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Soybean is one of the most important crops for producing high quality oil and protein. Mineral nutrient deficiencies are frequently observed in soybeans. However, there are few studies to understand the absorption process of mineral nutrients in soybeans. Here, we investigated the functions of soybean (Glycine max L.) IRT1.1 (IRON-REGULATED TRANSPORTER 1.1) in the transportation of mineral elements. Heterologous expression of GmIRT1.1 in yeast mutants revealed that GmIRT1.1 compensated for the growth defects of Δfet3fet4 and Δsmf1 mutants under iron (Fe) and manganese (Mn) deficiency conditions, respectively, and enhanced the sensitivity of the Δycf1 mutant to cadmium (Cd) toxicity. Expression analysis revealed that GmIRT1.1 was only significantly induced by Fe deficiency and was primarily expressed in roots. Furthermore, the GmIRT1.1 overexpression lines enhanced Arabidopsis tolerance to Fe deficiency, leading to increased accumulation of Fe in the roots and shoots. Additionally, the transgenic lines increased the sensitivity to Mn and Cd toxicity. Subcellular localization analysis revealed that GmIRT1.1 was localized on the plasma membrane. Moreover, the results obtained from the soybean hairy roots system indicated that the localization of GmIRT1.1 was dependent on the regulation of Fe homeostasis in plant. Consequently, these results suggested that GmIRT1.1 was responsible for the transportation of Fe, Mn and Cd.
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Currently, the treatment of diabetic wounds in clinical practice is still unsatisfactory due to the risks of oxidative damage and bacterial infection during the healing process. An optimal wound dressing should exhibit robust capabilities in scavenging reactive oxygen species (ROS) and combatting bacterial growth. In this study, we utilized borax as a crosslinker and prepared a pH/glucose dual-responsive composite hydrogel based on poly(vinyl alcohol) (PVA), sodium alginate (SA), and tannic acid (TA). This hydrogel, loaded with cerium dioxide, serves as an effective ROS scavenger, promoting wound closure by reducing the level of ROS in the wound area. Additionally, the hydrogel can release the antibacterial drug ofloxacin in response to the low pH and high glucose microenvironment in infected wounds. Results from skin defect model in diabetic mice demonstrated this ROS-scavenging and antibacterial hydrogel can suppress inflammation and accelerate wound healing. In summary, our work provides a new perspective on a local and stimulus-responsive drug delivery strategy for treating diabetic wounds.
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Antibacterianos , Diabetes Mellitus Experimental , Glucosa , Hidrogeles , Especies Reactivas de Oxígeno , Cicatrización de Heridas , Animales , Cicatrización de Heridas/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Especies Reactivas de Oxígeno/metabolismo , Ratones , Concentración de Iones de Hidrógeno , Hidrogeles/química , Hidrogeles/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Alginatos/química , Alginatos/farmacología , Taninos/química , Taninos/farmacología , Alcohol Polivinílico/química , Cerio/química , Cerio/farmacología , MasculinoRESUMEN
Upon infection, CD8+ T cells that have been primed in the draining lymph nodes migrate to the invaded tissue, where they receive cues prompting their differentiation into tissue-resident memory cells (Trm), which display niche-specific transcriptional features. Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in specific anatomical niches such as the large intestine (LI). Here, we report that LI Trm-generated following oral infection exhibits a distinct transcriptional profile compared to Trm in other tissues. Notably, we observe that local cues play a crucial role in the preferential establishment of LI Trm, favoring precursors that migrate to the tissue early during infection. Our investigations identify cognate antigen recognition as a major driver of Trm differentiation at this anatomical site. Local antigen presentation not only promotes the proliferation of effector cells and memory precursors but also facilitates the acquisition of transcriptional features characteristic of gut Trm. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.
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Disección Aórtica , Isquemia Mesentérica , Periodo Posparto , Humanos , Femenino , Disección Aórtica/cirugía , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/complicaciones , Disección Aórtica/etiología , Isquemia Mesentérica/etiología , Isquemia Mesentérica/cirugía , Adulto , Enfermedad Aguda , Aneurisma de la Aorta/cirugía , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/complicaciones , EmbarazoRESUMEN
Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is a significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract. There, the bacterium is usually present at low density but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood, yet it may be relevant to devise strategies to tackle CR-Kp colonization and infection. Here, we adopted an in vivo model to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, treatment increased the concentration of oxidative species and amino acids in the mouse intestine. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were strongly upregulated, however their deletion did not impair CR-Kp fitness in vivo upon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein, CRP, as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, crp deletion in CR-Kp resulted in strongly impaired gut colonization, although this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance toward bacterial fitness warrants further investigation. Additional analyses utilizing this model may identify key factors to tackle CR-Kp colonization of the intestine.
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Antibacterianos , Intestinos , Infecciones por Klebsiella , Klebsiella pneumoniae , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/inmunología , Animales , Ratones , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/inmunología , Intestinos/microbiología , Intestinos/inmunología , Antibacterianos/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Regulación Bacteriana de la Expresión Génica , Carbapenémicos/farmacología , Ratones Endogámicos C57BL , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Femenino , HumanosRESUMEN
BACKGROUND: Non-standardized insulin injection has an impact on the efficacy of glucose control. OBJECTIVES: The aim of the study was to explore the effectiveness of a nursing project in improving the insulin self-injection accuracy of diabetes mellitus patients. MATERIAL AND METHODS: A total of 200 type 2 diabetes patients who received insulin therapy with an insulin pen were recruited at the First Affiliated Hospital of Army Medical University (Chongqing, China). Patients were randomly assigned to a control (n = 100) or intervention (n = 100) group. Conventional health education was conducted in the control group, while a nursing project and conventional health education were undertaken in the intervention group. The following parameters were analyzed between the 2 groups: standardized insulin pen use at admission and discharge, glycosylated hemoglobin (HbA1c), time in range (TIR), and adipose hyperplasia incidence rate 6 months after discharge. RESULTS: Concerning standardized insulin self-injection, the intervention group was superior to the control group, and the difference between the 2 groups was statistically significant (p < 0.05). The HbA1c levels (p = 0.000), TIR (p = 0.005) and adipose hyperplasia incidence rate 6 months after discharge (p = 0.000) all improved in the intervention group compared to the control group. CONCLUSIONS: The application of the nursing project effectively improved the efficacy of glucose control in diabetes mellitus patients.
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The tilting of the cab seat when the tractor is in deep ploughing operation changes the sitting position of the driver, which may accelerate lumbar spine injury. This paper adopts the musculoskeletal model and the finite element model of the lumbar L4-L5 segment to predict the maximum Von-Mises stress and maximum strain of the driver's lumbar L4-L5 segment intervertebral disc. In this study, we used 3D motion capture to obtain the driver's spine position spatial data when the tractor tilted at different angles. A tractor-driver musculoskeletal model and a finite element model of the lumbar spine L4-L5 segments were created in AnyBody™ and Abaqus, respectively. The tractor-driver musculoskeletal model was used to calculate the load of the driver's lumbar spine L4-L5 segment at different angles of tractor tilt, which was used as the load condition of the finite element model of the lumbar spine L4-L5 segment, and then the influence of tractor tilt angle and vibration on the driver's lumbar spine L4-L5 disc was studied. The results show that the maximum Von-Mises stress and maximum strain of the driver's lumbar L4-L5 intervertebral disc will increase due to the tilt. The maximum Von-Mises stress occurs in the annulus II, and the maximum strain occurs in the upper end plate of the intervertebral disc. With the occurrence of tilt, the position of the maximum Von-Mises stress changes, which can lead to disc injury to the driver, and vibration may exacerbate this injury.
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Disco Intervertebral , Análisis de Elementos Finitos , Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Vibración , Movimiento (Física) , Rango del Movimiento Articular , Fenómenos BiomecánicosRESUMEN
The tilting of the tractors' seat during deep tillage operations affects the drivers' sitting position, which can lead to lumbar spine injuries. To investigate the effect of seat tilting on the driver's L4 biomechanics, we built a tractor-driver musculoskeletal model in AnyBody™. The maximum activity of the driver's erector spinae at different tilted angles were measured by sEMG and compared with the simulation results to validate the model. The spatial position of the driver's spine at different tilted angles were obtained by 3 D motion capture. The model simulated the driver's spine posture during the actual tilt and investigated the effects of different tilted angles and vibration on the biomechanics of the driver's L4 . The results showed that as the tilt angle of the tractor increased, the load on the driver's L4 also increased, especially the shear force increased at a faster rate than the axial and normal forces, with the shear force on the driver's L4 increasing from 0 N to 138.7 N when the tractor was tilted from 0° to 15°. When vibration was applied to the musculoskeletal model, the maximum value of the shear force on the driver became progressively greater as the angle of tilt of the tractor increased. Overall, tilting the tractor can have a large impact on the biomechanics of the driver's L4, and tilting the tractor may be an important cause of lumbar spine injuries for tractor drivers.
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Conducción de Automóvil , Columna Vertebral , Fenómenos Biomecánicos , Sedestación , VibraciónRESUMEN
Tissue-resident memory T cells (Trm), and particularly the CD8+ subset, have been shown to play a pivotal role in protection against infections and tumors. Studies in animal models and human tissues have highlighted that, while a core functional program is shared by Trm at all anatomical sites, distinct tissues imprint unique features through specific molecular cues. The intestinal tissue is often the target of pathogens for local proliferation and penetration into the host systemic circulation, as well as a prominent site of tumorigenesis. Therefore, promoting the formation of Trm at this location is an appealing therapeutic option. The various segments composing the gastrointestinal tract present distinctive histological and functional characteristics, which may reflect on the imprinting of unique functional features in the respective Trm populations. What these features are, and whether they can effectively be harnessed to promote local and systemic immunity, is still under investigation. Here, we review how Trm are generated and maintained in distinct intestinal niches, analyzing the required molecular signals and the models utilized to uncover them. We also discuss evidence for a protective role of Trm against infectious agents and tumors. Finally, we integrate the knowledge obtained from animal models with that gathered from human studies.
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Memoria Inmunológica , Neoplasias , Animales , Linfocitos T CD8-positivos , Humanos , Intestinos/patología , Células T de MemoriaRESUMEN
Carma3 is an intracellular scaffolding protein that can form complex with Bcl10 and Malt1 to mediate G protein-coupled receptor- or growth factor receptor-induced NF-κB activation. However, the in vivo function of Carma3 has remained elusive. Here, by establishing a Con A-induced autoimmune hepatitis model, we show that liver injury is exacerbated in Carma3 -/- mice. Surprisingly, we find that the Carma3 expression level is higher in liver sinusoidal endothelial cells (LSECs) than in hepatocytes in the liver. In Carma3 -/- mice, Con A treatment induces more LSEC damage, accompanied by severer coagulation. In vitro we find that Carma3 localizes at mitochondria and Con A treatment can trigger more mitochondrial damage and cell death in Carma3-deficient LSECs. Taken together, our data uncover an unrecognized role of Carma3 in maintaining LSEC integrity, and these results may extend novel strategies to prevent liver injury from toxic insults.
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Células Endoteliales , FN-kappa B , Animales , Células Endoteliales/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones , Mitocondrias/metabolismo , FN-kappa B/metabolismoRESUMEN
Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of the TNF-α-induced cell death program. The function of RIPK1 is tightly controlled by posttranslational modifications, including linear ubiquitin chain assembly complex-mediated linear ubiquitination. However, the physiological function and molecular mechanism by which linear ubiquitination of RIPK1 regulates TNF-α-induced intracellular signaling remain unclear. In this article, we identified Lys627 residue as a major linear ubiquitination site in human RIPK1 (or Lys612 in murine RIPK1) and generated Ripk1K612R/K612R mice, which spontaneously develop systemic inflammation triggered by sustained emergency hematopoiesis. Mechanistically, without affecting NF-κB activation, Ripk1K612R/K612R mutation enhances apoptosis and necroptosis activation and promotes TNF-α-induced cell death. The systemic inflammation and hematopoietic disorders in Ripk1K612R/K612R mice are completely abolished by deleting TNF receptor 1 or both RIPK3 and Caspase-8. These data suggest the critical role of TNF-α-induced cell death in the resulting phenotype in Ripk1K612R/K612R mice. Together, our results demonstrate that linear ubiquitination of RIPK1 on K612 is essential for limiting TNF-α-induced cell death to further prevent systemic inflammation.
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Apoptosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Muerte Celular , Células HEK293 , Humanos , Inflamación , Ratones , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , UbiquitinaciónRESUMEN
The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression of immunotherapy prognostic marker genes (IPMGs) in these pathways can predict the patient survival with high accuracy not only in the TCGA cohort (89.36%) but also in two other independent cohorts (80.91%), highlighting that the activity of the IPMGs can reflect the sensitivity of the tumor immune microenvironment (TIME) to immunotherapies. Using mouse models, we show that knockout of one of the IPMGs, MALT1, which is critical for the T-cell receptor signaling, can eliminate the antitumor effect of anti-PD-1 treatment completely by impairing the activation of CD8+ T cells. Notably, knockout of another IPMG, CLEC4D, a C-type lectin receptor that expressed on myeloid cells, also reduced the effect of anti-PD-1 treatment potentially through maintaining the immunosuppressive effects of myeloid cells. Our results suggest that priming TIME via activating the IPMGs may increase the response rate and the effect of immune checkpoint blockers.
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Increasing evidence has supported the crucial role of CARD14 in the pathogenesis of psoriasis, whereas the precise cellular signaling involved in skin physiopathology remains poorly understood. In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14 E138A/+- and Card14 ΔQ136/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.
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Interleucina-23/inmunología , Queratinocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Psoriasis/inmunología , Piel/inmunología , Células Th17/inmunología , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-23/genética , Queratinocitos/patología , Ratones , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Psoriasis/genética , Psoriasis/patología , Piel/patología , Células Th17/patologíaRESUMEN
OBJECTIVE: Circulating miR-146a is aberrantly expressed in patients with type 2 diabetes (T2D), probably resulting from gene polymorphisms. However, the role of polymorphism rs2910164 in T2D pathogenesis remains controversial. Thus, we designed a meta-analysis to investigate the association between rs2910164 and T2D. METHODS: PubMed and Embase were searched for eligible papers in English published through September 2, 2019. Random or fixed effect models were used to determine risk estimates according to heterogeneities. RESULTS: Four studies, involving 2,069 patients and 1,950 controls, were included. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. The pooled ORs and 95% CIs were 1.501 (0.887-2.541), 1.102 (0.931-1.304), 1.276 (0.900-1.811), 1.204 (0.878-1.652), 1.238 (0.880-1.740), and 1.350 (0.904-2.016) under the homozygote, heterozygote (CG vs. GG and CC vs. CG), dominant, allele, and recessive models, respectively. Heterogeneity was detected in most genetic models, with subgroup analyses performed by ethnicity, genotyping method, and disease duration. The co-dominant model was determined to be the most appropriate genetic model. CONCLUSIONS: Our findings suggested that polymorphism rs2910164 is not correlated with T2D susceptibility. However, the results should be interpreted with caution because of confounding factors.
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Diabetes Mellitus Tipo 2 , MicroARNs/genética , Pueblo Asiatico , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
A systematic review and meta-analysis was conducted in an attempt to systematically collect and evaluate the associations of epidemiological, comorbidity factors with the severity and prognosis of coronavirus disease 2019 (COVID-19). The systematic review and meta-analysis was conducted according to the guidelines proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Sixty nine publications met our study criteria, and 61 studies with more than 10,000 COVID-19 cases were eligible for the quantitative synthesis. We found that the males had significantly higher disease severity (RR: 1.20, 95% CI: 1.13-1.27, P <0.001) and more prognostic endpoints. Older age was found to be significantly associated with the disease severity and six prognostic endpoints. Chronic kidney disease contributed mostly for death (RR: 7.10, 95% CI: 3.14-16.02), chronic obstructive pulmonary disease (COPD) for disease severity (RR: 4.20, 95% CI: 2.82-6.25), admission to intensive care unit (ICU) (RR: 5.61, 95% CI: 2.68-11.76), the composite endpoint (RR: 8.52, 95% CI: 4.36-16.65,), invasive ventilation (RR: 6.53, 95% CI: 2.70-15.84), and disease progression (RR: 7.48, 95% CI: 1.60-35.05), cerebrovascular disease for acute respiratory distress syndrome (ARDS) (RR: 3.15, 95% CI: 1.23-8.04), coronary heart disease for cardiac abnormality (RR: 5.37, 95% CI: 1.74-16.54). Our study highlighted that the male gender, older age and comorbidities owned strong epidemiological evidence of associations with the severity and prognosis of COVID-19.
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Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Betacoronavirus , COVID-19 , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Pronóstico , Factores de Riesgo , SARS-CoV-2 , Factores SexualesRESUMEN
The paracaspase Malt1 is a key molecule in mediating Ag receptor-induced NF-κB activation in lymphocytes, but the role of Malt1 in the function of regulatory T (Treg) cells is still unclear. In this article, we reported that specific deletion of Malt1 in Treg cells would lead to Scurfy-like lethal autoimmune disease, which was caused by Treg cell dysfunction but not number loss. Interestingly, Foxp3CreMalt1fl/C472A mice, in which Malt1 protease was specifically inactivated in Treg cells, also displayed spontaneous inflammatory disorders, with severe hair loss and skin hyperplasia. Consistently, Foxp3CreMalt1fl/C472A mice showed enhanced antitumor response because of their decreased function and infiltration of Treg cells, as well as reduced CD8+ T cell exhaustion. Gene expression profiling analysis revealed dysregulated expression pattern of Treg effector genes upon Malt1 deletion or its protease inactivation. Together, our data unraveled a critical role of Malt1, especially its protease activity, in maintaining homeostasis and function of Treg cells.
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Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD8-positivos/patología , Hiperplasia , Linfocitos Infiltrantes de Tumor/patología , Ratones , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Linfocitos T Reguladores/patologíaRESUMEN
Infection by invasive fungi, such as Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, is one of the leading death causes for the increasing population of immunocompromised and immunodeficient patients. Several C-type lectin receptors (CLRs), including Dectin-1, -2, and -3 and Mincle can recognize fungal surface components and initiate the host antifungal immune responses. Nevertheless, it remains to be determined whether other CLRs are involved in antifungal immunity. Our recent study suggests that CD23 (CLEC4J), a CLR and also a well-known B cell surface marker, may function to sense C. albicans components in antifungal immunity. However, it is not clear how CD23 functions as a fungal pattern recognition receptor and whether the antifungal role of CD23 is specific to C. albicans or not. In this study, we show that CD23 can recognize both α-mannan and ß-glucan from the cell wall of C. albicans or A. fumigatus but cannot recognize glucuronoxylomannan from Cryptococcus Through forming a complex with FcRγ, CD23 can induce NF-κB activation. Consistently, CD23-deficient mice were highly susceptible to C. albicans and A. fumigatus but not to C. neoformans infection. The expression of CD23 in activated macrophages is critical for the activation of NF-κB. CD23 deficiency results in impaired expression of NF-κB-dependent genes, especially iNOS, which induces NO production to suppress fungal infection. Together, our studies reveal the CD23-induced signaling pathways and their roles in antifungal immunity, specifically for C. albicans and A. fumigatus, which provides the molecular basis for designing potential therapeutic agents against fungal infection.
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Aspergilosis/inmunología , Aspergillus fumigatus/fisiología , Linfocitos B/metabolismo , Candida albicans/fisiología , Candidiasis/inmunología , Criptococosis/inmunología , Cryptococcus neoformans/fisiología , Receptores de IgE/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo , Animales , Inmunidad Innata , Mananos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Polisacáridos/metabolismo , Células RAW 264.7 , Receptores de IgE/genética , Receptores de Reconocimiento de Patrones/genética , Transducción de Señal , beta-Glucanos/metabolismoRESUMEN
The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9S12N), is associated with several autoimmune diseases. However, the function of CARD9S12N has remained unknown. Here we generated CARD9S12N knock-in mice and found that CARD9S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive TH2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9S12N can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell-mediated pathologic responses.
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Aspergilosis Broncopulmonar Alérgica/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Interleucina-5/biosíntesis , Macrófagos Alveolares/inmunología , Células Th2/inmunología , Animales , Aspergilosis Broncopulmonar Alérgica/genética , Proteínas Adaptadoras de Señalización CARD/genética , Humanos , Interleucina-5/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Polimorfismo de Nucleótido Simple , Transducción de Señal/inmunologíaRESUMEN
Zinc transporter 8 (ZnT8) is exclusively expressed in the pancreatic islet and is essential for insulin crystallization, hexamerization and secretion. Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger protein that serves a major role in the negative feedback regulation of NF-κB signaling in response to multiple stimuli, and is a central regulator of immunopathology. Although the role of TNFAIP3 in diabetes has been extensively studied, its effect on ZnT8 has not been fully elucidated. The present study aimed to verify whether proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1ß (IL-1ß), are able to affect ZnT8 expression in islet cells. In addition, the study aimed to determine the effect of TNFAIP3 overexpression on cytokine-altered ZnT8 activity, considering its effect on NF-κB signaling. Cell-based studies using NIT-1 cells overexpressing TNFAIP3 were used to assess the effect of cytokines on ZnT8 and NF-κB activation, as well as the effect of TNFAIP3 on ZnT8 expression. Western blot analysis and immunofluorescence staining were employed to determine the protein expression and NF-κB activation, respectively. The results indicated that cytokine stimulation led to TNFAIP3 upregulation, ZnT8 downregulation and NF-κB activation. Furthermore, TNFAIP3 overexpression protected ZnT8 from cytokine-induced downregulation. In conclusion, the current results suggest that inflammation or TNFAIP3 dysfunction may be involved in the pathogenesis of diabetes via ZnT8 expression, besides from islet cell apoptosis. In addition, restricting inflammation and enhancing TNFAIP3 expression may exert a positive effect in diabetes prevention, treatment and pancreatic cell transplantation.