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BACKGROUND: The association of soluble suppression of tumorigenesis-2 (sST2) levels with prognosis in pulmonary embolism (PE) is unknown. OBJECTIVE: This study aimed to investigate the relationship between sST2 levels in patients with acute PE and 6-month mortality and recurrent hospitalizations. METHODS: This prospective study included 100 patients with acute PE. Patients were classified into two groups according to 6-month mortality and the presence of recurrent Cardiovascular-Related hospitalizations. Two groups were compared. A p-value of 0.05 was considered statistically significant. RESULTS: Soluble ST2 levels were significantly higher in the group with mortality and recurrent hospitalizations. (138.6 ng/mL (56.7-236.8) vs. 38 ng/mL (26.3-75.4); p<0.001) The best cut-off threshold for sST2 levels in the prediction of a composite outcome of 6-month mortality and/or recurrent Cardiovascular-Related hospitalization was found to be >89.9 with a specificity of 90.6% and a sensitivity of 65.2%, according to the receiver operating characteristic curve (area under the curve = 0.798; 95% CI, 0.705-0.891; p <0.0001). After adjusting for confounding factors that were either statistically significant in the univariate analysis or for the variables correlated with the sST2 levels, sST2 level (OR = 1.019, 95% CI: 1.009-1.028, p 0.001) and C-reactive protein (CRP ) (OR = 1.010, 95% CI: 1.001-1.021, p = 0.046) continued to be significant predictors of 6-month mortality and/or recurrent Cardiovascular-Related hospitalization in the multiple logistic regression model via backward stepwise method. CONCLUSION: Soluble ST2 level seems to be a biomarker to predict 6-month mortality and/or recurrent Cardiovascular-Related hospitalization in patients with acute PE.
FUNDAMENTO: A associação de supressão solúvel da tumorigênese-2 (sST2) com prognóstico em embolia pulmonar (EP) é desconhecida. OBJETIVO: Este estudo teve como objetivo investigar a relação entre os níveis de sST2 em pacientes com EP aguda e mortalidade em 6 meses e hospitalizações recorrentes. MÉTODOS: Este estudo prospectivo incluiu 100 pacientes com EP aguda. Os pacientes foram classificados em dois grupos de acordo com a mortalidade em 6 meses e a presença de hospitalizações recorrentes relacionadas a doenças cardiovasculares. Dois grupos foram comparados. Um valor de p de 0,05 foi considerado estatisticamente significativo. RESULTADOS: Os níveis de ST2 solúvel foram significativamente maiores no grupo com mortalidade e internações recorrentes. (138,6 ng/mL (56,7-236,8) vs. 38 ng/mL (26,3-75,4); p<0,001) O melhor limite de corte para níveis de sST2 na previsão de um desfecho composto de mortalidade em 6 meses e/ou a hospitalização recorrente relacionada a doenças cardiovasculares foi >89,9, com especificidade de 90,6% e sensibilidade de 65,2%, de acordo com a curva Receiver Operating Characteristic (área sob a curva = 0,798; IC 95%, 0,7050,891; p <0,0001). Após ajuste para fatores de confusão que foram estatisticamente significativos na análise univariada ou para as variáveis correlacionadas com os níveis de sST2, nível de sST2 (OR = 1,019, IC 95%: 1,009-1,028, p 0,001) e proteína C reativa (PCR). (OR = 1,010, IC 95%: 1,001-1,021, p = 0,046) continuaram a ser preditores significativos de mortalidade em 6 meses e/ou hospitalização recorrente relacionada a doenças cardiovasculares no modelo de regressão logística múltipla através do método backward stepwise. CONCLUSÕES: O nível de ST2 solúvel parece ser um biomarcador para prever mortalidade em 6 meses e/ou hospitalização recorrente relacionada a doenças cardiovasculares em pacientes com EP aguda.
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Proteína 1 Similar al Receptor de Interleucina-1 , Embolia Pulmonar , Humanos , Estudios Prospectivos , Pronóstico , Biomarcadores , Enfermedad AgudaRESUMEN
BACKGROUND: Acinetobacter baumannii international clone II (IC2) is a widespread pandemic clone, however, it is rarely described in South America. The present study reported an outbreak caused by XDR IC2 strains in a clinical setting in Rio de Janeiro in 2022. METHODS: Molecular epidemiology analysis was conducted with MLST to determine the clonal relationship and to assign a sequence type. The antimicrobial resistance profile of A. baumannii strains was assessed by the disk-diffusion method and MIC determination, and the presence of antibiotic resistance genes was determined by PCR and Sanger sequencing. The whole genome of one representative strain (AB91) was sequenced to prospect its resistome and virulome. RESULTS: The MLST revealed that all strains belonged to the ST2 (Pasteur scheme) that corresponded to the pandemic IC2 lineage. They presented the XDR phenotype, which was compatible with their resistome composed of several acquired resistance genes and altered housekeeping genes. Additionally, an expressive virulome was revealed in AB91 genome. Genomic comparison with the unique other available IC2 genome from Brazil revealed that outbreaks occurring during (São Paulo - 2020/2021) and after (Rio de Janeiro - 2022) COVID-19 pandemics were caused by the same IC2 lineage. CONCLUSIONS: This study suggests that the presence of a huge arsenal of resistance and virulence genes may have contributed to the persistence and the successful establishment of IC2 in Brazilian clinical settings during and after the COVID-19 pandemics in response to a series of events, such as the antibiotic overused during that period.
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Acinetobacter baumannii , COVID-19 , Humanos , Brasil/epidemiología , Acinetobacter baumannii/genética , Proteína 1 Similar al Receptor de Interleucina-1 , Tipificación de Secuencias Multilocus , COVID-19/epidemiología , Brotes de Enfermedades , Antibacterianos/farmacología , Carbapenémicos/farmacologíaRESUMEN
OBJECTIVES: Among the high-risk clones of Acinetobacter baumannii, called international clones (ICs), IC2 represents the main lineage causing outbreaks worldwide. Despite the successful global spread of IC2, the occurrence of IC2 is rarely reported in Latin America. Here, we aimed to evaluate the susceptibility and genetic relatedness of isolates from a nosocomial outbreak in Rio de Janeiro/Brazil (2022) and perform genomic epidemiology analyses of the available genomes of A. baumannii. METHODS: Sixteen strains of A. baumannii were subjected to antimicrobial susceptibility tests and genome sequencing. These genomes were compared phylogenetically with other IC2 genomes from the NCBI database, and virulence and antibiotic resistance genes were searched. RESULTS: The 16 strains represented carbapenem-resistant A. baumannii (CRAB) with an extensively drug-resistant profile. In silico analysis established the relationship between the Brazilian CRAB genomes and IC2/ST2 genomes in the world. The Brazilian strains belonged to three sub-lineages, associated with genomes from countries in Europe, North America, and Asia. These sub-lineages presented three distinct capsules, KL7, KL9, and KL56. The Brazilian strains were characterised by the co-presence of blaOXA-23 and blaOXA-66, in addition to the genes APH(6), APH(3"), ANT(3"), AAC(6'), armA, and the efflux pumps adeABC and adeIJK. A large set of virulence genes was also identified: adeFGH/efflux pump; the siderophores barAB, basABCDFGHIJ, and bauBCDEF; lpxABCDLM/capsule; tssABCDEFGIKLM/T6SS; and pgaABCD/biofilm. CONCLUSION: Widespread extensively drug-resistant CRAB IC2/ST2 is currently causing outbreaks in clinical settings in southeastern Brazil. This is due to at least three sub-lineages characterised by an enormous apparatus of virulence and resistance to antibiotics, both intrinsic and mobile.
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Acinetobacter baumannii , Carbapenémicos , Brasil/epidemiología , beta-Lactamasas/genética , Proteína 1 Similar al Receptor de Interleucina-1 , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Brotes de Enfermedades , Acinetobacter baumannii/genéticaRESUMEN
Third molar extraction surgery is a frequentprocedure in dentistry. Like any surgical procedure, it may lead to inflammatory responses, and postoperative pain is one of its main complications. Furthermore, temporomandibular disorder (TMD) is a collective termfor several clinicalproblems involving orofacial structures. Patients withparafunction are more sensitive to mechanical stimuli such as pressure during surgical procedures. Aim: To analyze postoperative pain in patients with and without bruxism subjected to third molar extraction surgery. Materials and Method: This was an observational study including four groups with a 1:1:1:! allocation ratio, conducted following ethical approval. Patients classified as ASA I with an indication for lower third molar extraction were recruited. Bruxism was self-reported. Two surgical techniques were used: one with only forceps and levers (ST1) and another with osteotomy and odontosection (ST2). Results: Four groups (bruxism and surgical techniques) were enrolled, each with a convenience sample (n=34). Postoperative pain levels were higher in patients with than without bruxism (p<0.05). The comparison between surgical techniques showed significantly higher pain levels only on the seventh day for ST2 groups (p<0.05). Oral mucosaflap incisions did not cause significantly higher persistence and pain levels. Conclusions: Bruxism, osteotomy, and odontosection may have increased postoperative pain levels, whereas performing an oral mucosa flap did not cause significant differences. Nevertheless, these preliminary data should be interpreted carefully. Randomized controlled trials are required to reinforce the findings of this study.
A cirurgia de extragao de terceiros molares é um procedimento frequente na odontologia. Como em qualquer procedimento cirúrgico, pode levar a respostas inflamatorias. A dor pós-operatória é uma das principais complicagoes após a cirurgia de extragao de terceiros molares. Além disso, disfungao temporomandibular (DTM) é um termo coletivo para vários problemas clínicos envolvendo estruturas orofaciais. Pacientes com parafungao sao mais sensíveis a estímulos mecánicos como pressao durante procedimentos cirúrgicos. Objetivo: Analisar a dor pós-operatória em pacientes com e sem bruxismo submetidos á cirurgia de extragao de terceiros molares. Material e Método: Um estudo observacional incluindo quatro grupos com uma proporgao de alocagao de 1:1:1:1 foi realizado após aprovagao ética. Foram recrutados pacientes classificados como ASA I com indicagao de exodontia de terceiros molares inferiores. O bruxismo foi autorreferido e foram realizadas duas técnicas cirúrgicas: uma com apenas fórceps e alavancas (ST1) e outra com osteotomia e odontosecgao (ST2). Resultados: Foram incluidos quatro grupos (bruxismo e técnicas cirúrgicas), cada um com uma amostra de conveniencia (n=34). Os níveis de dor pós-operatória foram maiores em pacientes com bruxismo (p<0,05). A comparagao entre as técnicas cirúrgicas mostrou níveis de dor significativamente maiores apenas no sétimo diapara os grupos ST2 (p<0,05). Incisoes de retalhos de mucosa oral nao mostraram níveis de dor significativamente maiores. Conclusoes: Bruxismo, osteotomia e odontosecgaopodem aumentar os níveis de dor pós-operatória, enquanto a realizagao de retalho de mucosa oral nao apresenta diferengas significativas. No entanto, a interpretagao cuidadosa desses dados preliminares é recomendada, e ensaios clínicos randomizados sao necessários para fortalecer os achados deste estudo.
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Bruxismo , Humanos , Bruxismo/complicaciones , Proteína 1 Similar al Receptor de Interleucina-1 , Tercer Molar/cirugía , Dolor Postoperatorio , PacientesRESUMEN
Schistosoma mansoni eggs retained in host tissues induce innate cytokine release, contributing to the induction of Type-2 immune responses and granuloma formation, important to restrain cytotoxic antigens, but leading to fibrosis. Interleukin(IL)-33 participates in experimental models of inflammation and chemically induced fibrosis, but its role in S. mansoni-induced fibrosis is still unknown. To explore the role of the IL-33/suppressor of the tumorigenicity 2 (ST2) pathway, serum and liver cytokine levels, liver histopathology, and collagen deposition were comparatively evaluated in S. mansoni-infected wild-type (WT) and IL-33-receptor knockout (ST2-/-) BALB/c mice. Our data show similar egg counts and hydroxyproline in the livers of infected WT and ST2-/- mice; however, the extracellular matrix in ST2-/- granulomas was loose and disorganised. Pro-fibrotic cytokines, such as IL-13 and IL-17, and the tissue-repairing IL-22 were significantly lower in ST2-/- mice, especially in chronic schistosomiasis. ST2-/- mice also showed decreased α-smooth muscle actin (α-SMA) expression in granuloma cells, in addition to reduced Col III and Col VI mRNA levels and reticular fibres. Therefore, IL-33/ST2 signalling is essential for tissue repairing and myofibroblast activation during S. mansoni infection. Its disruption results in inappropriate granuloma organisation, partly due to the reduced type III and VI collagen and reticular fibre formation.
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Schistosoma mansoni , Esquistosomiasis mansoni , Ratones , Animales , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-33/genética , Cirrosis Hepática/patología , Hígado/metabolismo , Fibrosis , Citocinas , Ratones Endogámicos BALB C , Colágeno/metabolismo , Granuloma/patologíaRESUMEN
The Interleukin (IL)-33 is important in several inflammatory diseases and its cellular receptor is the Interleukin 1 receptor-like 1 (IL1RL1), also called suppression of tumorigenicity 2 ligand (ST2L). This study investigated associations between single nucleotide variants (SNVs) in the IL33 gene and in the IL1RL1 (ST2) gene with periodontitis. Additionally, aimed to determine the role of Aggregatibacter actinomycetemcomitans (Aa) relative amount in the subgingival biofilm in these associations. A cross-sectional study was carried out with 506 individuals that answered a structured questionnaire used to collect their health status, socioeconomic-demographic, and behavioral characteristics. Periodontal examination was performed to determine the presence and severity of periodontitis, and subgingival biofilm samples were collected to quantify the relative amount of Aa by real time polymerase chain reaction. Human genomic DNA was extracted from whole blood cells and SNV genotyping was performed. Logistic regression estimated the association measurements, odds ratio (OR), and 95% confidence interval (95%CI), between the IL33 and ST2 genes with periodontitis, and subgroup analyses assessed the relative amount of Aa in these associations. 23% of individuals had periodontitis. Adjusted measurements showed a statistically significant inverse association between two SNVs of the ST2; rs148548829 (C allele) and rs10206753 (G allele). These two alleles together with a third SNV, the rs11693204 (A allele), were inversely associated with moderate periodontitis. One SNV of the IL33 gene also showed a statistically significant inverse association with moderate periodontitis. Nine SNVs of the ST2 gene were inversely associated with the relative amount of Aa. In the high Aa subgroup, there was a direct association between 11 SNVs of the ST2 gene and moderate periodontitis and two SNVs of the ST2 gene and severe periodontitis, and eight SNVs of the ST2 gene and periodontitis. These exploratory findings of genetic variants in IL-33/ST2 axis support the concept that the different tissue responses among individuals with periodontitis may be modulated by the host's genetics, influencing the physiopathology of the disease.
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Placa Dental , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Periodontitis , Humanos , Aggregatibacter actinomycetemcomitans/genética , Biopelículas , Estudios Transversales , Placa Dental/genética , Inmunidad , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-33/genética , Nucleótidos , Periodontitis/genética , Polimorfismo de Nucleótido SimpleRESUMEN
When discovered in the early 2000s, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. Yet research in other models has since revealed that IL-33 is a highly pleiotropic molecule with diverse functions. These activities are supported by elusive release mechanisms and diverse expression of the IL-33 receptor, STimulation 2 (ST2), on both immune and stromal cells. Interestingly, IL-33 also supports type 1 immune responses during viral and tumor immunity and after allogeneic hematopoietic stem cell transplantation. Yet the IL-33-ST2 axis is also critical to the establishment of systemic homeostasis and tissue repair and regeneration. Despite these recent findings, the mechanisms by which IL-33 governs the balance between immunity and homeostasis or can support both effective repair and pathogenic fibrosis are poorly understood. As such, ongoing research is trying to understand the potential reparative and regulatory versus pro-inflammatory and pro-fibrotic roles for IL-33 in transplantation. This review provides an overview of the emerging regenerative role of IL-33 in organ homeostasis and tissue repair as it relates to transplantation immunology. It also outlines the known impacts of IL-33 in commonly transplanted solid organs and covers the envisioned roles for IL-33 in ischemia-reperfusion injury, rejection, and tolerance. Finally, we give a comprehensive summary of its effects on different cell populations involved in these processes, including ST2 + regulatory T cells, innate lymphoid cell type 2, as well as significant myeloid cell populations.
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Interleucina-33 , Fibrosis Pulmonar , Humanos , Interleucina-33/metabolismo , Inmunidad Innata , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Linfocitos , FibrosisRESUMEN
Salmonella Heidelberg is a clinically-important serovar linked to food-borne illness, and commonly isolated from poultry products. Since 1962, Salmonella Heidelberg has been widely reported from poultry production systems in several countries, including Brazil. The emergence of multidrug-resistant (MDR) Salmonella Heidelberg strains in food animals underscores a significant food safety hazard. In our study, we performed antimicrobial susceptibility testing (AST) and Whole-genome sequencing (WGS) to identify the antimicrobial resistance (AMR) genes, pathogenicity mechanisms and virulence factors (VF) in Salmonella Heidelberg E2 strain recovered from a chicken carcass in Southern Brazil. Salmonella Heidelberg strain belonged to ST15 and showed to be susceptible to colistin (MIC ≤2 µg/mL) and multidrug-resistant to amoxicillin-clavulanic acid, gentamicin, ampicillin, cefaclor, cefazolin, ceftiofur, nalidixic acid, azithromycin, erythromycin, doxycycline, tetracycline and sulfonamide. We identified AMR genes mediating resistance to aminoglycosides (aac(6')-Iaa, aac(3)-VIa, aph(3')-Ia, aadA, 16S rrsD), ß-lactams (blaCTX-M-2), quinolones (parC), macrolides (acrB), tetracyclines (tet(A)), fosfomycin (fosA7) and sulfonamide (sul1). Interestingly, the mutation in parC T255S has never been reported among Salmonella Heidelberg strains. To our knowledge, this is the first report of a Salmonella enterica strain harbouring 16S rrsD 471G > A, acrB F28L and acrB L40P chromosomal point mutations. Three plasmid replicon types, ST2-IncHI2, ST2-IncHI2A and IncX1 were identified. Nine Salmonella Pathogenicity Islands and 98 virulence genes encoding virulence factors were identified associated with cell adhesion, invasion, intracellular survival and resistance to antimicrobial peptides. Although Salmonella Heidelberg E2 strain likely originated from poultry, cross-contamination during meat processing cannot be excluded. This study adds to our understanding of Salmonella Heidelberg transmission along the food-chain and informs ongoing regulatory discussions on Salmonella Heidelberg in poultry.
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Pollos , Salmonella enterica , Animales , Antibacterianos/farmacología , Brasil , Farmacorresistencia Bacteriana Múltiple/genética , Genómica , Proteína 1 Similar al Receptor de Interleucina-1 , Pruebas de Sensibilidad Microbiana , Aves de Corral , Salmonella , Sulfonamidas , Factores de VirulenciaRESUMEN
Type 2 Innate lymphoid cells (ILC2s) are tissue-resident immune cells activated by epithelial-derived alarmins upon tissue damage. They regulate immunity against helminth parasites and allergies by expressing type 2 immune response cytokines including IL-9, known to be critical for inducing and potentiating the immune response in such context. Although ILC2s are reported to be the main source of IL-9 in mice during N. brasiliensis infection, the mechanisms that regulate the expression of IL-9 in these cells are yet to be described. Recent studies have shown that in addition to cytokines, multiple molecules can differentially modulate the functions of ILC2s in various contexts both in vitro and in vivo. Among these stimuli are lipid mediators and neuropeptides, which activate the PKA pathway and have been associated with the regulation of type 2 immune cytokines. In this work we found that ILC2s in mice infected with N. brasiliensis can be classified into different groups based on the expression of IL-9 and ST2. These distinct populations were distributed in the lung and the small intestine. Through the development of an in vitro culture system, we sought to determine the stimuli that regulate the expression of these markers in ILC2s. We identified the alarmin IL-33 as being a key player for increased IL-9 expression. Additionally, we found the PKA pathway to be a dual regulator of ILC2 cells, working synergistically with IL-33 to enhance IL-9 production and capable of modulating proliferation and the expression of ILC2 markers. These data provide further evidence of a high heterogeneity between ILC2 subsets in a context dependent manner and calls for careful consideration when choosing the markers to identify these cells in vivo. Distinguishing ILC2 subsets and dissecting their mechanisms of activation is critical for a deeper understanding of the biology of these cells, allowing their manipulation for therapeutic purposes.
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Inmunidad Innata , Interleucina-33 , Animales , Citocinas , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-9/genética , Linfocitos , RatonesRESUMEN
BACKGROUND: Obesity is a chronic complex disease with great prevalence for children all over the world. Characterized for low-grade inflammation associated with several comorbidities such as resistance and type 2 diabetes mellitus (T2DM). OBJECTIVES: To investigate whether genetic variants in IL10, IL1RL1, IL1B, IRF4, TNF, IL6, and IL33 genes are associated with being overweight in children. METHODS: We performed the genotyping of 1004 children using Illumina 2.5 Human Omni bead chip, and association analysis on the genetic variants and the overweight through logistic regression adjusted for sex, age and components principal. RESULTS: Of the seven genes analyzed, 16 SNVs significantly associated. Eleven variants in IL1RL1, two in IL1B and one in IRF4 genes increased overweight risk and two SNVs in IL1RL1 were associated with protection against overweight. The rs2287047-A was negatively associated (OR: 0.66, CI95%: 0.19-0.45) and had a reduced IL1RL1 expression in whole blood (p 0.033) in silico eQTL. The rs12203592-T, in IRF4, was positively associated with being overweight, and led to an increased gene expression in whole blood (p < 0.001) and adipose tissue (p < 0.001). CONCLUSION: These results suggest that genetic variants in inflammatory genes may play an important role in the development of overweight in children.
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Diabetes Mellitus Tipo 2 , Factores Reguladores del Interferón/genética , Polimorfismo de Nucleótido Simple , Brasil , Niño , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-1beta/genética , Sobrepeso/genéticaRESUMEN
Implantation of biomedical/synthetic devices to replace and/or repair biological tissues very often induces an adverse healing response (scarce angiogenesis, excessive collagen deposition) which is detrimental to implant functionality and integration to host tissue. Interleukin-33/ST2 axis (IL-33/ST2) has been shown to modulate angiogenic and remodeling processes in several types of injuries. However, its effects on these processes after implantation of synthetic matrix have not been reported. Using synthetic matrix of polyether-polyurethane implanted subcutaneously in mice lacking ST2 receptor (ST2/KO), we characterized neovascularization and matrix remodeling in the fibrovascular tissue induced by the implants. Tissue accumulation was increased inside and around the implants in KO implants relative to the wild type (WT). More intense proliferative activity, using CDC 47 marker, was observed in KO implants compared with that of WT implants. Angiogenesis, using two endothelial cell markers, Von Willebrand Factor (VWF) and vascular endothelial cell VE cadherin and hemoglobin content, increased in implants of KO mice relative to control WT. Remodeling of the newly formed fibrovascular tissue (soluble collagen and PicroSirius Red-stained histological sections) showed predominance of type 1 collagen in ST2-KO implants versus type 3 in control implants. The number of positive cells for caspase-3, apoptotic marker, decreased in ST2 group. Our findings evidenced a role of IL-33/ST2 axis in restraining blood vessel formation and regulating the pattern of matrix remodeling in the fibrovascular tissue induced by synthetic implants. Intervention in this cytokine complex holds potential to accelerate integration of biomaterial and host tissue by improving blood supply and matrix remodeling.
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Matriz Extracelular/metabolismo , Reacción a Cuerpo Extraño/metabolismo , Mediadores de Inflamación/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/deficiencia , Interleucina-33/metabolismo , Neovascularización Fisiológica , Tejido Subcutáneo/metabolismo , Cicatrización de Heridas , Animales , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/patología , Fibrosis , Reacción a Cuerpo Extraño/etiología , Reacción a Cuerpo Extraño/genética , Reacción a Cuerpo Extraño/patología , Eliminación de Gen , Proteína 1 Similar al Receptor de Interleucina-1/genética , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Polietilenglicoles , Poliuretanos , Transducción de Señal , Tejido Subcutáneo/patología , Tapones Quirúrgicos de Gaza , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Although the literature shows that an increase in both the number and suppressive function of CD4+forkhead box P3 (FOXP3)+ T-regulatory cells (Tregs) during sepsis contributes to an immunosuppressed state, little is known about the identity of these cells. METHODS: Using the sepsis mouse model of cecal ligation and puncture (CLP), we analyzed the frequency and molecular signature of the T-cell immunoglobulin and ITIM domain (TIGIT)+ and TIGIT- Treg subsets, using flow cytometry and quantitative polymerase chain reaction. In addition, ST2-/- and signal transducer and activator of transcription 6 (STAT6)-/- mice were submitted to CLP or recombinant interleukin 33 (IL-33) treatment to investigate the mechanism whereby TIGIT+ Tregs differentiate during sepsis. RESULTS: Sepsis was marked by the sustained expansion of the highly suppressive TIGIT+ Treg subset, which expresses Helios, neuropilin 1, and high levels of Tnfrsf18 and Pdcd1 at 15 days after CLP. The increase in TIGIT+ Tregs was accompanied by higher susceptibility to nosocomial bacteria challenge, suggesting their association with post sepsis immunosuppression. Mechanistically, we found that the ST2 deletion abrogated the expansion of the TIGIT+ Treg subset during sepsis. Furthermore, treatment with recombinant IL-33 resulted in the expansion of TIGIT+ Tregs depending on the STAT6 and M2 macrophages. CONCLUSIONS: These findings demonstrated that only the TIGIT+ Tregs remain stably expanded at the late phase of sepsis. Moreover, the expansion of TIGIT+ Tregs is dependent on the IL-33/ST2/STAT6/M2 macrophage axis.
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Sepsis , Linfocitos T Reguladores , Animales , Factores de Transcripción Forkhead/genética , Terapia de Inmunosupresión , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Ratones , Receptores Inmunológicos/genéticaRESUMEN
Abstract Introduction: Nuocytes play an important role in Type 2 immunity. However, the contribution of ILC2s to allergic rhinitis remains to be clearly elucidated. Objective: To evaluate the role of nuocytes from mesenteric lymph node on allergic responses in mice. Methods: After intraperitoneal administration of interleukin IL-25 and IL-33 to wild-type and Il17br-/-Il1rl1-/- double-deficient mice, nuocytes were purified from the the nasal-associated lymphoid tissue and mesenteric lymph nodes. Then, we assessed productions of IL-5 and IL-13 in nuocytes' cultures. Finally, we adoptively transferred the mesenteric lymph node-derived nuocytes from wild-type and Il17br-/-Il1rl1-/- mice to the murine model of allergic rhinitis to evaluate their roles in nasal allergic responses. Results: We showed that nuocytes in the mesenteric lymph nodes of wild-type mice were upregulated after application of IL-25 and IL-33, and were induced to produce IL-5 and IL-13. Numbers of sneezing and nasal rubbing as well as eosinophils were all enhanced after the adoptive transfer of wild-type nuocytes. Concentrations of IL-5, IL-13, IL-25 and IL-33 in nasal lavage fluid of allergic mice were also increased. However, nuocytes fromIl17br-/-Il1rl1-/- mice did not increase sneezing and nasal rubbing and eosinophilia, and upregulate the above cytokines in the nasal lavage fluid. Conclusion: The findings demonstrate that nuocytes from the mesenteric lymph nodes of wildtype mice promote allergic responses in a mouse model.
Resumo Introdução: Os nuócitos desempenham um papel importante na imunidade do tipo 2. No entanto, a contribuição das interleucinas ILC2s na rinite alérgica ainda precisa ser elucidada. Objetivo: Avaliar o papel dos nuócitos de linfonodos mesentéricos nas respostas alérgicas em camundongos. Método: Após a administração intraperitoneal de interleucina (IL)-25 e IL-33 em camundongos do tipo selvagem e camundongos Il17br-/-Il1rl1-/- com deficiência dupla, os nuócitos foram purificados do tecido linfoide associado a mucosa nasal e linfonodos mesentéricos. Em seguida, avaliamos as produções de IL-5 e IL-13 em culturas de nuócitos. Finalmente, transferimos adotivamente os nuócitos derivados de linfonodos mesentéricos de camundongos do tipo selvagem e camundongos Il17br-/-Il1rl1-/- para o modelo murino de rinite alérgica para avaliar seu papel nas respostas alérgicas nasais. Resultados: Mostramos que os nuócitos nos linfonodos mesentéricos de camundongos do tipo selvagem estavam up-regulados após a aplicação de IL-25 e IL-33 e foram induzidos a produzir IL-5 e IL-13. Os espirros e friçcão nasal, bem como os eosinófilos, aumentaram após a transferência adotiva de nuócitos do tipo selvagem. As concentrações de IL-5, IL-13, IL-25 e IL-33 no líquido da lavagem nasal de camundongos alérgicos também estavam aumentadas. Entretanto, os nuócitos de camundongos Il17br-/-Il1rl1-/- não aumentaram os espirros e a friçcão nasal ou eosinofilia e up-regularam as citocinas acima no líquido de lavagem nasal. Conclusão: Os achados demonstram que os nuócitos dos linfonodos mesentéricos de camundongos selvagens promovem respostas alérgicas em um modelo de camundongo.
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Animales , Ratones , Rinitis Alérgica , Inmunidad Innata , Linfocitos , Citocinas , Modelos Animales de Enfermedad , Proteína 1 Similar al Receptor de Interleucina-1 , Ganglios Linfáticos , Mucosa NasalRESUMEN
Toxocariasis is a neglected disease that affects people around the world. Humans become infected by accidental ingestion of eggs containing Toxocara canis infective larvae, which upon reaching the intestine, hatch, penetrate the mucosa and migrate to various tissues such as liver, lungs and brain. Studies have indicated that Th2 response is the main immune defense mechanism against toxocariasis, however, there are still few studies related to this response, mainly the IL-33/ST2 pathway. Some studies have reported an increase in IL-33 during helminth infections, including T. canis. By binding to its ST2 receptor, IL-33 stimulating the Th2 polarized immune cell and cytokine responses. Thus, we aimed to investigate the role of the IL-33/ST2 pathway in the context of T. canis larval migration and the immunological and pathophysiological aspects of the infection in the liver, lungs and brain from Wild-Type (WT) BALB/c background and genetically deficient mice for the ST2 receptor (ST2-/-). The most important findings revealed that the IL-33/ST2 pathway is involved in eosinophilia, hepatic and cerebral parasitic burden, and induces the formation of granulomas related to tissue damage and pulmonary dysfunction. However, ST2-/- mice, the immune response was skewed to Th1/Th17 type than Th2, that enhanced the control of parasite burden related to IgG2a levels, tissue macrophages infiltration and reduced lung dysfunction. Collectively, our results demonstrate that the Th2 immune response triggered by IL-33/ST2 pathway mediates susceptibility to T. canis, related to parasitic burden, eosinophilia and granuloma formation in which consequently contributes to tissue inflammation and injury.
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Eosinófilos/fisiología , Inflamación/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Toxocara canis , Toxocariasis/inmunología , Animales , Femenino , Regulación de la Expresión Génica , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-33/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Células Th2/fisiología , Toxocariasis/patologíaRESUMEN
BACKGROUND: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVES: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured â¼30 patients who were eosinophil-high (≥300 cells/µL) and â¼95 patients who were eosinophil-low (<300 cells/µL) per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. CONCLUSIONS: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.
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Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Asma/inmunología , Progresión de la Enfermedad , Método Doble Ciego , Eosinófilos/inmunología , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/antagonistas & inhibidores , Interleucina-33/antagonistas & inhibidores , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Resultado del TratamientoRESUMEN
Morbidity during chronic schistosomiasis has been associated with the induction and modulation of type-2 granulomatous inflammatory response induced by antigens secreted by the eggs, which become trapped in capillary venules of the host tissues, especially in the liver and intestines. IL-33, an alarmin released after cell damage, binds to its ST2 (suppressor of tumorigenicity 2) receptor, expressed in an variety of immune cells, including ILC2 and macrophages, and stimulates the early production of IL-5 and IL-13, which leads to eosinophil infiltration and activation of a Th2 response. However, the role of IL-33/ST2 activation on Schistosoma-induced granuloma formation and modulation is mostly unknown. In the current work, we comparatively evaluated the immune response and granuloma formation in wild-type BALB/c (WT) and BALB/c mice genetically deficient in the IL-33 receptor (ST2-/-) experimentally infected with Schistosoma mansoni. Mice were infected with 25 or 50 S. mansoni cercariae and followed for up to 14 weeks to assess mortality. Mice from each experimental group were comparatively evaluated for parasite burden, liver immune response, and granuloma appearance during acute and chronic schistosomiasis. Our data showed that the number of circulating worms and eggs retained in the liver and eliminated in the feces was similar in WT and ST2-/- infected mice, but infected ST2-/- mice presented an enhanced rate of mortality. Interestingly, the production of type-2 cytokines by soluble egg antigens (SEA)-stimulated spleen cells, the serum concentrations of IL-5 and Immunoglobulin (Ig)-E, and the level of parasite-reactive IgG1 were similar in infected mice of both experimental groups. The concentrations of IL-4, IL-5, IL-13, and IFN-γ in liver homogenate of infected mice also did not differ between the strains at acute schistosomiasis, but there was a significant increase in IL-17 levels in ST2-/- infected mice at this phase. On the other hand, IL-4, IL-13, IL-10, IL-17, and IFN-γ concentrations were reduced and the ratios of IL-4/IFN-γ and IL-17/IFN-γ were higher in liver homogenate of chronically infected ST2-/- mice, suggesting unbalanced Th2 and Th17 responses. Moreover, liver granulomas of ST2-/- mice were larger and disorganized, showing an intense cellular infiltrate, rich in eosinophils and neutrophils. Our results suggest that the absence of the IL-33/ST2 pathway is not essential for the Schistosoma-induced Th2 response, but is necessary to prevent host mortality by modulating granuloma-mediated pathology.
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Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Schistosoma mansoni/metabolismo , Células Th2/citología , Animales , Antígenos/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Eritrocitos/metabolismo , Femenino , Granuloma/metabolismo , Sistema Inmunológico , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Neutrófilos/metabolismo , Esquistosomiasis mansoni , Bazo/metabolismo , Células Th17/metabolismoRESUMEN
INTRODUCTION: Nuocytes play an important role in Type 2 immunity. However, the contribution of ILC2s to allergic rhinitis remains to be clearly elucidated. OBJECTIVE: To evaluate the role of nuocytes from mesenteric lymph node on allergic responses in mice. METHODS: After intraperitoneal administration of interleukin IL-25 and IL-33 to wild-type and Il17br-/-Il1rl1-/- double-deficient mice, nuocytes were purified from the the nasal-associated lymphoid tissue and mesenteric lymph nodes. Then, we assessed productions of IL-5 and IL-13 in nuocytes' cultures. Finally, we adoptively transferred the mesenteric lymph node-derived nuocytes from wild-type and Il17br-/-Il1rl1-/- mice to the murine model of allergic rhinitis to evaluate their roles in nasal allergic responses. RESULTS: We showed that nuocytes in the mesenteric lymph nodes of wild-type mice were upregulated after application of IL-25 and IL-33, and were induced to produce IL-5 and IL-13. Numbers of sneezing and nasal rubbing as well as eosinophils were all enhanced after the adoptive transfer of wild-type nuocytes. Concentrations of IL-5, IL-13, IL-25 and IL-33 in nasal lavage fluid of allergic mice were also increased. However, nuocytes fromIl17br-/-Il1rl1-/- mice did not increase sneezing and nasal rubbing and eosinophilia, and upregulate the above cytokines in the nasal lavage fluid. CONCLUSION: The findings demonstrate that nuocytes from the mesenteric lymph nodes of wild-type mice promote allergic responses in a mouse model.
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Inmunidad Innata , Rinitis Alérgica , Animales , Citocinas , Modelos Animales de Enfermedad , Proteína 1 Similar al Receptor de Interleucina-1 , Ganglios Linfáticos , Linfocitos , Ratones , Mucosa NasalRESUMEN
Initially described as Th2 promoter cytokine, more recently, IL-33 has been recognized as an alarmin, mainly in epithelial and endothelial cells. While localized in the nucleus acting as a gene regulator, it can be also released after injury, stress or inflammatory cell death. As proinflammatory signal, IL-33 binds to the surface receptor ST2, which enhances mast cell, Th2, regulatory T cell, and innate lymphoid cell type 2 functions. Besides these Th2 roles, free IL-33 can activate CD8+ T cells during ongoing Th1 immune responses to potentiate its cytotoxic function. Celiac Disease (CD) is a chronic inflammatory disorder characterized by a predominant Th1 response leading to multiple pathways of mucosal damage in the proximal small intestine. By immunofluorescence and western blot analysis of duodenal tissues, we found an increased expression of IL-33 in duodenal mucosa of active CD (ACD) patients. Particularly, locally digested IL-33 releases active 18/21kDa fragments which can contribute to expand the proinflammatory signal. Endothelial (CD31+) and mesenchymal, myofibroblast and pericyte cells from microvascular structures in villi and crypts, showed IL-33 nuclear location; while B cells (CD20+) showed a strong cytoplasmic staining. Both ST2 forms, ST2L and sST2, were also upregulated in duodenal mucosa of CD patients. This was accompanied by increased number of CD8+ST2+ T cells and the expression of T-bet in some ST2+ intraepithelial lymphocytes and lamina propria cells. IL-33 and sST2 mRNA levels correlated with IRF1, an IFN induced factor relevant in responses to viral infections and interferon mediated proinflammatory responses highly represented in duodenal tissues in ACD. These findings highlight the potential contribution of IL-33 and its fragments to exacerbate the proinflammatory circuit and potentiate the cytotoxic activity of CD8+ T cells in CD pathology.
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Alarminas/inmunología , Enfermedad Celíaca/inmunología , Inflamación/inmunología , Interleucina-33/inmunología , Intestino Delgado/inmunología , Animales , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Citocinas/inmunología , Células HT29 , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/inmunología , Mucosa Intestinal/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Células Th2/inmunologíaRESUMEN
OBJECTIVE: To investigate the role of IL-33 in gouty arthritis. MATERIAL: 174 Balb/c (wild-type) and 54 ST2-/- mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels. METHODS: Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM. RESULTS: Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1ß and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1ß and TNF-α, and BMDMs from ST2-/- showed reduced levels of these cytokines after stimulus with MSU crystals. CONCLUSION: IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.
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Artritis Gotosa/patología , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-33/farmacología , Macrófagos/metabolismo , Dolor/inducido químicamente , Animales , Artritis Gotosa/inducido químicamente , Artritis Gotosa/metabolismo , Femenino , Humanos , Inflamación/psicología , Proteína 1 Similar al Receptor de Interleucina-1/genética , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Persona de Mediana Edad , Infiltración Neutrófila/efectos de los fármacos , Dolor/psicología , Peroxidasa/metabolismo , Superóxidos/metabolismo , Membrana Sinovial/patología , Ácido ÚricoRESUMEN
Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.