RESUMEN
How gut regionalization impacts microbiota and immunity is unclear. In this issue of Immunity, Earley et al. show that jejumal GATA4 expression controls bacteria colonization through retinol metabolism and IgA production. This metabolic-immune axis limits intestinal Th17 responses and immunopathology.
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Factor de Transcripción GATA4 , Microbioma Gastrointestinal , Microbiota , Células Th17/metabolismo , Células Th17/microbiologíaRESUMEN
Background Dysregulation of the balance between different T cell populations is believed to be an important basis for asthma.Objective To observe the changes in γδT subtypes in transgenic asthmatic mice after aerosol inhalation of Mycobacterium vaccae, and to further investigate the mechanism of M. vaccae in asthmatic mice and its relationship with γδT cells.Methods TCR-ß-/- mice were exposed to atomized normal saline or M. vaccae for 5 days and the γδT cells from the lung tissues were isolated. Changes in γδT17 and γδTreg populations were detected. Asthma was induced in BALB/c mice using ovalbumin, which was then transplanted with control or M. vaccae-primed γδT cells. First we analyzed the content of γδT cells that secrete IL-17 (IL-17 γδT cells) and Foxp3+ γδT cells in lung tissues and then measured the content of IL-17 in the bronchoalveolar lavage fluid (BALF) by ELISA.Results Exposure to M. vaccae increased and decreased the relative proportions of Foxp3+ γδT cells and IL-17+ γδT cells, respectively, thereby decreasing airway reactivity and inflammation levels in asthmatic mice, and significantly decreasing IL-17 levels in BALF. Furthermore, mice treated with these primed T cells showed a decrease in IL-17+ γδT cells, and a concomitant increase in Foxp3+ γδT cells in their lung tissues. Furthermore, adoptive transfer of M. vaccae-primed γδT cells decreased GATA3 and NICD and increased T-bet in lung.Conclusions The M. vaccae-primed γδT cells alleviated the symptoms of asthma by reversing Th2 polarization in the lungs and inhibiting the Notch/GATA3 pathway.
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Asma , Interleucina-17 , Linfocitos T Reguladores , Células Th17 , Animales , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead , Pulmón , Ratones , Ratones Endogámicos BALB C , Mycobacteriaceae , Ovalbúmina , Receptores de Antígenos de Linfocitos T , Solución Salina , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/microbiología , Células Th17/citología , Células Th17/microbiologíaRESUMEN
BACKGROUND & AIMS: An invasive form of intestinal Entamoeba (E.) histolytica infection, which causes amoebic liver abscess, is more common in men than in women. Immunopathological mechanisms are responsible for the more severe outcome in males. Here, we used a mouse model of hepatic amoebiasis to investigate the contribution of hepatic hypoxia-inducible factor (HIF)-1α to T helper 17 (Th17)/regulatory T cell (Treg) responses in the context of the sex-specific outcome of liver damage. METHODS: C57BL/6J mice were infected intrahepatically with E. histolytica trophozoites. HIF-1α expression was determined by qPCR, flow cytometry and immunohistochemistry. Tregs and Th17 cells were analysed by immunohistochemistry and flow cytometry. Finally, male and female hepatocyte-specific Hif1α knockout mice were generated, and the effect of HIF-1α on abscess development, the cytokine milieu, and Th17/Treg differentiation was examined. RESULTS: E. histolytica infection increased hepatic HIF-1α levels, along with the elevated frequencies of hepatic Th17 and Treg cells. While the Th17 cell population was larger in male mice, Tregs characterised by increased expression of Foxp3 in female mice. Male mice displayed increased IL-6 expression, contributing to immunopathology; this increase in IL-6 expression declined upon deletion of hepatic HIF-1α. In both sexes, hepatic deletion of HIF-1α reduced the Th17 cell frequency; however, the percentage of Tregs was reduced in female mice only. CONCLUSIONS: Hepatic HIF-1α modulates the sex-specific outcome of murine E. histolytica infection. Our results suggest that in male mice, Th17 cells can be modulated by hepatic HIF-1α via IL-6, indicating marked involvement in the immunopathology underlying abscess development. Strong expression of Foxp3 by hepatic Tregs from female mice suggests a potent immunosuppressive function, leading to initiation of liver regeneration. LAY SUMMARY: Infection with the parasite Entamoeba histolytica activates immunopathological mechanisms in male mice, which lead to liver abscesses that are larger than those in female mice. In the absence of the protein HIF-1α in hepatocytes, abscess formation is reduced; moreover, the sex difference in abscess size is abolished. These results suggest that HIF-1α modulates the immune response involved in the induction of immunopathology, resulting in differential disease susceptibility in males and females.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/farmacología , Absceso Hepático Amebiano/genética , Células Th17/metabolismo , Animales , Modelos Animales de Enfermedad , Entamoeba/efectos de los fármacos , Entamoeba/patogenicidad , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Absceso Hepático Amebiano/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Células Th17/microbiologíaRESUMEN
Candida albicans is usually a benign member of the human gut microbiota, but can become pathogenic under certain circumstances, for example in an immunocompromised host. The innate immune system, in particular neutrophils and macrophages, constitutes a crucial first line of defense against fungal invasion, however adaptive immunity may provide long term protection and thus allow vaccination of at risk patients. While TH1 and TH17 cells are important for antifungal responses, the role of B cells and antibodies in protection from C. albicans infection is less well defined. In this study, we show that C. albicans hyphae but not yeast, as well as fungal cell wall components, directly activate B cells via MyD88 signaling triggered by Toll- like receptor 2, leading to increased IgG1 production. While Dectin-1 signals and specific recognition by the B cell receptor are dispensable for B cell activation in this system, TLR2/MyD88 signals cooperate with CD40 signals in promoting B cell activation. Importantly, recognition of C. albicans via MyD88 signaling is also essential for induction of IL-6 secretion by B cells, which promotes TH17 polarization in T-B cell coculture experiments. B cells may thus be activated directly by C. albicans in its invasive form, leading to production of antibodies and T cell help for fungal clearance.
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Linfocitos B/inmunología , Candida albicans/inmunología , Candidiasis/inmunología , Diferenciación Celular , Hifa/inmunología , Inmunoglobulina G/metabolismo , Interleucina-6/metabolismo , Células Th17/inmunología , Receptor Toll-Like 2/metabolismo , Animales , Linfocitos B/metabolismo , Linfocitos B/microbiología , Candida albicans/patogenicidad , Candidiasis/metabolismo , Candidiasis/microbiología , Células Cultivadas , Técnicas de Cocultivo , Interacciones Huésped-Patógeno , Humanos , Hifa/patogenicidad , Activación de Linfocitos , Ratones Endogámicos C57BL , Fenotipo , Vías Secretoras , Transducción de Señal , Células Th17/metabolismo , Células Th17/microbiologíaRESUMEN
OBJECTIVE: Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. APPROACH: Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1-/- and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. RESULTS: REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1-/- mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS: The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.
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Citocinas/metabolismo , Mucosa Gástrica/microbiología , Gastritis/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Células Th17/microbiología , Factores de Transcripción/metabolismo , Animales , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , Gastritis/inmunología , Gastritis/metabolismo , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/inmunología , Helicobacter pylori/metabolismo , Interacciones Huésped-Patógeno , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Fenotipo , Fosforilación , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Granuloma formation is the pathologic hallmark of tuberculosis (TB). Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box P3 (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (-) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV- granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV- than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV- TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Granuloma/inmunología , Infecciones por VIH/inmunología , Histiocitos/inmunología , Tuberculosis Latente/inmunología , Células Th17/inmunología , Tuberculosis Ganglionar/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/microbiología , Linfocitos T CD8-positivos/virología , Coinfección , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Expresión Génica , Granuloma/microbiología , Granuloma/patología , Granuloma/virología , VIH/inmunología , VIH/patogenicidad , Infecciones por VIH/microbiología , Infecciones por VIH/patología , Infecciones por VIH/virología , Histiocitos/microbiología , Histiocitos/virología , Humanos , Inmunohistoquímica , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Tuberculosis Latente/microbiología , Tuberculosis Latente/patología , Tuberculosis Latente/virología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/virología , Recuento de Linfocitos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Células Th17/microbiología , Células Th17/virología , Tuberculosis Ganglionar/microbiología , Tuberculosis Ganglionar/patología , Tuberculosis Ganglionar/virologíaRESUMEN
Multiple sclerosis is a chronic autoimmune disease involving the central nervous system, and shows a high disability rate. Its pathogenesis is complicated, and there is no good treatment. In recent years, with in-depth studies on the regulation of gastrointestinal flora, the relationship between the mammalian immune system and the intestinal flora has been extensively explored. Changes in the composition and structure of the gastrointestinal flora can affect the characteristics and development of the host immune system and even induce a series of central nervous system inflammation events. The occurrence and development of multiple sclerosis are closely related to the continuous destruction of the intestinal barrier caused by intestinal dysbacteriosis. In this study, we analyzed Lactobacillus acidipiscis in a mouse model of experimental autoimmune encephalomyelitis (EAE). We found that the amount of L. acidipiscis in the intestinal tract was inversely proportional to the progress of EAE development. In addition, the number of CD4+ FOXP3+ regulatory T cells in the mesenteric lymph nodes of mice increased significantly after the mice were fed with L. acidipiscis, and the differentiation of CD4+ T cells to Th1 and Th17 cells was inhibited. However, the protective effect of L. acidipiscis was lost in γδ T cell-deficient mice and hence was concluded to depend on the presence of regulatory γδ T cells in the intestinal epithelium. Moreover, including L. acidipiscis enhanced the development of Vγ1+γδ T cells but suppressed that of Vγ4+γδ T cells. In summary, our results demonstrated the ability of L. acidipiscis to induce generation of regulatory γδ T cells that suppress the development of the encephalomyelitic Th1 and Th17 cells and the progress of EAE.
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Encefalomielitis Autoinmune Experimental/prevención & control , Microbioma Gastrointestinal , Mucosa Intestinal/microbiología , Linfocitos Intraepiteliales/microbiología , Lactobacillus/inmunología , Probióticos , Animales , Diferenciación Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disbiosis , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/microbiología , Femenino , Genes Codificadores de la Cadena gamma de los Receptores de Linfocito T , Interacciones Huésped-Patógeno , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Lactobacillus/crecimiento & desarrollo , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/microbiologíaRESUMEN
To fight tuberculosis, better vaccination strategies are needed. Live attenuated Mycobacterium tuberculosis-derived vaccine, MTBVAC, is a promising candidate in the pipeline, proven to be safe and immunogenic in humans so far. Independent studies have shown that pulmonary mucosal delivery of Bacillus Calmette-Guérin (BCG), the only tuberculosis (TB) vaccine available today, confers superior protection over standard intradermal immunization. Here we demonstrate that mucosal MTBVAC is well tolerated, eliciting polyfunctional T helper type 17 cells, interleukin-10, and immunoglobulins in the airway and yielding a broader antigenic profile than BCG in rhesus macaques. Beyond our previous work, we show that local immunoglobulins, induced by MTBVAC and BCG, bind to M. tuberculosis and enhance pathogen uptake. Furthermore, after pulmonary vaccination, but not M. tuberculosis infection, local T cells expressed high levels of mucosal homing and tissue residency markers. Our data show that pulmonary MTBVAC administration has the potential to enhance its efficacy and justifies further exploration of mucosal vaccination strategies in preclinical efficacy studies.
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Vacuna BCG/administración & dosificación , Inmunidad Mucosa , Mycobacterium tuberculosis/inmunología , Mucosa Respiratoria/inmunología , Vacunas contra la Tuberculosis/administración & dosificación , Tuberculosis Pulmonar/prevención & control , Administración Intranasal , Animales , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Femenino , Regulación de la Expresión Génica , Inyecciones Intradérmicas , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/microbiología , Macaca mulatta , Masculino , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/microbiología , Mycobacterium tuberculosis/patogenicidad , Mucosa Respiratoria/microbiología , Células TH1/inmunología , Células TH1/microbiología , Células Th17/inmunología , Células Th17/microbiología , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaAsunto(s)
Susceptibilidad a Enfermedades/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Mastocitos/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Leishmaniasis Cutánea/parasitología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Infiltración Neutrófila , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Células Th17/microbiologíaRESUMEN
The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.
Asunto(s)
Trasplante de Microbiota Fecal , Enfermedades Inflamatorias del Intestino/microbiología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Colitis/prevención & control , Colon/microbiología , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/microbiología , Citocinas/inmunología , Modelos Animales de Enfermedad , Heces/microbiología , Femenino , Microbioma Gastrointestinal/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/microbiología , Células Th17/microbiologíaRESUMEN
OBJECTIVE: The pathogenesis and mechanism of colitis may be related to intestinal flora, genetic susceptibility, environmental and immune factors. Among these various factors, the importance of environmental factors in the pathogenesis of colitis has been increasingly recognized. The purpose of this study was to investigate the effects of hypoxia on intestinal mucosal immunity. METHODS: Experimental colitis was induced by oral gavage of Citrobacter rodentium (C. rodentium) in mice, then divided into normoxia group and hypoxia group. Mice were sacrificed after 2 weeks. Physiological and blood biochemical indicators were monitored to verify the hypoxia model. The body weight, fecal bacterial output, colon length and colon histopathology were observed to evaluate severity of colitis. The concentration of cytokines in colonic tissues were detected by ELISA. The percentage of CD4+ IFN-γ+ (Th1) and CD4+ IL-17+ (Th17) cells in mesenteric lymph nodes (MLN) were detected by ï¬ow cytometry. The levels of mucosal antimicrobial peptides (AMPs), related inflammatory factors and transcription factors in colon tissues were detected by qRT-PCR. RESULTS: Mice in hypoxic C. rodentium infection (Hypoxiaâ¯+â¯C.r.) group exhibited significant decrease in body weight, increase in fecal bacterial pathogen output, and more severe histopathological damage in the colon compared with the C. rodentium infection (Nomoxiaâ¯+â¯C.r.) group. Meanwhile, the level of NF-κB, TLR4, COX-2, IL-6 and TNF-α of colonic tissue were increased, while IL17, IL-22, and Reg3γ were decreased. The percentage of CD4+ IFN-γ+ (Th1) and CD4+ IL-17+ (Th17) cells in MLN were significantly decreased in mice of Hypoxiaâ¯+â¯C.r. group, accompanied by the decreased of IFN-γ and IL-17. In addition, the level of the T-bet, RORγt, IL-12 and IL-23 were decreased in mice of Hypoxiaâ¯+â¯C.r. group. CONCLUSIONS: Hypoxic exposure signiï¬cantly exacerbates the symptoms and the pathological damage of mice with colitis and inï¬uences the immune function by down-regulating Th1 and Th17 responses in C. rodentium-induced colitis in mice.
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Citrobacter rodentium/inmunología , Colitis/inmunología , Colon/inmunología , Infecciones por Enterobacteriaceae/inmunología , Hipoxia/inmunología , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Animales , Colitis/metabolismo , Colitis/microbiología , Colitis/patología , Colon/metabolismo , Colon/microbiología , Colon/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/patología , Femenino , Interacciones Huésped-Patógeno , Hipoxia/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Brote de los Síntomas , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/microbiología , Receptor Toll-Like 4/metabolismoRESUMEN
Emerging evidences indicated that the dysbiosis of microbiota was related to the onset of systemic lupus erythematosus (SLE). Bacteroides fragilis (B. fragilis) ATCC 25285, a human commensal, was discovered to improve inflammatory diseases. However, whether B. fragilis (ATCC 25285) has the beneficial effects on the treatment of lupus nephritis has still remained elusive. In the present study, oral treatment with B. fragilis (ATCC 25285) ameliorated the activity of MRL/lpr mice, including decreased levels of autoantibodies and symptoms of lupus nephritis. Furthermore, we demonstrated that treatment with B. fragilis (ATCC 25285) could promote CD1d expression in B cells by Est-1 pathway, while inhibit CD86 expression via SHP-2 signaling pathway to repair the immune response of B cells in MRL/lpr mice. In addition, our findings revealed a possible role of treatment with B. fragilis (ATCC 25285) in relieving intestinal inflammation in MRL/lpr mice. Meanwhile, it was uncovered that B. fragilis (ATCC 25285) restored the Th17/Treg balance in MRL/lpr mice that was consistent with the role of B. fragilis in other autoimmune diseases. Overall, the current study may highlight the potential application of B. fragilis (ATCC 25285) to treat manifestations of SLE in high-risk individuals.
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Antígenos CD1d/metabolismo , Linfocitos B/microbiología , Antígeno B7-2/metabolismo , Bacteroides fragilis/fisiología , Nefritis Lúpica/terapia , Probióticos , Animales , Antígenos CD1d/inmunología , Autoanticuerpos/sangre , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígeno B7-2/inmunología , Modelos Animales de Enfermedad , Femenino , Nefritis Lúpica/inmunología , Nefritis Lúpica/metabolismo , Nefritis Lúpica/microbiología , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Proto-Oncogénica c-ets-1/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/microbiologíaRESUMEN
Septic arthritis is a condition of bone disorder caused predominantly by Staphylococcus aureus. Following the bacterial entry activated immune cells specially macrophages and dendritic cells release pro-inflammatory mediators such as IL-6, TNF-α, IL-1ß etc., which not only create an inflammatory microenvironment but also play crucial roles in the proliferation of different CD+ T cell subsets. Among them, Th17 and Tregs are of major concern in recent times because of their potential roles in regulating the ongoing inflammation in many diseases including experimental arthritis. But the downstream signalling mechanism of these cells in regulating the severity of inflammation in case of septic arthritis is not known yet. So, here we have established a murine model of S. aureus induced septic arthritis and kept the animal upto 15â¯days post-infection. To examine the signalling mechanism, Th17 and Treg cells were isolated from blood, spleen and synovial joints of control and infected mice and observed the expression of JNK, NFκB and RANKL in the lysate of isolated Th17 and Tregs. We have also estimated the levels of serum IL-21 and TGF-ß. NFκB, JNK and RANKL expression was found to be higher at 3 and 15â¯days post-infection along with serum IL-21 levels. On the other hand, maximum TGF-ß level was observed at 9â¯days post-infection along with increased Treg population. In conclusion it was hypothesized that bone resorption is related with downstream signalling pathways of Th17 cells, which stimulate osteoclast generation via NFκB/JNK-RANKL axis and helps in the persistence of the disease.
Asunto(s)
Artritis Infecciosa/inmunología , Inflamación/inmunología , Infecciones Estafilocócicas/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/microbiología , Artritis Experimental/patología , Artritis Infecciosa/genética , Artritis Infecciosa/microbiología , Artritis Infecciosa/patología , Regulación de la Expresión Génica/genética , Humanos , Inflamación/genética , Inflamación/microbiología , Inflamación/patología , Interleucina-1beta/genética , Articulaciones/inmunología , Articulaciones/microbiología , Articulaciones/patología , MAP Quinasa Quinasa 4/genética , Ratones , Osteoclastos/inmunología , Osteoclastos/microbiología , Osteoclastos/patología , Ligando RANK/genética , Transducción de Señal/genética , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/patogenicidad , Linfocitos T Reguladores/microbiología , Células Th17/microbiología , Factor de Crecimiento Transformador beta/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Mycobacterium tuberculosis-specific (M. tuberculosis-specific) T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a nonhuman primate aerosol model, we studied the kinetics, phenotypes, and functions of M. tuberculosis antigen-specific T cells in peripheral and lung compartments of M. tuberculosis-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage, for up to 24 weeks postinfection. We found substantially higher frequencies of M. tuberculosis-specific effector and memory CD4+ and CD8+ T cells producing IFN-γ in the airways compared with peripheral blood, and these frequencies were maintained throughout the study period. Moreover, M. tuberculosis-specific IL-17+ and IL-17+IFN-γ+ double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of M. tuberculosis-specific CD4+ T cells that homed to the airways expressed the chemokine receptor CXCR3 and coexpressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and nongranulomatous regions of the lung and inversely correlated with M. tuberculosis burden. Our findings provide insights into antigen-specific T cell responses associated with asymptomatic M. tuberculosis infection that are relevant for developing better strategies to control TB.
Asunto(s)
Tuberculosis Latente/genética , Pulmón/inmunología , Receptores CCR6/genética , Receptores CXCR3/genética , Tuberculosis Pulmonar/genética , Animales , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/microbiología , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Tuberculosis Latente/patología , Pulmón/microbiología , Pulmón/patología , Macaca mulatta , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Células TH1/inmunología , Células TH1/microbiología , Células Th17/inmunología , Células Th17/microbiología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patologíaRESUMEN
Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Intestinos/inmunología , Intestinos/microbiología , Células Th17/inmunología , Células Th17/fisiología , Adolescente , Adulto , Animales , Dieta Alta en Grasa/métodos , Dieta Cetogénica/métodos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Microbiota/fisiología , Persona de Mediana Edad , Células Th17/microbiología , Adulto JovenRESUMEN
Dendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with specific pathogens to prime CD4 T cells in vitro and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More specifically, the transcriptome of in vitro C. rodentium-primed Th17 cells resembled that of Th17 cells primed following infection in vivo but was remarkably distinct from cytokine-polarized Th17 cells. We identified caspase-1 as a unique gene up-regulated only in pathogen-primed Th17 cells and discovered a critical role for T cell-intrinsic caspase-1, independent of inflammasome, in optimal priming of Th17 responses. T cells lacking caspase-1 failed to induce colitis or confer protection against C. rodentium infection due to suboptimal Th17 cell differentiation in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation.
Asunto(s)
Caspasa 1/genética , Diferenciación Celular/genética , Células Th17/metabolismo , Células Th17/microbiología , Transcripción Genética/genética , Animales , Línea Celular Tumoral , Polaridad Celular , Citrobacter rodentium , Colitis/genética , Colitis/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/microbiología , Femenino , Técnicas de Inactivación de Genes , Inflamasomas/metabolismo , Activación de Linfocitos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , TranscriptomaRESUMEN
The delineation of the pathogenic interaction between the host skin immune responses and dermatophytes has remained indigent. The obscure enigma in host-dermatophyte immunopathogenic interactions is the T regulatory (Treg) and T-helper (Th) 17 cell role in maintaining immune homeostasis. We attempted to understand the regulation and recognition of lineage-specific response in chronic dermatophytic skin infection patients. The percentages of Th17 (CD4+CD161+IL23R+) and Treg (CD4+CD25+FoxP3+) cell subpopulations in the peripheral circulation of thirty chronic dermatophytic skin infection patients and twenty healthy individuals was determined. The serum cytokine levels were estimated for disease correlation. The mean duration of the disease was 10.68 ± 8.72 months, with Trichophyton mentagrophytes complex as the major pathogen. Total serum IgE level of patients was significantly higher compared to healthy controls (305 ± 117 vs 98.53 ± 54.55 IU/ml; p < 0.01). Expression of Th17 and Treg cell markers on CD4+ T cells was significantly elevated in patients than controls (p < 0.05). Comparatively, serum interleukin (IL)-4 and interferon (IFN)-γ levels were increased, with low IL-10 levels in patients. Our data envisages a complex immune dysfunction in chronic dermatophytosis, arising either as a result of dermatophyte exposure or paradoxical precedence of disease establishment. Designing new treatment strategies and preventing recurrences are challenges for future research.
Asunto(s)
Arthrodermataceae/fisiología , Dermatomicosis/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adolescente , Adulto , Enfermedad Crónica , Dermatomicosis/sangre , Dermatomicosis/microbiología , Femenino , Humanos , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-4/sangre , Masculino , Linfocitos T Reguladores/microbiología , Células Th17/microbiología , Adulto JovenRESUMEN
The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasiliensis is characterized by a compact aggregate of mature cells, surrounded by a fibroblast- and collagen-rich content. Granuloma formation requires signaling elicited by inflammatory molecules such as members of the interleukin-1 family. Two members of this family have been thoroughly studied, namely IL-1α and IL-1ß. In this study, we addressed the mechanisms underlying IL-1α secretion and its functional role on the host resistance to fungal infection. We found that, the expression of caspase-11 triggered by P. brasiliensis infection of macrophages depends on IFN-ß production, because its inhibition reduced procaspase-11 levels. Curiously, caspase-11 deficiency did not impair IL-1ß production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1α, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1α to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1α deficiency accounted for a significant reduction of Th17 lymphocytes in lungs of infected mice, correlating with diminished neutrophil infiltration in the lungs. Strikingly, we identified that IL-1α directly reprograms the transcriptional profile of Th17-committed lymphocytes, increasing cellular proliferation, as for boosting IL-17 production by these cells. Beyond neutrophil chemotaxis in vivo, IL-17 also amplified IL-1α production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-ß/caspase-11/IL-1α pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity.
Asunto(s)
Caspasas/fisiología , Inmunidad Innata/inmunología , Interleucina-1alfa/metabolismo , Macrófagos/inmunología , Paracoccidioides/inmunología , Paracoccidioidomicosis/inmunología , Células Th17/inmunología , Animales , Caspasas Iniciadoras , Inflamasomas , Macrófagos/metabolismo , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Paracoccidioidomicosis/metabolismo , Paracoccidioidomicosis/microbiología , Células Th17/metabolismo , Células Th17/microbiologíaRESUMEN
Porphyromonas gingivalis is considered a keystone pathogen that contributes to the initiation and progression of periodontitis in humans. P. gingivalis has also been detected in human placentas associated with adverse pregnancy outcomes. The spread of P. gingivalis from the oral cavity to the reproductive tract thus represents a potential mechanism whereby periodontitis can lead to adverse pregnancy outcomes. In a murine model of pregnancy and oral infection with P. gingivalis, C57BL/6J mice developed low fetal weight, whereas C57BL/6NCrl mice did not. Although C57BL/6NCrl mice harbor segmented filamentous bacteria that drive a Th17 response, fetal weight was independent of frequency of Th17 or Th1 in either substrain. Low fetal weight was instead correlated with increasing amounts of P. gingivalis DNA in the placentas of the C57BL/6J dams. In contrast, fetal weight in C57BL/6NCrl mice was independent of P. gingivalis in the placenta. Differences in genetics or microbiome that influence the ability of P. gingivalis to colonize the placenta may drive differential fetal weight outcomes between C57BL/6J and C57BL/6NCrl mice and, potentially, between diverse human populations.
Asunto(s)
Infecciones por Bacteroidaceae/microbiología , Peso Fetal , Periodontitis/microbiología , Porphyromonas gingivalis/patogenicidad , Complicaciones Infecciosas del Embarazo/microbiología , Células Th17/microbiología , Animales , Infecciones por Bacteroidaceae/inmunología , Infecciones por Bacteroidaceae/patología , Modelos Animales de Enfermedad , Femenino , Feto , Expresión Génica , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Boca/inmunología , Boca/microbiología , Periodontitis/inmunología , Periodontitis/patología , Placenta/inmunología , Placenta/microbiología , Porphyromonas gingivalis/inmunología , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/patología , Especificidad de la Especie , Células Th17/inmunologíaRESUMEN
Bordetella bronchiseptica is an etiologic agent of respiratory diseases in animals and humans. Despite the widespread use of veterinary B. bronchiseptica vaccines, there is limited information on their composition and relative efficacy and on the immune responses that they elicit. Furthermore, human B. bronchiseptica vaccines are not available. We leveraged the dual antigenic and adjuvant functions of Bordetella colonization factor A (BcfA) to develop acellular B. bronchiseptica vaccines in the absence of an additional adjuvant. BALB/c mice immunized with BcfA alone or a trivalent vaccine containing BcfA and the Bordetella antigens FHA and Prn were equally protected against challenge with a prototype B. bronchiseptica strain. The trivalent vaccine protected mice significantly better than the canine vaccine Bronchicine and provided protection against a B. bronchiseptica strain isolated from a dog with kennel cough. Th1/17-polarized immune responses correlate with long-lasting protection against bordetellae and other respiratory pathogens. Notably, BcfA strongly attenuated the Th2 responses elicited by FHA and Prn, resulting in Th1/17-skewed responses in inherently Th2-skewed BALB/c mice. Thus, BcfA functions as both an antigen and an adjuvant, providing protection as a single-component vaccine. BcfA-adjuvanted vaccines may improve the efficacy and durability of vaccines against bordetellae and other pathogens.