RESUMEN
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
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Metabolismo Energético , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-33/metabolismo , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Biomarcadores , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Inflamación/etiología , Activación de Macrófagos/genética , Mitocondrias/genética , Mitocondrias/inmunología , Mitocondrias/metabolismo , Fagocitos , Transducción de SeñalRESUMEN
Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-κB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-κB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.
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Desdiferenciación Celular , Transformación Celular Neoplásica , Neoplasias del Colon/patología , Células Madre Neoplásicas/patología , Animales , Colon/patología , Células Epiteliales/patología , Femenino , Humanos , Masculino , Ratones , FN-kappa B/metabolismo , Vía de Señalización WntRESUMEN
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunologic, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs). METHODS: Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n = 22), PSC-IBD (n = 45), and control individuals (n = 27) was performed to detect OMVs in the systemic circulation and liver. RESULTS: In both preclinical model systems and in patients with PSC-IBD, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on Toll-like receptor 4 and NLRP3-gasdermin-D. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2-/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort. CONCLUSIONS: This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier and, thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy.
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BACKGROUND: Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment. METHODS: Data from the European Anaphylaxis Registry (2007-2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly. RESULTS: Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use. CONCLUSION: The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines.
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Anafilaxia , Hipersensibilidad a las Drogas , Humanos , Femenino , Anafilaxia/diagnóstico , Hipersensibilidad a las Drogas/diagnóstico , Epinefrina/uso terapéutico , Sistema de Registros , Fenotipo , Antibacterianos/uso terapéuticoRESUMEN
INTRODUCTION: Tuberculosis (TB) and intestinal helminths have huge public health importance, and they are geographically overlapped. Data about the burden of intestinal helminth and TB co-infection in these areas are fragmented. In this systematic review and meta-analysis we compile the current literatures and generate pooled prevalence. We also identity factors associated with intestinal helminth co-infection among TB patients. METHODS: Original articles published in English language up to March 23, 2022 were systematically searched from electronic database (PubMed/Medline, Scopus, Science Direct, Google Scholars and HINARI). The search was done using medical subject heading terms and keywords. Identified articles were exported into the EndNote library. The identified articles were screened using PRISMA flow diagram. Then the methodological quality of included articles was evaluated and rated using the modified version of Newcastle-Ottawa Scale. Data were extracted using Microsoft Excel. Sensitivity analysis and Egger regression test were used for the assessment of heterogeneity and publication bias. Finally the results are presented with a meta-analysis of pooled estimates, forest plots, and tables. The quantitative data were analyzed using Stata version 14. RESULTS: From a total of 5457 searched articles, 22 eligible articles were included in the review. The pooled prevalence of helminth co-infection among TB cases was 29.69% (95%CI: 21.10, 38.29). TB patients were found to more frequently harbor one or more intestinal helminths than TB negative individuals (OR = 1.72 (95%CI: 1.20, 2.48)). Among the reported helminths, Schistosoma mansoni and Strongyloides stercoralis had the highest pooled prevalence among TB cases. However, unlike other individual helminths, only Strongyloides stercoralis (OR = 2.67 (95% CI, 1.20-6.76)) had significant association with TB cases compared to TB negatives. BMI was significantly associated with intestinal helminth co-infection among TB patients (OR = 2.75 (95%CI: 1.19, 6.38)). CONCLUSIONS: Patients with TB have been shown to harbor co-infection with one or more intestinal helminths with considerable proportions when compared with TB-negative individuals. The higher prevalence of helminth infection in TB cases might indicate that co-infection promotes active TB disease. Thus, routine intestinal helminth screening and assessment of their nutritional status is suggested for TB patients.
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Coinfección , Helmintos , Tuberculosis Pulmonar , Tuberculosis , Animales , Humanos , Coinfección/epidemiología , Factores de Riesgo , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/epidemiología , Tuberculosis/complicaciones , Tuberculosis/epidemiología , África , AsiaRESUMEN
Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c+ dendritic cells (DCs) into the skin and spleen of psoriatic mice with diacerein treatment. As CD11c+ DCs play a pivotal role in psoriasis pathology, we consider diacerein to be a promising novel therapeutic candidate for psoriasis.
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Dermatitis , Psoriasis , Animales , Ratones , Bazo/metabolismo , Ratones Endogámicos C57BL , Piel/metabolismo , Psoriasis/patología , Dermatitis/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
TNF blockade is a successful treatment for human autoimmune disorders like rheumatoid arthritis and inflammatory bowel disease yet increases susceptibility to tuberculosis and other infections. The C-type lectin receptors (CLR) MINCLE, MCL, and DECTIN-2 are expressed on myeloid cells and sense mycobacterial cell wall glycolipids. In this study, we show that TNF is sufficient to upregulate MINCLE, MCL, and DECTIN-2 in macrophages. TNF signaling through TNFR1 p55 was required for upregulation of these CLR and for cytokine secretion in macrophages stimulated with the MINCLE ligand trehalose-6,6-dibehenate or infected with Mycobacterium bovis bacillus Calmette-Guérin. The Th17 response to immunization with the MINCLE-dependent adjuvant trehalose-6,6-dibehenate was specifically abrogated in TNF-deficient mice and strongly attenuated by TNF blockade with etanercept. Together, interference with production or signaling of TNF antagonized the expression of DECTIN-2 family CLR, thwarting vaccine responses and possibly increasing infection risk.
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Lectinas Tipo C/metabolismo , Mycobacterium bovis/fisiología , Receptores Inmunológicos/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Células Th17/inmunología , Tuberculosis/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Células Cultivadas , Etanercept/administración & dosificación , Lectinas Tipo C/genética , Activación de Macrófagos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Inmunológicos/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Fosfatos de Azúcar/metabolismo , Trehalosa/análogos & derivados , Trehalosa/metabolismo , Tuberculosis/veterinaria , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ-induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ-induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.
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Factores Cordón/metabolismo , Proteínas de Unión al GTP/metabolismo , Inflamación/microbiología , Lectinas Tipo C/metabolismo , Macrófagos/fisiología , Proteínas de la Membrana/metabolismo , Mycobacterium tuberculosis/fisiología , Tuberculosis/microbiología , Animales , Presentación de Antígeno , Células Cultivadas , Proteínas de Unión al GTP/genética , Perfilación de la Expresión Génica , Humanos , Inflamación/inmunología , Interferón gamma/metabolismo , Lectinas Tipo C/genética , Activación de Macrófagos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Tuberculosis/inmunologíaRESUMEN
BACKGROUND: There is controversy whether taking ß-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT). METHODS: In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking ß-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment. RESULTS: In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took ß-blockers, 11.9% ACEI, 5.0% ß-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43-1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of ß-blockers or ACEI (OR: 1.14, 95% CI: 0.89-1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took ß-blockers, none an ACEI. CONCLUSIONS: This trial provides robust evidence that taking ß-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).
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Anafilaxia , Venenos de Abeja , Mordeduras y Picaduras de Insectos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Desensibilización Inmunológica , Humanos , Estudios Prospectivos , Factores de RiesgoRESUMEN
Immune sensing of Mycobacterium tuberculosis relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor (CLR) MINCLE. To explore the kinase signaling linking the TDM-MINCLE interaction to gene expression, we employed quantitative phosphoproteome analysis. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14,000 phospho-sites identified on 3727 proteins. MINCLE-dependent phosphorylation was observed for canonical players of CLR signaling (e.g. PLCγ, PKCδ), and was enriched for PKCδ and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85α. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatics analysis of both data sets concurred in the requirement for MINCLE for innate immune response pathways and processes. In contrast, MINCLE-independent phosphorylation and transcriptome responses were linked to cell cycle regulation. Collectively, our global analyses show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.
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Factores Cordón/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Fosfoproteínas/metabolismo , Proteoma/metabolismo , Proteómica , Transducción de Señal , Animales , Ciclo Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Factores Cordón/farmacología , Citocinas/metabolismo , Activación Enzimática/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucolípidos/metabolismo , Cinética , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/genética , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mycobacterium tuberculosis/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Quinasa Syk/metabolismo , Transcriptoma/genética , Trehalosa/metabolismoRESUMEN
The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1 Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma.
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Linfocitos B/clasificación , Linfocitos B/fisiología , Factores de Transcripción Forkhead/metabolismo , Proteínas Represoras/metabolismo , Animales , Anticuerpos/metabolismo , Antígenos CD19/metabolismo , Factores de Transcripción Forkhead/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Proteínas Represoras/genética , Linfocitos T/fisiología , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
AIMS: Despite their low individual metastatic potential, thin melanomas (≤1 mm Breslow thickness) contribute significantly to melanoma mortality overall. Therefore, identification of prognostic biomarkers is particularly important in this subgroup of melanoma. Prompted by preclinical results, we investigated cyclin D1 protein and Ki-67 expression in in-situ, metastatic and non-metastatic thin melanomas. METHODS AND RESULTS: Immunohistochemistry was performed on 112 melanoma specimens, comprising 22 in situ, 48 non-metastatic and 42 metastatic thin melanomas. Overall, epidermal and dermal cyclin D1 and Ki-67 expression were semiquantitatively evaluated by three independent investigators and compared between groups. Epidermal Ki-67 expression did not differ statistically in in-situ and invasive melanoma (P = 0.7). Epidermal cyclin D1 expression was significantly higher in thin invasive than in in-situ melanoma (P = 0.003). No difference was found in cyclin D1 expression between metastatic and non-metastatic invasive tumours. Metastatic and non-metastatic thin melanomas did not show significant differences in epidermal expression of Ki-67 and cyclin D1 (P = 0.148 and P = 0.611, respectively). In contrast, strong dermal expression of Ki-67 was more frequent in metastatic than non-metastatic samples (28.6 versus 8.3%, respectively, P = 0.001). The prognostic value of dermal Ki-67 expression was confirmed by multivariate analysis (P = 0.047). CONCLUSION: We found an increased expression of cyclin D1 in invasive thin melanomas compared to in-situ melanomas, which supports a potential role of this protein in early invasion in melanoma, as suggested by preclinical findings. Moreover, our results confirm that high dermal Ki-67 expression is associated with an increased risk of development of metastasis in thin melanoma and could possibly serve as a prognostic biomarker in clinical practice, especially if combined with additional methods.
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Biomarcadores de Tumor/análisis , Ciclina D1/metabolismo , Antígeno Ki-67/metabolismo , Melanoma/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Pronóstico , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Patients with a history of anaphylaxis are at risk of future anaphylactic reactions. Thus, secondary prevention measures are recommended for these patients to prevent or attenuate the next reaction. METHODS: Data from the Anaphylaxis Registry were analyzed to identify secondary prevention measures offered to patients who experienced anaphylaxis. Our analysis included 7788 cases from 10 European countries and Brazil. RESULTS: The secondary prevention measures offered varied across the elicitors. A remarkable discrepancy was observed between prevention measures offered in specialized allergy centers (84% of patients were prescribed adrenaline autoinjectors following EAACI guidelines) and outside the centers: Here, EAACI guideline adherence was only 37%. In the multivariate analysis, the elicitor of the reaction, age of the patient, mastocytosis as comorbidity, severity of the reaction, and reimbursement/availability of the autoinjector influence physician's decision to prescribe one. CONCLUSIONS: Based on the low implementation of guidelines concerning secondary prevention measures outside of specialized allergy centers, our findings highlight the importance of these specialized centers and the requirement of better education for primary healthcare and emergency physicians.
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Anafilaxia , Prevención Secundaria , Anafilaxia/epidemiología , Anafilaxia/etiología , Anafilaxia/prevención & control , Brasil , Epinefrina , Europa (Continente)/epidemiología , Humanos , Sistema de RegistrosRESUMEN
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.
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Encéfalo/metabolismo , Endopeptidasas/deficiencia , Interferones/metabolismo , Microglía/metabolismo , Modelos Neurológicos , Transducción de Señal/fisiología , Animales , Western Blotting , Clonación Molecular , Cartilla de ADN/genética , Endopeptidasas/genética , Endopeptidasas/metabolismo , Técnicas Histológicas , Ratones , Ratones Noqueados , Análisis por Micromatrices , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Estadísticas no Paramétricas , Ubiquitina TiolesterasaRESUMEN
Several spleen tyrosine kinase-coupled C-type lectin receptors (CLRs) have emerged as important pattern recognition receptors for infectious danger. Because encounter with microbial pathogens leads to the simultaneous ligation of several CLRs and TLRs, the signals emanating from different pattern recognition receptors have to be integrated to achieve appropriate biological responses. In this review, we briefly summarize current knowledge about ligand recognition and core signaling by Syk-coupled CLRs. We then address mechanisms of synergistic and antagonistic crosstalk between different CLRs and with TLRs. Emerging evidence suggests that signal integration occurs through 1) direct interaction between receptors, 2) regulation of expression levels and localization, and 3) collaborative or conflicting signaling interference. Accordingly, we aim to provide a conceptual framework for the complex and sometimes unexpected outcome of CLR ligation in bacterial and fungal infection.
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Lectinas Tipo C/metabolismo , Transducción de Señal , Quinasa Syk/metabolismo , Animales , Células Dendríticas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lectinas Tipo C/inmunología , Ratones , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismoRESUMEN
RATIONALE: In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or noninfectious diseases via antibody-independent mechanisms. In tuberculosis (TB), B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. OBJECTIVES: To document the role of B cells in TB in an unbiased manner. METHODS: We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice and validated the identified key pathways using in vitro and in vivo assays. The obtained data were substantiated using B cells from pleural effusion of patients with TB. MEASUREMENTS AND MAIN RESULTS: B cells isolated from Mtb-infected mice displayed a STAT1 (signal transducer and activator of transcription 1)-centered signature, suggesting a role for IFNs in B-cell response to infection. B cells stimulated in vitro with Mtb produced type I IFN, via a mechanism involving the innate sensor STING (stimulator of interferon genes), and antagonized by MyD88 (myeloid differentiation primary response 88) signaling. In vivo, B cells expressed type I IFN in the lungs of Mtb-infected mice and, of clinical relevance, in pleural fluid from patients with TB. Type I IFN expression by B cells induced an altered polarization of macrophages toward a regulatory/antiinflammatory profile in vitro. In vivo, increased provision of type I IFN by B cells in a murine model of B cell-restricted Myd88 deficiency correlated with an enhanced accumulation of regulatory/antiinflammatory macrophages in Mtb-infected lungs. CONCLUSIONS: Type I IFN produced by Mtb-stimulated B cells favors macrophage polarization toward a regulatory/antiinflammatory phenotype during Mtb infection.
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Linfocitos B/metabolismo , Interferón Tipo I/metabolismo , Macrófagos/metabolismo , Tuberculosis/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Pulmón/metabolismo , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis , Transducción de Señal , Bazo/metabolismo , Bazo/microbiologíaRESUMEN
Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [...].
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Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Susceptibilidad a Enfermedades , Fosfatasas de Especificidad Dual/química , Regulación de la Expresión Génica , Humanos , Inmunomodulación , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins. Finally, the pharmacological targeting of DUSPs is desirable to modulate immune and inflammatory responses.
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Fosfatasas de Especificidad Dual/inmunología , Inmunidad , Animales , Fosfatasas de Especificidad Dual/genética , Regulación Enzimológica de la Expresión Génica , Humanos , Infecciones/genética , Infecciones/inmunología , Inflamación/genética , Inflamación/inmunología , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/inmunología , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/inmunología , Modelos MolecularesRESUMEN
Immunoglobulin G (IgG) glycosylation can modulate antibody effector functions. Depending on the precise composition of the sugar moiety attached to individual IgG glycovariants either pro- or anti-inflammatory effector pathways can be initiated via differential binding to type I or type II Fc-receptors. However, an in depth understanding of how individual IgG subclasses are glycosylated during the steady state and how their glycosylation pattern changes during vaccination is missing. To monitor IgG subclass glycosylation during the steady state and upon vaccination of mice with different T-cell dependent and independent antigens, tryptic digests of serum, and antigen-specific IgG preparations were analyzed by reversed phase-liquid chromatography-mass spectrometry. We show that there is a remarkable difference with respect to how individual IgG subclasses are glycosylated during the steady state. More importantly, upon T-cell dependent and independent vaccinations, individual antigen-specific IgG subclasses reacted differently with respect to changes in individual glycoforms, suggesting that the IgG subclass itself is a major determinant of restricting or allowing alterations in specific IgG glycovariants.
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Antígenos/inmunología , Inmunoglobulina G/inmunología , Vacunación/métodos , Animales , Formación de Anticuerpos/inmunología , Femenino , Glicopéptidos/inmunología , Glicopéptidos/metabolismo , Glicosilación , Inmunoglobulina G/metabolismo , Espectrometría de Masas/métodos , Ratones Endogámicos C57BL , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Azúcares/química , Azúcares/inmunología , Azúcares/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient respiration due to mitochondrial defects, and concomitant enhancement of lactate production due to increased aerobic glycolysis. We analysed 48 melanoma samples by immunohistochemistry and found that 38% of melanomas are characterized by areas of isolated or combined deficiencies of complexes of the oxidative phosphorylation (OXPHOS) system, whereby the incidence of OXPHOS-deficient areas is associated with an increased Breslow index; 62% of melanomas showed high expression of all OXPHOS complexes. Expression of carbonic anhydrase IX was low, indicating that melanomas generally are well-oxygenated. Expression of HIF-1α and MCT4 was high, which might be a consequence of increased lactate dehydrogenase A levels in melanomas. Our data indicate that there are two types of melanomas: one that features a classic Warburg effect, whereas the other one, despite being glycolytic, maintains a high level of OXPHOS complexes.