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1.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33649207

RESUMO

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.


Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Células Supressoras Mieloides/imunologia , Espécies Reativas de Oxigênio/imunologia , Aloenxertos , Animais , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Camundongos , Camundongos Knockout
2.
BMC Biol ; 21(1): 243, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37926812

RESUMO

BACKGROUND: Accumulating evidence supports that the Western diet (WD), a diet high in saturated fat and sugary drinks, contributes to the pathogenesis of anxiety disorders, which are the most prevalent mental disorders worldwide. However, the underlying mechanisms by which WD causes anxiety remain unclear. Abundant expression of taste receptor type 1 member 3 (TAS1R3) has been identified in the hypothalamus, a key brain area involved in sensing peripheral nutritional signals and regulating anxiety. Thus, we investigated the influence of excessive WD intake on anxiety and mechanisms by which WD intake affects anxiety development using wild-type (WT) and Tas1r3 deficient (Tas1r3-/-) mice fed a normal diet (ND) or WD for 12 weeks. RESULTS: WD increased anxiety in male WT mice, whereas male Tas1r3-/- mice were protected from WD-induced anxiety, as assessed by open field (OF), elevated plus maze (EPM), light-dark box (LDB), and novelty-suppressed feeding (NSF) tests. Analyzing the hypothalamic transcriptome of WD-fed WT and Tas1r3-/- mice, we found 1,432 genes significantly up- or down-regulated as a result of Tas1r3 deficiency. Furthermore, bioinformatic analysis revealed that the CREB/BDNF signaling-mediated maintenance of neuronal regeneration, which can prevent anxiety development, was enhanced in WD-fed Tas1r3-/- mice compared with WD-fed WT mice. Additionally, in vitro studies further confirmed that Tas1r3 knockdown prevents the suppression of Creb1 and of CREB-mediated BDNF expression caused by high levels of glucose, fructose, and palmitic acid in hypothalamic neuronal cells. CONCLUSIONS: Our results imply that TAS1R3 may play a key role in WD-induced alterations in hypothalamic functions, and that inhibition of TAS1R3 overactivation in the hypothalamus could offer therapeutic targets to alleviate the effects of WD on anxiety.


Assuntos
Ansiedade , Dieta Ocidental , Receptores Acoplados a Proteínas G , Animais , Masculino , Camundongos , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo , Dieta Ocidental/efeitos adversos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/genética
3.
BMC Med ; 21(1): 165, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-37118698

RESUMO

BACKGROUND: Long-term intake of a Western diet (WD), characterized by a high-fat content and sugary drinks, is hypothesized to contribute to the development of inflammatory bowel disease (IBD). Despite the identified clinical association, the molecular mechanisms by which dietary changes contribute to IBD development remain unknown. Therefore, we examined the influence of long-term intake of a WD on intestinal inflammation and the mechanisms by which WD intake affects IBD development. METHODS: Mice fed normal diet or WD for 10 weeks, and bowel inflammation was evaluated through pathohistological and infiltrated inflammatory cell assessments. To understand the role of intestinal taste receptor type 1 member 3 (TAS1R3) in WD-induced intestinal inflammation, cultured enteroendocrine cells harboring TAS1R3, subjected to RNA interference or antagonist treatment, and Tas1r3-deficient mice were used. RNA-sequencing, flow cytometry, 16S metagenomic sequencing, and bioinformatics analyses were performed to examine the involved mechanisms. To demonstrate their clinical relevance, intestinal biopsies from patients with IBD and mice with dextran sulfate sodium-induced colitis were analyzed. RESULTS: Our study revealed for the first time that intestinal TAS1R3 is a critical mediator of WD-induced intestinal inflammation. WD-fed mice showed marked TAS1R3 overexpression with hallmarks of serious bowel inflammation. Conversely, mice lacking TAS1R3 failed to exhibit inflammatory responses to WD. Mechanistically, intestinal transcriptome analysis revealed that Tas1r3 deficiency suppressed mTOR signaling, significantly increasing the expression of PPARγ (a major mucosal defense enhancer) and upregulating the expression of PPARγ target-gene (tight junction protein and antimicrobial peptide). The gut microbiota of Tas1r3-deficient mice showed expansion of butyrate-producing Clostridia. Moreover, an increased expression of host PPARγ-signaling pathway proteins was positively correlated with butyrate-producing microbes, suggesting that intestinal TAS1R3 regulates the relationship between host metabolism and gut microflora in response to dietary factors. In cultured intestinal cells, regulation of the TAS1R3-mTOR-PPARγ axis was critical for triggering an inflammatory response via proinflammatory cytokine production and secretion. Abnormal regulation of the axis was observed in patients with IBD. CONCLUSIONS: Our findings suggest that the TAS1R3-mTOR-PPARγ axis in the gut links Western diet consumption with intestinal inflammation and is a potential therapeutic target for IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Paladar , Dieta Ocidental/efeitos adversos , PPAR gama , Colite/induzido quimicamente , Colite/metabolismo , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/patologia , Serina-Treonina Quinases TOR/efeitos adversos , Butiratos/efeitos adversos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
4.
Eur J Nutr ; 61(1): 447-459, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34476568

RESUMO

PURPOSE: We aimed to investigate the link of vitamin C status with vitality and psychological functions in a cross-sectional study, and examine their causal relationship through a randomized controlled trial (RCT). METHODS: We first conducted a population-based cross-sectional investigation of healthy young adults (n = 214, 20-39 years), and analyzed the associations of serum vitamin C concentrations with vitality (fatigue and attention) and mood status (stress, depression, and positive and negative affect) using Pearson's correlation and multiple linear regression analyses. Next, we performed a double-blind RCT in healthy subjects whose serum vitamin C concentrations were inadequate (< 50 µmol/L). Subjects were randomly allocated to receive 500 mg of vitamin C twice a day for 4 weeks (n = 24) or a placebo (n = 22). We assessed vitality, which included fatigue, attention, work engagement, and self-control resources, and measured mood status, including stress, depression, positive and negative affect, and anxiety. ELISA determined serum brain-derived neurotrophic factor (BDNF), and a Stroop color-word test evaluated attention capacity and processing speed. RESULTS: In the cross-sectional data, the serum vitamin C concentration was positively associated with the level of attention (r = 0.16, p = 0.02; standardized ß = 0.21, p = 0.003), while no significant associations with the levels of fatigue and mood variables being found. In the RCT, compared to the placebo, the vitamin C supplementation significantly increased attention (p = 0.03) and work absorption (p = 0.03) with distinct tendency of improvement on fatigue (p = 0.06) and comprehensive work engagement (p = 0.07). The vitamin C supplementation did not affect mood and serum concentrations of BDNF. However, in the Stroop color-word test, the subjects supplemented with vitamin C showed better performance than those in the placebo group (p = 0.04). CONCLUSION: Inadequate vitamin C status is related to a low level of mental vitality. Vitamin C supplementation effectively increased work motivation and attentional focus and contributed to better performance on cognitive tasks requiring sustained attention. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: Cross-sectional study: KCT0005074 (cris.nih.go.kr)/1 June, 2020 (retrospectively registered). Intervention study: KCT0004276 (cris.nih.go.kr)/4 September, 2019.


Assuntos
Suplementos Nutricionais , Vitaminas , Afeto , Ácido Ascórbico , Estudos Transversais , Método Duplo-Cego , Humanos , Vitamina D , Adulto Jovem
5.
Eur J Nutr ; 59(8): 3591-3601, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32055962

RESUMO

PURPOSE: Growing evidence shows that nutrient metabolism affects inflammatory bowel diseases (IBD) development. Previously, we showed that deficiency of indoleamine 2,3-dioxygenase 1 (Ido1), a tryptophan-catabolizing enzyme, reduced the severity of dextran sulfate sodium (DSS)-induced colitis in mice. However, the roles played by intestinal microbiota in generating the differences in disease progression between Ido1+/+ and Ido1-/- mice are unknown. Therefore, we aimed to investigate the interactions between the intestinal microbiome and host IDO1 in governing intestinal inflammatory responses. METHODS: Microbial 16s rRNA sequencing was conducted in Ido1+/+ and Ido1-/- mice after DSS treatment. Bacteria-derived tryptophan metabolites were measured in urine. Transcriptome analysis revealed the effects of the metabolite and IDO1 expression in HCT116 cells. Colitis severity of Ido1+/+ was compared to Ido1-/- mice following fecal microbiota transplantation (FMT). RESULTS: Microbiome analysis through 16S-rRNA gene sequencing showed that IDO1 deficiency increased intestinal bacteria that use tryptophan preferentially to produce indolic compounds. Urinary excretion of 3-indoxyl sulfate, a metabolized form of gut bacteria-derived indole, was significantly higher in Ido1-/- than in Ido1+/+ mice. Transcriptome analysis showed that tight junction transcripts were significantly increased by indole treatment in HCT116 cells; however, the effects were diminished by IDO1 overexpression. Using FMT experiments, we demonstrated that bacteria from Ido1-/- mice could directly attenuate the severity of DSS-induced colitis. CONCLUSIONS: Our results provide evidence that a genetic defect in utilizing tryptophan affects intestinal microbiota profiles, altering microbial metabolites, and colitis development. This suggests that the host and intestinal microbiota communicate through shared nutrient metabolic networks.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Triptofano
6.
Biol Blood Marrow Transplant ; 25(10): 1933-1943, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31195137

RESUMO

Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently receive empiric antibiotics during the neutropenic period before engraftment. Several recent studies have shown that anaerobes in the intestine are important mediators of intestinal homeostasis, and that commensal bacteria can be potent modulators of the severity of acute graft-versus-host disease (aGVHD). However, the relationships among the type of antibiotic used during the neutropenic period, changes in the intestinal microbiota, and subsequent occurrence of aGVHD are not clear. In this study, a total of 211 patients undergoing HSCT were stratified into 3 groups: patients not treated with any antibiotics during the neutropenic period (group 1; n = 43), patients treated with cefepime only (group 2; n = 87), and patients treated with carbapenem antibiotics, defined as meropenem or prepenem with or without previous cefepime therapy (group 3; n = 81). Intestinal microbiota analyses were performed on pre- and post-HSCT stool samples, and immunophenotypic analyses were performed on pre- and post-HSCT peripheral blood samples. Among the 211 patients, 95 (45%) developed aGVHD (grade ≥II), including 54 with intestinal GVHD. The incidence of intestinal GVHD was higher in group 3 compared with group 1 and group 2 (32.1%, 11.6%, and 26.4%, respectively; P = .044). After adjusting for potentially significant variables identified by univariate analysis, multivariate analyses identified broad-spectrum antibiotic use during the neutropenic period as associated with the occurrence of intestinal GVHD (hazard ratio, 3.25; 95% confidence interval, 1.13 to 9.34; P = .029). Accordingly, loss of bacterial diversity in terms of alterations in intestinal microbiota after HSCT was observed in patients who received broad-spectrum antibiotics. Moreover, alterations in the frequencies of several intestinal bacteria phyla were associated with the occurrence of intestinal GVHD. Evaluation of circulating immune cell subsets according to type of antibiotic used during the neutropenic period revealed delayed recovery of myeloid-derived suppressor cells in the broad-spectrum antibiotic use group. Our data indicate that the use of broad-spectrum antibiotics during the neutropenic period is associated with a higher incidence of intestinal GVHD via loss of microbiome diversity. Further studies are needed to determine whether maintaining bacterial diversity can help prevent the development of aGVHD.


Assuntos
Antibacterianos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Adulto , Idoso , Antibacterianos/farmacologia , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Biol Blood Marrow Transplant ; 24(1): 32-42, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28844945

RESUMO

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Monócitos/patologia , Células Supressoras Mieloides/enzimologia , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto , Feminino , Perfilação da Expressão Gênica , Doença Enxerto-Hospedeiro/etiologia , Granulócitos/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Infecções/etiologia , Masculino , Pessoa de Meia-Idade , Monócitos/enzimologia , Células Supressoras Mieloides/patologia
8.
Biochem Biophys Res Commun ; 495(1): 519-525, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29108995

RESUMO

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer and various pathological conditions. However, the phenotypic and functional heterogeneity of human MDSCs represents a major hurdle for the development of therapeutic strategies targeting or regulating MDSCs in tumor progression, inflammation, and graft-versus-host disease (GVHD). We previously shown that circulating HLA-DR-CD14+ monocytic MDSCs are a major contributor to clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we identified, using high-throughput screening, a set of surface markers that are strongly expressed in HLA-DR-CD14+ monocytic MDSCs isolated from the peripheral blood (PB) of patients receiving allo-HSCT. Subsequent experiments showed the consistent dominant expression of CD1d in monocytic MDSCs of allo-HSCT PB in comparison with granulocytic MDSCs. In addition, CD1d-expressing cells isolated from PB of allo-HSCT patients showed the suppressive activity of T cell proliferation and higher expression of MyD88 and IDO compared with CD1d- cells. Our results suggest that CD1d could be a valuable marker for further therapeutic evaluation of human monocytic MDSCs for immune-related diseases, including GVHD.


Assuntos
Antígenos CD1d/análise , Transplante de Células-Tronco Hematopoéticas , Ativação Linfocitária , Células Supressoras Mieloides/imunologia , Linfócitos T/imunologia , Antígenos CD1d/imunologia , Células Cultivadas , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA-DR/análise , Humanos , Receptores de Lipopolissacarídeos/análise , Receptores de Lipopolissacarídeos/imunologia , Monócitos/citologia , Monócitos/imunologia , Células Supressoras Mieloides/citologia , Linfócitos T/citologia , Receptor de TWEAK/análise , Receptor de TWEAK/imunologia , Transplante Homólogo
9.
Am J Pathol ; 187(9): 2020-2033, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28727987

RESUMO

A number of mouse strains transgenic for B-cell receptors specific for nucleic acids or other autoantigens have been generated to understand how autoreactive B cells are regulated in normal and autoimmune mice. Previous studies of nonautoimmune C57BL/6 mice heterozygous for both the IgH and IgL knockins of the polyreactive autoantibody, 564, produced high levels of autoantibodies in a largely Toll-like receptor 7-dependent manner. Herein, we describe studies of mice homozygous for the knockins that also expressed high levels of autoantibodies but, unlike the heterozygotes, exhibited a high incidence of mature B-cell lymphomas and enhanced susceptibility to bacterial infections. Microarray analyses and serological studies suggested that lymphomagenesis might be related to chronic B-cell activation promoted by IL-21. Strikingly, mice treated continuously with antibiotic-supplemented water did not develop lymphomas or abscesses and exhibited less autoimmunity. This mouse model may help us understand the reasons for enhanced susceptibility to lymphoma development exhibited by humans with a variety of autoimmune diseases, such as Sjögren syndrome, systemic lupus erythematosus, and highly active rheumatoid arthritis.


Assuntos
Autoanticorpos/genética , Autoimunidade , Microbioma Gastrointestinal , Síndromes de Imunodeficiência/genética , Linfoma de Células B/genética , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor 7 Toll-Like/metabolismo
10.
J Autoimmun ; 81: 13-23, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28325644

RESUMO

TREX1/DNASE III, the most abundant 3'-5' DNA exonuclease in mammalian cells, is tail-anchored on the endoplasmic reticulum (ER). Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Goutières syndrome (AGS). Mutations in the C-terminus of TREX1 cause loss of localization to the ER and dysregulation of oligosaccharyltransferase (OST) activity, and are associated with retinal vasculopathy with cerebral leukodystrophy (RVCL) and in some cases with systemic lupus erythematosus (SLE). Here we investigate mice with conditional expression of the most common RVCL mutation, V235fs, and another mouse expressing a conditional C-terminal mutation, D272fs, associated with a case of human SLE. Mice homozygous for either mutant allele express the encoded human TREX1 truncations without endogenous mouse TREX1, and both remain DNase active in tissues. The two mouse strains are similar phenotypically without major signs of retinal, cerebral or renal disease but exhibit striking elevations of autoantibodies in the serum. The broad range of autoantibodies is primarily against non-nuclear antigens, in sharp contrast to the predominantly DNA-related autoantibodies produced by a TREX1-D18N mouse that specifically lacks DNase activity. We also found that treatment with an OST inhibitor, aclacinomycin, rapidly suppressed autoantibody production in the TREX1 frame-shift mutant mice. Together, our study presents two new mouse models based on TREX1 frame-shift mutations with a unique set of serologic autoimmune-like phenotypes.


Assuntos
Autoimunidade/genética , Autoimunidade/imunologia , Exodesoxirribonucleases/genética , Mutação da Fase de Leitura , Fosfoproteínas/genética , Aclarubicina/análogos & derivados , Aclarubicina/farmacologia , Substituição de Aminoácidos , Animais , Apoptose/genética , Apoptose/imunologia , Autoanticorpos/imunologia , Autoimunidade/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ativação Enzimática , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos Transgênicos , Fenótipo , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Retina/imunologia , Retina/metabolismo , Retina/patologia , Timócitos/imunologia , Timócitos/metabolismo , Transcriptoma
11.
Blood ; 126(20): 2291-301, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26400962

RESUMO

The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M(+) B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Vigilância Imunológica , Linfoma Difuso de Grandes Células B/imunologia , Proteínas Supressoras de Tumor/deficiência , Animais , Proteínas Mutadas de Ataxia Telangiectasia/imunologia , Caspases/genética , Caspases/imunologia , Linhagem Celular Tumoral , Instabilidade Cromossômica/imunologia , Loci Gênicos/imunologia , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B/genética , NF-kappa B/imunologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Proteínas Supressoras de Tumor/imunologia
12.
Am J Pathol ; 185(11): 3102-14, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26363366

RESUMO

SJL/J mice exhibit a high incidence of mature B-cell lymphomas that require CD4(+) T cells for their development. We found that their spleens and lymph nodes contained increased numbers of germinal centers and T follicular helper (TFH) cells. Microarray analyses revealed high levels of transcripts encoding IL-21 associated with high levels of serum IL-21. We developed IL-21 receptor (IL21R)-deficient Swiss Jim Lambart (SJL) mice to determine the role of IL-21 in disease. These mice had reduced numbers of TFH cells, lower serum levels of IL-21, and few germinal center B cells, and they did not develop B-cell tumors, suggesting IL-21-dependent B-cell lymphomagenesis. We also noted a series of features common to SJL disease and human angioimmunoblastic T-cell lymphoma (AITL), a malignancy of TFH cells. Gene expression analyses of AITL showed that essentially all cases expressed elevated levels of transcripts for IL21, IL21R, and a series of genes associated with TFH cell development and function. These results identify a mouse model with features of AITL and suggest that patients with the disease might benefit from therapeutic interventions that interrupt IL-21 signaling.


Assuntos
Linfadenopatia Imunoblástica/patologia , Subunidade alfa de Receptor de Interleucina-21/metabolismo , Interleucinas/metabolismo , Linfoma de Células B/patologia , Linfoma de Células T/patologia , Transdução de Sinais , Animais , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Centro Germinativo/patologia , Humanos , Linfadenopatia Imunoblástica/prevenção & controle , Imunoglobulina G/sangue , Subunidade alfa de Receptor de Interleucina-21/genética , Interleucinas/genética , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sequência de DNA , Baço/patologia
13.
J Biol Chem ; 289(49): 34250-7, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25331958

RESUMO

B cell lymphoma 6 (BCL6) corepressor (BCOR) was discovered as a BCL6-interacting corepressor, but little is known about its other biological activities in normal B cell development and function. Previously, we found that interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein, directly targets a large number of genes in germinal center B cells including BCL6. In this study, we screened potential binding partners of IRF8 using a retrovirus-based protein complementation assay screen in a mouse pre-B cell line. We found that IRF8 interacts directly with BCOR and that the α-helical region of IRF8 and the BCL6 binding domain of BCOR are required for this interaction. In addition, IRF8 protein interacts directly with BCL6. Using an siRNA-mediated IRF8 knockdown mouse B cell lymphoma cell line, we showed that IRF8 represses Bcor and enhances Bcl6 transcription. Taken together, these data suggest that a complex comprising BCOR-BCL6-IRF8 modulates BCL6-associated transcriptional regulation of germinal center B cell function.


Assuntos
Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Linfócitos/metabolismo , Proteínas Repressoras/genética , Animais , Linhagem Celular Tumoral , Núcleo Celular/genética , Proteínas de Ligação a DNA/metabolismo , Genes Reporter , Vetores Genéticos , Células HEK293 , Humanos , Fatores Reguladores de Interferon/antagonistas & inibidores , Fatores Reguladores de Interferon/metabolismo , Luciferases/genética , Luciferases/metabolismo , Linfócitos/citologia , Camundongos , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/metabolismo , Retroviridae/genética , Transdução de Sinais , Transcrição Gênica
14.
J Immunol ; 190(3): 987-96, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23267023

RESUMO

FcR specific for pentameric IgM (FCMR) is expressed at high levels by B cells. Although circulating IgM has profound effects on responses to pathogens, autoimmunity, and B cell homeostasis, the biologic consequences of its binding to FCMR are poorly understood. We interrogated FCMR contributions to B cell function by studying mice that lack FCMR. FCMR transcripts are expressed at different levels by various B cell subsets. FCMR-deficient mice have reduced numbers of developing B cells, splenic follicular and peritoneal B-2 cells, but increased levels of peritoneal B-1a cells and autoantibodies. After immunization, germinal center B cell and plasma cell numbers are increased. FCMR-deficient B cells are sensitive to apoptosis induced by BCR ligation. Our studies demonstrate that FCMR is required for B cell differentiation and homeostasis, the prevention of autoreactive B cells, and responsiveness to antigenic challenge.


Assuntos
Antígenos/imunologia , Linfócitos B/citologia , Imunoglobulina M/imunologia , Síndromes de Imunodeficiência/imunologia , Linfopoese/imunologia , Receptores Fc/imunologia , Animais , Formação de Anticorpos/imunologia , Apoptose/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Biopolímeros , Medula Óssea/imunologia , Medula Óssea/patologia , Centro Germinativo/patologia , Homeostase/imunologia , Imunização , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/imunologia , Peritônio/patologia , Plasmócitos/patologia , RNA Mensageiro/biossíntese , Receptores de Antígenos de Linfócitos B/imunologia , Receptores Fc/biossíntese , Receptores Fc/deficiência , Receptores Fc/genética , Baço/imunologia , Baço/patologia , Linfócitos T/imunologia
15.
Proc Natl Acad Sci U S A ; 109(49): 20077-82, 2012 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-23169635

RESUMO

Innate-like B-1a cells contribute significantly to circulating natural antibodies and mucosal immunity as well as to immunoregulation. Here we show that these classic functions of B-1a cells segregate between two unique subsets defined by expression of plasma cell alloantigen 1 (PC1), also known as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). These subsets, designated B-1a.PC1(lo) and B-1a.PC1(hi), differ significantly in IgH chain utilization. Adoptively transferred PC1(lo) cells secreted significantly more circulating natural IgM and intestinal IgA than PC1(hi) cells. In contrast, PC1(hi) cells produced more IL-10 than PC1(lo) cells when stimulated with LPS and phorbol 12-myristate 13-acetate (PMA). PC1(hi) cells were also more efficient than PC1(lo) cells in regulating Th1 cell differentiation, even though both B-1a subsets were comparably active in stimulating T-cell proliferation. Furthermore, PC1(lo) cells generated antigen-specific IgM responses to pneumococcal polysaccharide antigens, whereas PC1(hi) cells do not. We found that PC1(lo) cells develop from an early wave of B-1a progenitors in fetal life, whereas PC1(hi) cells are generated from a later wave after birth. We conclude that identification of B-1a.PC1(lo) and B-1a.PC1(hi) cells extends the concept of a layered immune system with important implications for developing effective vaccines and promoting the generation of immunoregulatory B cells.


Assuntos
Linfócitos B Reguladores/imunologia , Imunidade Inata/imunologia , Diester Fosfórico Hidrolases/metabolismo , Plasmócitos/metabolismo , Pirofosfatases/metabolismo , Transferência Adotiva , Animais , Linfócitos B Reguladores/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Diester Fosfórico Hidrolases/imunologia , Plasmócitos/imunologia , Pirofosfatases/imunologia , Estatísticas não Paramétricas , Linfócitos T/imunologia
16.
Blood ; 119(2): 465-8, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-22110250

RESUMO

The splenic marginal zone (MZ) is comprised of specialized populations of B cells, dendritic cells, and macrophages that are uniquely arrayed outside the white pulp follicles to screen the blood for bacterial and other particulate Ags. Mechanisms responsible for MZ B-cell formation, localization, retention, and function are understood to include antigenic specificity, transcription factors, integrins, and surface receptors for soluble ligands such as S1P. Here, we add to this repertoire by demonstrating that the receptor for CXCL12, CXCR7, is expressed on MZ but not on follicular B cells. Treatment of mice with CXCR7 inhibitors led to disruption of MZ architecture, reduced numbers of MZ B cells, and altered granulocyte homeostasis associated with increasing serum levels of CXCL12. CXCR7 thus appears to function as a scavenger receptor for CXCL12 on MZ B cells.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocina CXCL12/sangue , Receptores CXCR/metabolismo , Baço/citologia , Baço/metabolismo , Animais , Linfócitos B/patologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Granulócitos/citologia , Granulócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR/antagonistas & inibidores , Baço/imunologia
17.
Heliyon ; 10(2): e24577, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38312691

RESUMO

Male infertility is a global health concern. However, its underlying pathophysiology remains unclear. Taste receptor type 1 member 3 (TAS1R3) is highly expressed in the testes, indicating its potential involvement in male fertility. Using wild-type and Tas1r3 knockout (KO) mice, we investigated whether TAS1R3 modulates male reproductive function. Tas1r3 KO mice exhibited reduced male fertility compared to WT mice, with fewer live pups per litter and a delayed first litter. Testicular transcriptome analysis indicated suppressed PKA/CREB/StAR signaling-mediated testosterone synthesis in Tas1r3 KO mice. In silico single-cell RNA sequencing revealed considerably higher Tas1r3 expression in Leydig cells than in other testicular cell subtypes. An in vitro study validated that Tas1r3 knockdown downregulated the expression of Creb1 and steroidogenic genes in Leydig cells. Our results suggest that testicular TAS1R3 is intricately involved in male reproduction via the PKA/CREB/StAR signaling pathway, highlighting its potential as a promising target for addressing male infertility.

18.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1869(3): 159433, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38007088

RESUMO

Western diet (WD), characterized by a high intake of fats and sugary drinks, is a risk factor for male reproductive impairment. However, the molecular mechanisms underlying this remain unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is highly expressed in extra-oral tissues, particularly in the testes. Here, we investigated to determine the effects of WD intake on male reproduction and whether TAS1R3 mediates WD-induced impairment in male reproduction. Male C57BL/6 J wild-type (WT) and Tas1r3 knockout (KO) mice were fed either a normal diet and plain water (ND) or a 60 % high-fat-diet and 30 % (w/v) sucrose water (WD) for 18 weeks (n = 7-9/group). Long-term WD consumption significantly impaired sperm count, motility and testicular morphology in WT mice with marked Tas1r3 overexpression, whereas Tas1r3 KO mice were protected from WD-induced reproductive impairment. Testicular transcriptome analysis revealed downregulated AMP-activated protein kinase (AMPK) signaling and significantly elevated AMPK-targeted nuclear receptor 4A1 (Nr4a1) expression in WD-fed Tas1r3 KO mice. In vitro studies further validated that Tas1r3 knockdown in Leydig cells prevented the suppression of Nr4a1 and downstream steroidogenic genes (Star, Cyp11a1, Cyp17a1, and Hsd3b1) caused by high glucose, fructose, and palmitic acid levels, and maintained the levels of testosterone. Additionally, we analyzed the public human dataset to assess the clinical implications of our findings and confirmed a significant association between TAS1R3 and male-infertility-related diseases. Our findings suggest that TAS1R3 regulates WD-induced male reproductive impairment via the AMPK/NR4A1 signaling and can be a novel therapeutic target for male infertility.


Assuntos
Infertilidade Masculina , Paladar , Camundongos , Masculino , Humanos , Animais , Paladar/genética , Proteínas Quinases Ativadas por AMP , Dieta Ocidental/efeitos adversos , Camundongos Endogâmicos C57BL , Sêmen , Camundongos Knockout , Infertilidade Masculina/genética , Água
19.
J Immunol ; 186(3): 1458-66, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21178004

RESUMO

Transcriptional control of marginal zone (MZ) and follicular (FO) B cell development remains incompletely understood. The transcription factor, IFN regulatory factor (IRF)8, is known to play important roles in the differentiation of early B cells. In this article, we demonstrate that IRF8 is also required for normal development of MZ and FO B cells. Mice with a conventional knockout of Irf8 (IRF8(-/-)) or a point mutation in the IRF association domain of IRF8 had increased numbers of MZ B cells. To determine the B cell-intrinsic effects of IRF8 deficiency, we generated mice with a conditional allele of Irf8 crossed with CD19-Cre mice (designated IRF8-conditional knockout [CKO]). These mice had enlarged MZ and increased numbers of MZ and FO B cells compared with controls. The FO B cells of CKO mice exhibited reduced expression of CD23 and moderately increased expression of CD21. Gene-expression profiling showed that increased B cell production in IRF8-CKO mice was associated with changes in expression of genes involved in regulation of transcription, signaling, and inflammation. Functional studies showed that IRF8-CKO mice generated normal Ab responses to T-independent and T-dependent Ags. Thus, IRF8 controls the expansion and maturation of MZ and FO B cells but has little effect on B cell function.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Fatores Reguladores de Interferon/fisiologia , Baço/citologia , Baço/imunologia , Animais , Subpopulações de Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Feminino , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutagênese Insercional , Mutação Puntual , Estrutura Terciária de Proteína/genética , Baço/patologia
20.
J Immunol ; 187(9): 4695-704, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21964024

RESUMO

Dysregulation of the T cell-dependent Ab response can lead to numerous immunological disorders, ranging from systemic lupus erythematosus to B cell lymphomas. Cellular processes governed by MHC class II proteins play a major role in this response and its dysregulation. The extent to which processes controlled by the diverse family of MHC class I proteins impact such autoimmune and neoplastic disorders, however, is less clear. In this study, we genetically dissect the contributions of individual MHC class I family members and the pathological processes under their control in the systemic lupus erythematosus-like disease of BXSB.Yaa mice and B cell lymphomagenesis of SJL mice. This study reveals a powerful repressive regulatory axis comprised of MHC class I-dependent CD8(+) T cells and NK cells. These results indicate that the predominant role of the MHC class I protein family in such immunological disorders is to protect from more aggressive diseases.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Linfoma de Células B/imunologia , Linfoma de Células B/prevenção & controle , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Antígenos H-2/genética , Antígeno de Histocompatibilidade H-2D , Antígenos de Histocompatibilidade Classe I/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Lúpus Eritematoso Sistêmico/mortalidade , Linfoma de Células B/mortalidade , Camundongos , Camundongos Endogâmicos , Vírus da Leucemia Murina de Moloney/imunologia , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética
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