Serum interleukin-33 combined with FEF75% z-score and FeNO improves the diagnostic accuracy of asthma in children.

OBJECTIVE: To investigate the diagnostic efficacy of serum IL-33 single indicator and combined indicators for asthma in children. METHODS: 132 children were initially diagnosed with asthma during acute exacerbation and 100 healthy children were included. Serum IL-33 concentration differences were compared between asthmatic and normal children. Correlations between IL-33 with pulmonary function parameters, FeNO, peripheral blood EOS counts and serum total IgE were analyzed in asthmatic children. ROC curves were used to assess IL-33 diagnostic efficacy and its combined indicators. To prevent overfitting of the predictive model, the hold-out cross-validation method was used. RESULTS: (1) Serum IL-33 concentrations were significantly higher in children with asthma than in normal children (p < 0.001). (2) IL-33 concentration was negatively correlated with FVC z-score, FEV1 z-score and FEF75% z-score in asthmatic children (p < 0.05). (3) The area under the ROC curve of IL-33 was 0.821, which was higher than those of FeNO, FVC z-score, and FEV1 z-score. (4) Cross-validation of the combined indicators showed that IL-33 significantly improved asthma diagnostic efficacy. The combination of IL-33, FEF75% z-score, and FeNO showed the highest diagnostic efficacy, with the AUC, sensitivity, and specificity of the combined indicator being 0.954, 90.1%, and 89. 0%, respectively, and good extrapolation of the predictive model. CONCLUSION: Serum IL-33 is higher in children with asthma and increases with the severity of pulmonary ventilation obstruction. A single indicator of serum IL-33 demonstrates moderate diagnostic accuracy, and its combination with FEF75% z-score and FeNO significantly improves the diagnostic accuracy in childhood asthma.

Serum interleukin-33 combined with FEF75% z-score and FeNO improves the diagnostic accuracy of asthma in children

Abstract Objective To investigate the diagnostic efficacy of serum IL-33 single indicator and combined indicators for asthma in children. Methods 132 children were initially diagnosed with asthma during acute exacerbation and 100 healthy children were included. Serum IL-33 concentration differences were compared between asthmatic and normal children. Correlations between IL-33 with pulmonary function parameters, FeNO, peripheral blood EOS counts and serum total IgE were analyzed in asthmatic children. ROC curves were used to assess IL-33 diagnostic efficacy and its combined indicators. To prevent overfitting of the predictive model, the hold-out cross-validation method was used. Results (1) Serum IL-33 concentrations were significantly higher in children with asthma than in normal children (p < 0.001). (2) IL-33 concentration was negatively correlated with FVC z-score, FEV1 z-score and FEF75% z-score in asthmatic children (p < 0.05). (3) The area under the ROC curve of IL-33 was 0.821, which was higher than those of FeNO, FVC z-score, and FEV1 z-score. (4) Cross-validation of the combined indicators showed that IL-33 significantly improved asthma diagnostic efficacy. The combination of IL-33, FEF75% z-score, and FeNO showed the highest diagnostic efficacy, with the AUC, sensitivity, and specificity of the combined indicator being 0.954, 90.1%, and 89. 0%, respectively, and good extrapolation of the predictive model. Conclusion Serum IL-33 is higher in children with asthma and increases with the severity of pulmonary ventilation obstruction. A single indicator of serum IL-33 demonstrates moderate diagnostic accuracy, and its combination with FEF75% z-score and FeNO significantly improves the diagnostic accuracy in childhood asthma.

Interleukin-33 Expression on Treatment Outcomes and Prognosis in Brazilian Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

Interleukin-33 (IL-33), a member of the interleukin-1(IL-1) family of cytokines, remains poorly understood in the context of human breast cancer and its impact on treatment outcomes. This study aimed to elucidate IL-33 expression patterns within tumor samples from a cohort of Brazilian female breast cancer patients undergoing neoadjuvant chemotherapy while exploring its correlation with clinicopathological markers. In total, 68 samples were meticulously evaluated, with IL-33 expression quantified through a quantitative polymerase chain reaction. The findings revealed a substantial upregulation of IL-33 expression in breast cancer patient samples, specifically within the Triple-negative and Luminal A and B subtypes, when compared to controls (healthy breast tissues). Notably, the Luminal B subtype displayed a marked elevation in IL-33 expression relative to the Luminal A subtype (p < 0.05). Moreover, a progressive surge in IL-33 expression was discerned among Luminal subtype patients with TNM 4 staging criteria, further underscoring its significance (p < 0.005). Furthermore, chemotherapy-naïve patients of Luminal A and B subtypes exhibited heightened IL-33 expression (p < 0.05). Collectively, our findings propose that chemotherapy could potentially mitigate tumor aggressiveness by suppressing IL-33 expression in breast cancer, thus warranting consideration as a prognostic marker for gauging chemotherapy response and predicting disease progression in Luminal subtype patients. This study not only sheds light on the intricate roles of IL-33 in breast cancer but also offers valuable insights for future IL-33-related research endeavors within this context.

Cerebrospinal fluid levels of sortilin-1, lipocalin-2, autotaxin, decorin and interleukin-33 in patients with idiopathic intracranial hypertension / Níveis de sortilina-1, lipocalina-2, autotaxina, decorina e interleucina-33 no líquido cefalorraquidiano em pacientes com hipertensão intracraniana idiopática

Abstract Background Idiopathic intracranial hypertension (IIH) is characterized by increased cerebrospinal fluid (CSF) pressure of unknown cause. It has been suggested that the inflammatory process plays a role in the pathophysiology of the disease. Sortilin-1, lipocalin-2, autotaxin, decorin, and interleukin-33 (IL-33) are among the factors involved in inflammatory processes. Objective To investigate the CSF levels of sortilin-1, lipocalin-2, autotaxin, decorin, and IL-33 in patients with IIH. Methods A total of 24 IIH patients and 21 healthy controls were included in the study. Demographic characteristics of the patients and of the control group as well as CSF pressures were evaluated. Sortilin-1, lipocalin-2, autotaxin, decorin and IL-33 levels in the CSF were measured. Results The CSF levels lipocalin-2, sortilin-1, autotaxin, IL-33 and CSF pressure were significantly higher in the patients group compared with the control group (p < 0.001). Decorin levels were reduced in patients (p < 0.05). There was no correlation between the autotaxin and IL-33 levels and age, gender, CSF pressure, and body mass index. The results of our study showed that inflammatory activation plays an important role in the development of the pathophysiology of IIH. In addition, the fact that the markers used in our study have never been studied in the etiopathogenesis of IIH is important in explaining the molecular mechanism of this disease. Conclusion Studies are needed to evaluate the role of these cytokines in the pathophysiology of the disease. It is necessary to evaluate the effects of these molecules on this process.

Resumo Antecedentes A hipertensão intracraniana idiopática (HII) é caracterizada pelo aumento da pressão do líquido cefalorraquidiano (LCR) de causa desconhecida. Tem sido sugerido que o processo inflamatório desempenha um papel na fisiopatologia da doença. Sortilina-1, lipocalina-2, autotaxina, decorina e interleucina-33 (IL-33) estão entre os fatores envolvidos nos processos inflamatórios. Objetivo Investigar os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR de pacientes com HII. Métodos Um total de 24 pacientes com HII e 21 controles saudáveis foram incluídos no estudo. Foram avaliadas as características demográficas dos pacientes e do grupo controle, bem como as pressões liquóricas. Os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR foram medidos. Resultados Os níveis no líquido cefalorraquidiano lipocalina-2, sortilina-1, autotaxina, IL-33 e pressão liquórica foram significativamente maiores no grupo de pacientes em comparação com o grupo controle (p < 0,001). Os níveis de decorina foram reduzidos nos pacientes (p < 0,05). Não houve correlação entre os níveis de autotaxina e IL-33 e idade, sexo, pressão liquórica e índice de massa corporal. Os resultados do nosso estudo mostraram que a ativação inflamatória desempenha um papel importante no desenvolvimento da fisiopatologia da HII. Além disso, o fato de os marcadores utilizados em nosso estudo nunca terem sido estudados na etiopatogenia da HII é importante para explicar o mecanismo molecular dessa doença. Conclusão Estudos são necessários para avaliar o papel dessas citocinas na fisiopatologia da doença. É necessário avaliar os efeitos dessas moléculas nesse processo

Effect of IL-33 on pyroptosis of macrophages in mice with sepsis via NF-κB/p38 MAPK signaling pathway

ABSTRACT Purpose To demonstrate the effect of IL-33 on the macrophage pyroptosis in mice with sepsis through the NF-kB/p38 MAPK signal pathway. Methods In total, 24 C57BL/6 mice were divided into the sham operation group (sham) and the cecal ligation and puncture group (CLP). After CLP, 24 IL-33-/- mice were divided into the IL-33-/- group and the IL-33-/- intervention group. The latter group was intraperitoneally injected with IL-33. Mouse mortality was observed after CLP. Macrophage apoptosis in peritoneal lavage fluid was detected by flow cytometry. Serum inflammatory factor level was detected by ELISA. Apoptotic protein expression and NF-κB/p38 MAKP signaling pathway protein expression were detected by qRT-PCR and Western blot. Results Knocking out IL-33 significantly reduced the mortality of CLP mice, as well as the mRNA expression of IL-33 and the levels of serum inflammatory factors, including IL-33, IL-1β, and IL-18. It also reduced the rate of macrophage apoptosis and the expression of the apoptotic protein caspase-1 p10; increased the expression of IκBα; and reduced the protein expression of NF-κB and p38 MAPK. These effects were reversed after exogenous injection of IL-33. Conclusions IL-33 can increase the level of macrophage pyroptosis in mice with sepsis (by activating the NF-kB/p38MAPK signal pathway) and the mortality of these mice.

IL-33 and ST2 as predictors of disease severity in children with viral acute lower respiratory infection.

BACKGROUND: Mechanisms influencing severity of acute lower respiratory infection (ALRI) in children are not established. We aimed to assess the role of inflammatory markers and respiratory viruses in ALRI severity. METHODS: Concentrations of interleukin(IL)-33, soluble suppression of tumorigenicity (sST)2, IL-1ß, tumor necrosis factor α, IL-4, IL-6 and IL- 8 and types of respiratory viruses were evaluated in children at the first and fifth days after hospital admission. Disease severity was defined as need for mechanical ventilation. RESULTS: Seventy-nine children <5 years-old were included; 33(41.8%) received mechanical ventilation. No associations between virus type, viral load or co-detections and severity of disease were observed. Detection of IL-33 and sST2 in nasopharyngeal aspirates (NPA) on admission were associated with higher risk for mechanical ventilation (RR = 2.89 and RR = 4.57, respectively). IL-6 and IL-8 concentrations were higher on Day 5 in mechanically ventilated children. IL-6 NPA concentrations decreased from Day 1 to Day 5 in children who did not receive mechanical ventilation. Increase in sST2 NPA concentrations from Day 1 to Day 5 was associated with longer hospital length of stay (p < 0.01). CONCLUSIONS: An exacerbated local activation of the IL-33/ST2 axis and persistently high sST2 concentrations over time were associated with severity of viral ALRI in children.

Corrigendum: Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer.

[This corrects the article DOI: 10.3389/fimmu.2019.01394.].

Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer.

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.

Altered levels of inhibitory cytokines in patients with thalassemia major and gingival inflammation / Níveis alterados de citocinas inibitórias em pacientes com talassemia major e inflamação gengival

Objective: To evaluate local and systemic levels of interleukin-10 (IL-10), IL-33, and tumor necrosis factor alpha (TNF-α) in Thalassemia major (TM) in the presence of gingival inflammation. Material and Methods: 58 patients (TM, n=29 and systemically healthy controls, n=29) were included to the study. IL-10, IL-33, and TNF-α levels were evaluated in gingival crevicular fluid (GCF), saliva and serum. Clinical periodontal measurements were recorded. Results: GCF IL-33 total amounts in TM and gingivitis group were elevated compared to systemically and periodontally healthy group (p=0.01). GCF IL-10, IL33 and TNF-α concentrations were higher in TM and periodontally healthy group than the systemically healthy and gingivitis group (p=0.02, p=0.008, p=0.003). Serum IL-10 levels were elevated in TM and gingivitis compared to the systemically healthy and gingivitis (p=0.0009) and systemically and periodontally healthy (p=0.0007) groups. Serum IL-10 and TNF-α levels in TM and periodontally healthy group were higher than systemically and periodontally healthy group (p=0.01 and p=0.02). Conclusion: TM may potentially alter circulating levels of IL-33 and IL-10 and therefore, may affect the degree of periodontal inflammation locally or vice versa. Yet, the underlying mechanism linking the hematologic condition is not clear and deserves further investigation. (AU)

Objetivo: Avaliar os níveis locais e sistêmicos de interleucina-10 (IL-10), IL-33 e fator de necrose tumoral alfa (TNF-α) na Talassemia Major (TM) na presença de inflamação gengival. Material e Métodos: 58 pacientes (TM, n = 29 e controles sistemicamente saudáveis, n = 29) foram incluídos no estudo. Os níveis de IL-10, IL-33 e TNF-α foram avaliados em fluido crevicular gengival (FCG), saliva e soro. As medições periodontais clínicas foram registradas. Resultados: As quantidades totais de IL-33 no FCG do grupo de TM e gengivite foram elevadas em comparação com o grupo sistemicamente e periodontalmente saudável (p = 0,01). As concentrações de IL-10 , IL-33 e TNF-α do FCG foram maiores no grupo TM e periodontalmente saudáveis do que no grupo sistemicamente saudável e gengivite (p = 0,02, p = 0,008, p = 0,003). Os níveis séricos de IL-10 estavam elevados na TM e gengivite em comparação com os grupos sistemicamente saudável e gengivite (p = 0,0009) e sistemicamente e periodontalmente saudáveis (p = 0,0007). Os níveis séricos de IL-10 e TNF-α no grupo TM e periodontalmente saudáveis foram maiores do que os grupos sistemicamente e periodontalmente saudáveis (p = 0,01 ep = 0,02). Conclusão: A TM pode alterar potencialmente os níveis circulantes de IL-33 e IL-10 e, portanto, pode afetar o grau de inflamação periodontal localmente ou vice-versa. No entanto, o mecanismo subjacente que liga a condição hematológica não é claro e merece uma investigação mais aprofundada. (AU)

Interleukin-33 contributes to disease severity in Dengue virus infection in mice.

The excessive inflammation often present in patients with severe dengue infection is considered both a hallmark of disease and a target for potential treatments. Interleukin-33 (IL-33) is a pleiotropic cytokine with pro-inflammatory effects whose role in dengue has not been fully elucidated. We demonstrate that IL-33 plays a disease-exacerbating role during experimental dengue infection in immunocompetent mice. Mice infected with dengue virus serotype 2 (DENV2) produced high levels of IL-33. DENV2-infected mice treated with recombinant IL-33 developed markedly more severe disease compared with untreated mice as assessed by mortality, granulocytosis, liver damage and pro-inflammatory cytokine production. Conversely, ST2-/- mice (deficient in IL-33 receptor) infected with DENV2 developed significantly less severe disease compared with wild-type mice. Furthermore, the increased disease severity and the accompanying pathology induced by IL-33 during dengue infection were reversed by the simultaneous treatment with a CXCR2 receptor antagonist (DF2156A). Together, these results indicate that IL-33 plays a disease-exacerbating role in experimental dengue infection, probably driven by CXCR2-expressing cells, leading to elevated pro-inflammatory response-mediated pathology. Our results also indicate that IL-33 is a potential therapeutic target for dengue infection.

ST2 regulates bone loss in a site-dependent and estrogen-dependent manner.

Interleukin-33 (IL-33) and its receptor, ST2, are implicated in bone remodeling. The lack of estrogen after menopause results in an accelerated bone loss. Here we investigated the role of ST2 in the bone loss induced by estrogen deficiency. ST2-deficient mice (ST2-/- ) and their littermates (wildtype [WT]) were ovariectomized (OVX), while ovary-intact mice were used as controls. Bone sites were analyzed by microcomputed tomography, histomorphometry, and quantitative real-time polymerase chain reaction (qPCR). Deletion of IL-33 or ST2 resulted in a similar bone loss in the femur and maxilla. Ovariectomy in WT mice caused bone loss in the same areas. The lack of ST2 in OVX mice did not alter bone remodeling in the femur but prevented bone loss in the maxilla. Consistently, ovariectomy increased the IL-33 messenger RNA (mRNA) levels in the maxilla but not in the femur. Under mechanical stimulation, ovariectomy and ST2 deletion independently increased bone remodeling induced by orthodontic tooth movement, which was also associated with a greater number of osteoclasts and a reduced number of osteoblasts in the maxillary bone. ST2-/- OVX mice, however, displayed twice as many osteoblasts as that of WT OVX mice. Ovariectomy and ST2 deletion differently altered the cytokine mRNA levels in the maxilla. Remarkably, interleukin-10 expression was decreased in both WT OVX and ST2-/- mice, and this reduction was completely restored in ST2-/- OVX mice. The results demonstrate that estrogen and IL33/ST2 independently protect against bone loss. However, the ovariectomy-induced bone loss is IL-33/ST2-dependent in the maxilla but not in the femur, indicating a bimodal and site-specific role of ST2 in bone remodeling.

Interleukin-33 Receptor (ST2) Deficiency Improves the Outcome of Staphylococcus aureus-Induced Septic Arthritis.

The ST2 receptor is a member of the Toll/IL-1R superfamily and interleukin-33 (IL-33) is its agonist. Recently, it has been demonstrated that IL-33/ST2 axis plays key roles in inflammation and immune mediated diseases. Here, we investigated the effect of ST2 deficiency in Staphylococcus aureus-induced septic arthritis physiopathology. Synovial fluid samples from septic arthritis and osteoarthritis individuals were assessed regarding IL-33 and soluble (s) ST2 levels. The IL-33 levels in samples from synovial fluid were significantly increased, whereas no sST2 levels were detected in patients with septic arthritis when compared with osteoarthritis individuals. The intra-articular injection of 1 × 107 colony-forming unity/10 µl of S. aureus American Type Culture Collection 6538 in wild-type (WT) mice induced IL-33 and sST2 production with a profile resembling the observation in the synovial fluid of septic arthritis patients. Data using WT, and ST2 deficient (-/-) and interferon-γ (IFN-γ)-/- mice showed that ST2 deficiency shifts the immune balance toward a type 1 immune response that contributes to eliminating the infection due to enhanced microbicide effect via NO production by neutrophils and macrophages. In fact, the treatment of ST2-/- bone marrow-derived macrophage cells with anti-IFN-γ abrogates the beneficial phenotype in the absence of ST2, which confirms that ST2 deficiency leads to IFN-γ expression and boosts the bacterial killing activity of macrophages against S. aureus. In agreement, WT cells achieved similar immune response to ST2 deficiency by IFN-γ treatment. The present results unveil a previously unrecognized beneficial effect of ST2 deficiency in S. aureus-induced septic arthritis.

The relationship between circulating irisin, retinol binding protein-4, adiponectin and inflammatory mediators in patients with metabolic syndrome

ABSTRACT Objective We wanted to investigate whether there is a relationship between circulating irisin, retinol binding protein-4 (RBP-4), adiponectin and proinflammatory mediators implicated in the development of insulin resistance (IR) in metabolic syndrome (MetS). Subjects and methods In 180 individuals, including controls and patients with MetS, we measured fasting plasma insulin, high sensitivity C-reactive protein (hsCRP), pentraxin-3 (PTX-3), interleukin-33 (IL-33), irisin, RBP-4, and adiponectin using ELISA kits. Results While fasting plasma hsCRP, PTX-3, IL-33, irisin, RBP-4 concentrations were higher, adiponectin levels were lower in patients with MetS than in controls. A correlation analysis revealed that plasma irisin levels were positively associated with MetS components such as waist circumference and waist-hip ratio, low density lipoprotein (LDL) and markers of systemic inflammation such as PTX-3, hsCRP, uric acid, and RBP-4. Adiponectin levels were negatively associated with waist circumference, waist-hip ratio, PTX-3 and LDL. Conclusions Although the precise mechanisms are still unclear, irisin, RBP-4, adiponectin and PTX-3 are hallmarks of the MetS, which is related to low-grade inflammation. It is conceivable that irisin and adiponectin might contribute to the development of MetS and may also represent novel MetS components. Future clinical studies are needed to confirm and extend these data.

Association between pro-inflammatory cytokine interleukin-33 and periodontal disease in the elderly: A retrospective study.

BACKGROUND: Senescence is a multifactorial process that in humans may be accompanied by inflammation and immune dysfunction in the oral cavity. Notably, periodontal disease, considered one of the most common inflammatory disorders in the oral cavity, has also been linked to the onset of other chronic inflammatory diseases common in the elderly. Thus, investigating immunity and inflammation during senescence may not only illuminate the pathophysiology of periodontal disease, but also identify new therapeutic targets. MATERIALS AND METHODS: To this end, we retrospectively and systematically reviewed studies of immune molecules associated with periodontal disease. These studies were identified in PubMed from three independent searches based on distinct sets of search terms. RESULTS: The data highlight the need to further investigate inflammatory molecules involved in chronic periodontal disease in the elderly, but strongly suggest that interleukin (IL)-33 is involved. Indeed, various genetic and environmental factors appear to contribute to pathogenesis via IL-33. CONCLUSION: The IL-33 axis may be promising therapeutic target in elderly patients.

IL33 in rheumatoid arthritis: potential contribution to pathogenesis.

A better understanding of the inflammatory mechanisms of rheumatoid arthritis and the development of biological therapy revolutionized its treatment, enabling an interference in the synovitis - structural damage - functional disability cycle. Interleukin 33 was recently described as a new member of the interleukin-1 family, whose common feature is its pro-inflammatory activity. Its involvement in the pathogenesis of a variety of diseases, including autoimmune diseases, raises the interest in the possible relationship with rheumatoid arthritis. Its action has been evaluated in experimental models of arthritis as well as in serum, synovial fluid and membrane of patients with rheumatoid arthritis. It has been shown that the administration of interleukin-33 exacerbates collagen-induced arthritis in experimental models, and a positive correlation between cytokine concentrations in serum and synovial fluid of patients with rheumatoid arthritis and disease activity was found. This review discusses evidence for the role of interleukin-33 with a focus on rheumatoid arthritis.

IL33 in rheumatoid arthritis: potential contribution to pathogenesis / Ação da IL33 na artrite reumatoide: contribuição para a fisiopatalogia

ABSTRACT A better understanding of the inflammatory mechanisms of rheumatoid arthritis and the development of biological therapy revolutionized its treatment, enabling an interference in the synovitis – structural damage – functional disability cycle. Interleukin 33 was recently described as a new member of the interleukin-1 family, whose common feature is its pro-inflammatory activity. Its involvement in the pathogenesis of a variety of diseases, including autoimmune diseases, raises the interest in the possible relationship with rheumatoid arthritis. Its action has been evaluated in experimental models of arthritis as well as in serum, synovial fluid and membrane of patients with rheumatoid arthritis. It has been shown that the administration of interleukin-33 exacerbates collagen-induced arthritis in experimental models, and a positive correlation between cytokine concentrations in serum and synovial fluid of patients with rheumatoid arthritis and disease activity was found. This review discusses evidence for the role of interleukin-33 with a focus on rheumatoid arthritis.

RESUMO A melhor compreensão dos mecanismos inflamatórios da artrite reumatoide e o desenvolvimento da terapia biológica revolucionaram o tratamento da doença, permitindo uma interferência no ciclo sinovite–dano estrutural–incapacidade funcional. A interleucina 33 foi recentemente descrita como um novo membro da família da interleucina 1, cuja característica comum é a atividade pró-inflamatória. Por estar envolvida na patogênese de uma grande variedade de doenças, incluindo doenças autoimunes, a interleucina 33 começa a ser estudada na doença reumatoide. Ela tem sido avaliada em modelos experimentais de artrite, no soro, no líquido e membrana sinoviais de pacientes com artrite reumatoide. Demonstrou-se que a administração da interleucina 33 exacerba a artrite induzida por colágeno em modelos experimentais, e concentrações dessa citocina no soro e no líquido sinovial de pacientes com artrite reumatoide correlacionaram-se positivamente com a atividade da doença. Esse manuscrito apresenta a interleucina 33 e discute as evidências do seu papel em diferentes doenças, com ênfase na artrite reumatoide.

IL-33 signaling is essential to attenuate viral-induced encephalitis development by downregulating iNOS expression in the central nervous system.

BACKGROUND: Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection. METHODS: Wild-type (WT), ST2 (ST2(-/-)), and nitric oxide synthase-deficient mice (iNOS(-/-)) and Stat6 (Stat6(-/-))-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells. RESULTS: We have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2(-/-) mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS(-/-) mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology. CONCLUSIONS: We provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-γ modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis.

Osteoprotective Effects of Estrogen in the Maxillary Bone Depend on ERα.

Estrogen deficiency results in disruption of maxillary alveolar bone microarchitecture. Most of the actions of estrogen in long bones occur via estrogen receptor α (ERα). However, the function of ERα in the maxillary bone has not been defined. We aimed to investigate the role and underlying mechanisms of ERα in the physiological and mechanically induced alveolar bone remodeling in female and male mice. Wild-type (WT) and ERα(-/-) (ERKOα) mice were subjected to mechanically stimulated bone remodeling by inducing orthodontic tooth movement (OTM). The maxillary bone was analyzed using histomorphometric analysis, micro-computed tomography, quantitative polymerase chain reaction, and energy-dispersive spectroscopy. Bone marrow cells (BMCs) from WT and ERKOα mice were tested for their capacity to differentiate into osteoblasts and osteoclasts. Both male and female ERKOα mice exhibited marked reduction of alveolar bone mass and increased OTM. This response was associated with an increased number of osteoclasts and reduced number of apoptotic cells and osteoblasts in the periodontium and alveolar bone. Consistently, ERKOα mice exhibited lower levels of calcium in bone and increased expression of IL-33 (interleukin-33), TNF-α (tumor necrosis factor α), and IL-1ß (interleukin-1ß) and decreased expression of dentin matrix acidic phosphoprotein and alkaline phosphatase in periodontal tissues. Moreover, the differentiation of osteoclasts and osteoblasts in vitro was significantly higher in BMCs obtained from ERKOα. ERα is required to maintain the microarchitecture of maxillary alveolar bone. This process is linked to bone cell differentiation and apoptosis, as well as local production of inflammatory molecules such as IL-33, TNF-α, and IL-1ß.

Adiponectin in Asthma and Obesity: Protective Agent or Risk Factor for More Severe Disease?

PURPOSE: The relationship between asthma and obesity is well established, although the pathophysiological mechanisms linking both diseases remain unknown. Adiponectin is a hormone secreted by adipose cells, plays a role in the modulation of inflammation and may be the key linking these two types of inflammation. METHODS: We conducted a cross-sectional study with asthma with different body mass indices (BMI); the patients were classified as eutrophic, overweight, or obese. We assessed disease control using the GINA consensus, and the levels of adiponectin, C-reactive protein (CRP) and interleukin 33 (IL-33) in each of the patients. RESULTS: We evaluated 75 of the 96 patients eligible for the study, including 25 in each BMI group. The CRP levels were significantly higher in the obese patients compared with both the eutrophic (p = 0.01) and the overweight (p = 0.03) patients. The mean adiponectin level was 21.82 ± 9.93 mg/L for the eutrophic asthmatics, which is a level that was significantly higher than in the overweight (15.31 ± 6.27 mg/L, p = 0.0140) and the obese (16.69 ± 11.45 mg/L, p = 0.0287) patients. The patients with higher adiponectin levels exhibited smaller FEV1 (p = 0.02) and lower FVC (p = 0.003). The IL-33 levels were not different between the groups. CONCLUSIONS: Adiponectin does not protect against the development of inflammation in the setting of asthma and may in fact exacerbate the disease via its anti-TH1 inflammatory effects, allowing for increased TH2 differentiation and a more severe allergic response.

Exogenous interleukin-33 targets myeloid-derived suppressor cells and generates periphery-induced Foxp3⁺ regulatory T cells in skin-transplanted mice.

Interleukin-33 (IL-33) has been a focus of study because of its variety of functions shaping CD4(+) T-cell biology. In the present work, we evaluated the modulatory effect of IL-33 on suppressor cells in an in vivo transplantation model. C57BL/6 wild-type mice were grafted with syngeneic or allogeneic skin transplants and treated with exogenous IL-33 daily. After 10 days of treatment, we analysed draining lymph node cellularity and found in allogeneic animals an increment in myeloid-derived suppressor cells, which co-express MHC-II, and become enriched upon IL-33 treatment. In line with this observation, inducible nitric oxide synthase and arginase 1 expression were also increased in allogeneic animals upon IL-33 administration. In addition, IL-33 treatment up-regulated the number of Foxp3(+) regulatory T (Treg) cells in the allogeneic group, complementing the healthier integrity of the allografts and the increased allograft survival. Moreover, we demonstrate that IL-33 promotes CD4(+) T-cell expansion and conversion of CD4(+)  Foxp3(-) T cells into CD4(+)  Foxp3(+) Treg cells in the periphery. Lastly, the cytokine pattern of ex vivo-stimulated draining lymph nodes indicates that IL-33 dampens interferon-γ and IL-17 production, stimulating IL-10 secretion. Altogether, our work complements previous studies on the immune-modulatory activity of IL-33, showing that this cytokine affects myeloid-derived suppressor cells at the cell number and gene expression levels. More importantly, our research demonstrates for the first time that IL-33 allows for in vivo Foxp3(+) Treg cell conversion and favours an anti-inflammatory or tolerogenic state by skewing cytokine production. Therefore, our data suggest a potential use of IL-33 to prevent allograft rejection, bringing new therapeutics to the transplantation field.