Atlas como Assunto , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/patologia , Cromatina/química , Cromatina/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Neoplasias/imunologia , Neoplasias/patologia , Análise de Componente Principal , Análise de Célula Única , Fatores de Transcrição/classificação , Fatores de Transcrição/imunologia , Transcrição Genética , Transposases/genética , Transposases/metabolismo
3.
Medicine (Baltimore) ; 100(9): e24556, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655922

RESUMO

ABSTRACT: Previous studies from various countries have reported anti-dense fine speckled pattern (DFS)70 antibody prevalence but few studies have been from Asia. We investigated the prevalence of anti-DFS70 autoantibodies in a Japanese cohort of healthy individuals (HI) and patients with antinuclear antibody-associated autoimmune rheumatic diseases (AARD).Enzyme-linked immunosorbent assay and indirect immunofluorescence were performed using samples from 250 HI and 276 AARD patients.The overall anti-DFS70 antibody prevalence in HI was 16.4%, with 12.8% for males and 20.0% for females (sex difference; P = .12). In AARD patients, the anti-DFS70 antibody prevalence in systemic lupus erythematosus, mixed connective tissue disease, systemic sclerosis, dermatomyositis and polymyositis (DM/PM), Sjögren syndrome, and rheumatoid arthritis (RA) was 22.1%, 14.3%, 14.3%, 3.0%, 21.3%, and 18.1%, respectively (no significant difference between AARD patients except DM/PM and HI). The prevalence of isolated anti-DFS70 antibody in HI and all AARD patients excluding RA was 14.8% (37/250) and 4.4% (9/204), respectively (P  < .01 vs HI). Among anti-DFS70 antibody-positive cases, 63.4% (26/41) were DFS pattern by IIF and 23.5% (8/34) were HI and AARD patients excluding RA, respectively.The anti-DFS70 antibody prevalence in HI and AARD patients in Japan was similar. Furthermore, the anti-DFS70 antibody prevalence in HI and AARD in Japan is higher than in HI and AARD in regions other than Asia. This makes AARD differential diagnosis by antinuclear antibody screening difficult.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Reumáticas/sangue , Fatores de Transcrição/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antinucleares/imunologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Doenças Reumáticas/imunologia , Adulto Jovem
4.
Biochem Biophys Res Commun ; 552: 164-169, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33751933

RESUMO

Human mesenchymal stem cells (MSCs) are known to have anti-inflammatory and immunomodulatory functions; thus, several MSC products have been applied as cell therapy in clinical trials worldwide. Recent studies have demonstrated that MSC spheroids have superior anti-inflammatory and immunomodulatory functions to a single cell suspension. Current methods to prepare MSC spheroids include hanging drop, concave microwell aggregation, spinner flask, and gravity circulation. However, all these methods have limitations such as low scalability, easy cell clumping, low viability, and irregular size distribution. Here, we present a nano-patterned culture plasticware named PAMcell™ 3D plate to overcome these limitations. Nano-sized silica particles (700 nm) coated with RGD peptide were arrayed into fusiform onto the PLGA film. This uniform array enabled the seeded MSCs to grow only on the silica particles, forming uniform-sized semi-spheroids within 48 h. These MSC spheroids have been shown to have enhanced stemness, anti-inflammatory, and immunomodulatory functions, as revealed by the increased expression of stem cell markers (Oct4, Sox2, and Nanog), anti-inflammatory (IL-10, TSG6, and IDO), and immunomodulatory molecules (HGF, VEGF, CXCR4) both at mRNA and protein expression levels. Furthermore, these MSC spheroids demonstrated an increased palliative effect on glycemic control in a multiple low-dose streptozotocin-induced diabetes model compared with the same number of MSC single cell suspensions. Taken together, this study presents a new method to produce uniform-sized MSC spheroids with enhanced anti-inflammatory and immunomodulatory functions in vitro and in vivo.


Assuntos
Tecido Adiposo/citologia , Anti-Inflamatórios/imunologia , Técnicas de Cultura de Células/métodos , Fatores Imunológicos/imunologia , Células-Tronco Mesenquimais/imunologia , Esferoides Celulares/imunologia , Animais , Técnicas de Cultura de Células/instrumentação , Células Cultivadas , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/terapia , Expressão Gênica/imunologia , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Esferoides Celulares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
5.
PLoS Pathog ; 17(3): e1009345, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33651854

RESUMO

Sensing and responding to environmental signals is critical for bacterial pathogens to successfully infect and persist within hosts. Many bacterial pathogens sense temperature as an indication they have entered a new host and must alter their virulence factor expression to evade immune detection. Using secondary structure prediction, we identified an RNA thermosensor (RNAT) in the 5' untranslated region (UTR) of tviA encoded by the typhoid fever-causing bacterium Salmonella enterica serovar Typhi (S. Typhi). Importantly, tviA is a transcriptional regulator of the critical virulence factors Vi capsule, flagellin, and type III secretion system-1 expression. By introducing point mutations to alter the mRNA secondary structure, we demonstrate that the 5' UTR of tviA contains a functional RNAT using in vitro expression, structure probing, and ribosome binding methods. Mutational inhibition of the RNAT in S. Typhi causes aberrant virulence factor expression, leading to enhanced innate immune responses during infection. In conclusion, we show that S. Typhi regulates virulence factor expression through an RNAT in the 5' UTR of tviA. Our findings demonstrate that limiting inflammation through RNAT-dependent regulation in response to host body temperature is important for S. Typhi's "stealthy" pathogenesis.


Assuntos
Regulação Bacteriana da Expressão Gênica/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Salmonella typhi/genética , Temperatura , Febre Tifoide/microbiologia , Proteínas de Bactérias/metabolismo , Humanos , Evasão da Resposta Imune/imunologia , Salmonella typhi/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
6.
Eur J Immunol ; 51(2): 311-318, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32845012

RESUMO

Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+ mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi (MHCIIhi CD80hi ) compartment into mTECA/hi (CD24- Sca1- ), mTECB/hi (CD24+ Sca1- ), and mTECC/hi (CD24+ Sca1+ ). While mTECA/hi included mostly Aire-expressing cells, mTECB/hi contained Aire+ and Aire- cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi , mTECB/hi , and mTECC/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTECC/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Queratinócitos/imunologia , Timo/imunologia , Fatores de Transcrição/genética , Animais , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/imunologia
7.
Acta Neurol Scand ; 143(2): 131-139, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32762037

RESUMO

BACKGROUND: Myositis-specific autoantibodies (MSAs) have been found to be present predominantly in patients with idiopathic inflammatory myopathies (IIMs). This study aimed to investigate the prevalence of MSAs and their associated complications in a cohort of patients with IIMs. METHODS: This was a multicentered prospective study. Consecutive adult Chinese patients with IIMs in the regional hospitals in Hong Kong were followed up from July 2016 to January 2018. Clinical characteristics, treatment history, and disease complications were documented. A commercially available immunoblot assay was used to detect the MSAs. RESULTS: Out of the 201 patients studied, at least one MSA was found in 63.2% of patients. The most common among the identified MSAs were the anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) and the anti-transcriptional intermediary factor 1-gamma antibody (anti-TIF1-γ Ab) (both 13.9%), followed by anti-Jo-1 antibody (12.4%). Anti-MDA5 was present exclusively in dermatomyositis (DM) and was strongly associated with digital ulcers, amyopathy, and rapidly progressive interstitial lung disease (RP-ILD). Anti-TIF1γ was strongly associated with refractory rash and malignancy. Independent risk factors of RP-ILD included anti-MDA5 (OR 14.5), clinically amyopathic DM (OR 13.9), and history of pulmonary tuberculosis (OR 12.2). Cox regression analysis showed that anti-TIF1γ (HR 3.55), DM (HR 3.82), and family history of cancer (HR 3.40) were independent predictors of malignancy. CONCLUSIONS: MSA testing enables dividing of patients with IIMs into phenotypically homogeneous subgroups and prediction of potentially life-threatening complications.


Assuntos
Autoanticorpos/imunologia , Miosite/imunologia , Adulto , Anticorpos Antinucleares/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/classificação , Miosite/patologia , Fatores de Transcrição/imunologia
8.
Am J Physiol Gastrointest Liver Physiol ; 320(1): G54-G65, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33146549

RESUMO

We previously demonstrated that water intake increased mesenteric lymph flow and the total flux of IL-22 in rat jejunum. The drained water and the higher permeability of albumin in the jejunal microcirculation contributed to increase the lymph flow and IL-22 transport via the activation of great bulk flow in the jejunal villi. To address the effects of water intake-mediated great bulk flow-dependent mechanical force on jejunal physiological function and immunological regulation of innate lymphoid cells (ILC)-3, we examined the effects of shear stress stimulation on cultured rat myofibroblast cells. Next, we investigated the effects of water intake on podoplanin and IL-22 expressions in cultured human intestinal epithelial cells and rat in vivo jejunal preparations, respectively. Shear stress stimulation of the myofibroblast cells induced ATP release via an activation of cell surface F1/F0 ATP synthase. ATP produced podoplanin expression in the intestinal epithelial cells. Water intake accelerated immunohistochemical expressions of podoplanin and IL-22 in the interepithelial layers and lamina propria of the jejunum. ATP dose-dependently increased IL-22 mRNA expression in ILC-3, which are housed in the lamina propria. Water intake also increased immunohistochemical and mRNA expressions of ecto-nucleoside triphosphate diphosphohydrolases 2 and 5 in jejunal villi. In conclusion, water intake-mediated shear stress stimulation-dependent ATP release from myofibroblast cells maintains higher tissue colloid osmotic pressure in the jejunal microcirculation through podoplanin upregulation in the interepithelial layers. ATP induces IL-22 mRNA expression in ILC-3 in jejunal villi, which may contribute to regulation of mucosal immunity in small intestine.NEW & NOTEWORTHY We investigated effects of shear stress stimulation on cultured myofibroblast cells and water intake on podoplanin and IL-22 expressions in rat jejunal villi. The stimulation induced ATP release from the cells. Water intake accelerated podoplanin and IL-22 expression levels. ATP increased IL-22 mRNA expression in innate lymphoid cells (ILC)-3. Hence, water intake maintains higher osmotic pressure in the jejunal villi through ATP release and podoplanin upregulation. Water intake may regulate the mucosal immunity.


Assuntos
Trifosfato de Adenosina/metabolismo , Ingestão de Líquidos , Imunidade Inata/imunologia , Glicoproteínas de Membrana/metabolismo , Miofibroblastos/imunologia , Trifosfato de Adenosina/imunologia , Ingestão de Líquidos/imunologia , Humanos , Imunidade nas Mucosas/fisiologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Miofibroblastos/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
9.
J Agric Food Chem ; 69(1): 447-458, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33347291

RESUMO

MYB transcription factors (TFs) participate in many biological processes. However, the molecular mechanisms by which MYB TFs affect plant resistance to apple ring rot remain poorly understood. Here, the R2R3-MYB gene MdMYB73 was cloned from "Royal Gala" apples and functionally characterized as a positive regulator of the defense response to Botryosphaeria dothidea. qRT-PCR and GUS staining demonstrated that MdMYB73 was strongly induced in apple fruits and transgenic calli after inoculation with B. dothidea. MdMYB73 overexpression improved resistance to B. dothidea in apple calli and fruits, while MdMYB73 suppression weakened. Increased resistance to B. dothidea was also observed in MdMYB73-expressing Arabidopsis thaliana. Interestingly, salicylic acid (SA) contents and the expression levels of genes related with SA synthesis and signaling were greater in MdMYB73-overexpressing plant materials compared to wild-type controls after inoculation, suggesting that MdMYB73 might enhance resistance to B. dothidea via the SA pathway. Finally, we discovered that MdMYB73 interacts with MdWRKY31, a positive regulator of B. dothidea. Together, MdWRKY31 and MdMYB73 enhanced B. dothidea resistance in apples. Our results clarify the mechanisms by which MdMYB73 improves resistance to B. dothidea and suggest that resistance may be affected by regulating the SA pathway.


Assuntos
Ascomicetos/fisiologia , Malus/imunologia , Doenças das Plantas/imunologia , Proteínas de Plantas/imunologia , Ácido Salicílico/imunologia , Fatores de Transcrição/imunologia , Resistência à Doença , Regulação da Expressão Gênica de Plantas , Malus/genética , Malus/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Fatores de Transcrição/genética
10.
Front Immunol ; 11: 562138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133072

RESUMO

Objective: Anti-DFS70 antibodies correlating with the nuclear dense fine speckled (DFS) pattern in the HEp-2 indirect immunofluorescence assay (IFA) are less common in patients with systemic autoimmune rheumatic disease (SARD) than in healthy subjects and their clinical associations remain elusive. We hosted a multi-center HEp-2 IFA training program to improve the ability of clinical laboratories to recognize the DFS pattern and to investigate the prevalence and relevance of anti-DFS70 antibodies. Methods: DFS pattern sera identified by HEp-2 IFA in 29 centers in China were redirected to a central laboratory for anti-DFS70 testing by line immunoblot assay (LIA), enzyme-linked immunosorbent assay (ELISA), and IFA with HEp-2 ELITE/DFS70-KO substrate. Anti-extractable nuclear antigen antibodies were measured by LIA and the clinical relevance was examined in adult and pediatric patients. Results: HEp-2 IFA positive rate and DFS pattern in positive sera were 36.2% (34,417/95,131) and 1.7% (582/34,417) in the patient cohort, and 10.0% (423/4,234) and 7.8% (33/423) in a healthy population, respectively. Anti-DFS70 prevalence among sera presenting the DFS pattern was 96.0, 93.7, and 49.6% by ELISA, LIA, and HEp-2 ELITE, respectively. 15.5% (52/336) of adult and 50.0% (20/40) of pediatric anti-DFS70 positive patients were diagnosed with SARD. Diseases most common in anti-DFS70 positive patients were spontaneous abortion (28.0%) in adults and juvenile idiopathic arthritis (22.5%) in pediatric patients. Conclusion: Accurate DFS pattern identification increased the detection rate of anti-DFS70 antibodies by ELISA and LIA. Anti-DFS70 antibodies are remarkably high in cases of spontaneous abortion and in pediatric SARD patients, but not prevalent in adult SARD patients.


Assuntos
Aborto Espontâneo/epidemiologia , Aborto Espontâneo/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Artrite Juvenil/epidemiologia , Artrite Juvenil/imunologia , Autoanticorpos/sangue , Fatores de Transcrição/imunologia , Aborto Espontâneo/sangue , Adulto , Artrite Juvenil/sangue , Autoanticorpos/imunologia , Criança , China/epidemiologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Fenótipo , Gravidez , Prevalência
11.
Nucleic Acids Res ; 48(21): 12055-12073, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33179750

RESUMO

Proper cytokine gene expression is essential in development, homeostasis and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we used enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1380 interactions between 265 TFs and 108 cytokine gene promoters. Our eY1H-derived network greatly expands the known repertoire of TF-cytokine gene interactions and the set of TFs known to regulate cytokine genes. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that can be targeted with commercially-available drugs to synergistically modulate cytokine production. Finally, we integrated the eY1H data with single cell RNA-seq and phenotypic datasets to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.


Assuntos
Linhagem da Célula/imunologia , Citocinas/genética , Redes Reguladoras de Genes/imunologia , Linfócitos/imunologia , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Linhagem da Célula/genética , Citocinas/classificação , Citocinas/imunologia , Conjuntos de Dados como Assunto , Células Dendríticas/citologia , Células Dendríticas/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfócitos/classificação , Linfócitos/citologia , Macrófagos/citologia , Macrófagos/imunologia , Anotação de Sequência Molecular , Monócitos/citologia , Monócitos/imunologia , Cultura Primária de Células , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/imunologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Análise de Célula Única , Células THP-1 , Fatores de Transcrição/classificação , Fatores de Transcrição/imunologia , Transcrição Genética , Técnicas do Sistema de Duplo-Híbrido
12.
Immunity ; 53(4): 775-792.e9, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33002412

RESUMO

Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Células Progenitoras Linfoides/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-18/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Transdução de Sinais/imunologia , Análise de Célula Única/métodos , Fator 1 de Transcrição de Linfócitos T/imunologia , Fatores de Transcrição/imunologia
13.
Immunity ; 53(4): 745-758.e4, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33010223

RESUMO

Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.


Assuntos
Elementos Facilitadores Genéticos/genética , Elementos Facilitadores Genéticos/imunologia , Células Matadoras Naturais/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Animais , Cromatina/genética , Cromatina/imunologia , Feminino , Expressão Gênica/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Toxoplasma/imunologia , Toxoplasmose/genética , Toxoplasmose/imunologia
14.
Nat Commun ; 11(1): 5332, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087697

RESUMO

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Pancreáticas/imunologia , Fatores de Transcrição/imunologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-A1/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Placenta/imunologia , Gravidez , Prognóstico , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/genética
15.
Rinsho Shinkeigaku ; 60(11): 768-772, 2020 Nov 27.
Artigo em Japonês | MEDLINE | ID: mdl-33115992

RESUMO

A 74-year-old man was administered nivolumab to treat recurrent squamous cell carcinoma of the lungs. He developed fatigue, redness on the front of his neck, muscle weakness, and difficulty in swallowing after receiving the third course of nivolumab. Physical and neurological examinations showed proximal limb muscle weakness, periorbital erythema, and erythema of the front of his neck as well as fingers. Laboratory investigations revealed elevated serum CK and aldolase levels, and he was diagnosed with dermatomyositis. We initiated steroid pulse therapy and intravenous immunoglobulin therapy; however, he died of advanced lung cancer. Immune checkpoint inhibitor-induced neuromuscular disease is increasingly being observed in clinical practice. We report a rare case of dermatomyositis with squamous cell carcinoma of the lungs secondary to nivolumab treatment.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Dermatomiosite/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Idoso , Autoanticorpos , Dermatomiosite/diagnóstico , Dermatomiosite/terapia , Evolução Fatal , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunoterapia , Masculino , Metilprednisolona/administração & dosagem , Pulsoterapia , Tacrolimo/uso terapêutico , Fatores de Transcrição/imunologia
16.
Int Immunopharmacol ; 89(Pt B): 107083, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068860

RESUMO

Acne is a common inflammatory skin disease with the dysregulation of innate and adaptive immunity. However, the underlying mechanism of acne has not been completely elucidated. In this study, we identified gene signatures and the immune-related regulatory network in acne using integrated bioinformatics methods. Here, 303 Differentially expressed genes (DEGs) and 28 Hub genes were identified in acne (GSE53795 and GSE108110), which were associated with the inflammation-related signaling pathway. Subsequently, the CIBERSORT algorithm revealed the increased proinflammatory cells in acne. Moreover, we identified 3 kinases (FGR, HCK and LYN) and 2 transcription factors (TFs) (IRF8 and ZBTB16) from DEGs as the key genes, which regulated immune cell infiltration via targeting immune-related genes in acne. The upregulated 3 kinases (FGR, HCK and LYN) and IRF8, and the downregulated ZBTB16 were also confirmed in GSE6475 and in Acne mice. Based on the expression levels of these key genes, the tissues could be divided into 2 clusters using consensus cluster analysis. GSEA analysis showed that inflammation-related signaling pathways significantly enriched in cluster 2, indicating the important role of kinase and TFs on immune regulation in acne. Finally, we found that isotretinoin and trifarotene (CD5789) treatment repressed the expression of immune genes but not the expression of the kinases and TFs, indicating that kinases and TFs may be novel therapeutic target for acne. In conclusion, 3 kinases and 2 TFs were identified and validated as key regulators in the immune-related regulatory networks in acne, providing a more comprehensive understanding and novel therapeutic targets of acne.


Assuntos
Acne Vulgar/genética , Acne Vulgar/imunologia , Regulação da Expressão Gênica , Acne Vulgar/tratamento farmacológico , Animais , Análise por Conglomerados , Biologia Computacional/métodos , Bases de Dados Genéticas , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Isotretinoína/administração & dosagem , Isotretinoína/farmacologia , Camundongos Endogâmicos BALB C , Fosfotransferases/efeitos dos fármacos , Fosfotransferases/genética , Fosfotransferases/imunologia , Mapas de Interação de Proteínas/imunologia , Retinoides/administração & dosagem , Retinoides/farmacologia , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/imunologia , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Transcriptoma/imunologia
17.
Eur J Cancer ; 140: 119-129, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33080474

RESUMO

BACKGROUND: ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. METHODS: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry. RESULTS: ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. CONCLUSIONS: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Mutação/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/imunologia , Reparo do DNA/genética , Reparo do DNA/imunologia , Proteínas de Ligação a DNA/imunologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adulto Jovem
18.
Int J Mol Sci ; 21(19)2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32992926

RESUMO

Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.


Assuntos
Macrófagos/imunologia , Progranulinas/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Fatores de Transcrição/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Macrófagos/patologia , Camundongos , Progranulinas/genética , Células RAW 264.7 , Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/genética
19.
J Agric Food Chem ; 68(42): 11726-11734, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32981311

RESUMO

Anemia is a common chronic kidney disease (CKD) complication contributing to increased morbidity and mortality. Collagen-based traditional Chinese nutraceuticals have long been used in antianemic therapies. This study aims to investigate the therapeutic effectiveness of porcine collagen hydrolysate (CH) and its underlying mechanism in the treatment of renal anemia by using adenine-induced CKD mice, RAW264.7 macrophages, and HepG2 hepatoma cells, with prolyl-hydroxyproline as a reference compound for collagen-derived hydroxyproline-containing di-/tripeptides. CH was found to alleviate renal filtering dysfunction, systemic and kidney inflammation, liver hepcidin overproduction and anemia and to increase erythropoietin production and hypoxia inducible factor (HIF)-2α stability in liver and kidney in CKD mice. Prolyl-hydroxyproline exerted direct anti-inflammatory effects on lipopolysaccharide-activated macrophages and elicited stimulating and inhibiting activities on erythropoietin expression and hepcidin overproduction, respectively, in HepG2 cells by HIF-2α activation. Overall, CH was effective in correcting renal anemia via anti-inflammatory renoprotection and HIF-2α-dependent erythropoietin and hepcidin regulation.


Assuntos
Anemia/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Colágeno/química , Eritropoetina/metabolismo , Hepcidinas/metabolismo , Hidrolisados de Proteína/administração & dosagem , Insuficiência Renal Crônica/complicações , Fatores de Transcrição/imunologia , Anemia/etiologia , Animais , Anti-Inflamatórios/química , Eritropoetina/genética , Feminino , Hepcidinas/genética , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hidrolisados de Proteína/química , Suínos , Fatores de Transcrição/genética
20.
Fish Shellfish Immunol ; 106: 866-875, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32889097

RESUMO

The innate immune response is an important line of defense against invading pathogens in invertebrates. Signaling pathways, including the IMD pathway, play critical roles in the production of antimicrobial peptides (AMPs), which induce the transcription of immune effectors that protect against bacterial invasion. In the present study, the cDNA of IMD from Eriocheir sinensis was cloned (designated EsIMD) and shown to be significantly upregulated following Gram-positive and Gram-negative bacterial infection. In vivo and in vitro studies collectively suggested that both the Gram-negative bacterium Vibrio parahemolyticus and the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis elicit the translocation of Relish. Moreover, EsIMD positively regulated EsRelish translocation from the cytoplasm to the nucleus following stimulation with both Gram-positive and Gram-negative bacteria. EsRelish knockdown in hemocytes significantly suppressed AMPs' expression. Furthermore, both Lys-type and DAP-type peptidoglycan-containing bacteria activated the IMD pathway and elicited antibacterial responses in crab. Conclusively, these findings demonstrate that both Gram-positive and Gram-negative bacteria activate IMD signaling, via a mechanism that is distinct with that by which Gram-negative bacteria activate IMD signaling in Drosophila. These findings might pave the way for a better understanding of the innate immune system and the fundamental network of the IMD signaling pathway in crustacean.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Proteínas de Artrópodes/imunologia , Braquiúros/imunologia , Fatores de Transcrição/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Proteínas de Artrópodes/genética , Bacillus subtilis , Braquiúros/genética , Braquiúros/microbiologia , Infecções por Bactérias Gram-Positivas/genética , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/veterinária , Hemócitos/imunologia , Staphylococcus aureus , Fatores de Transcrição/genética , Vibrioses/genética , Vibrioses/imunologia , Vibrioses/veterinária , Vibrio parahaemolyticus
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...