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OBJECTIVE: The objective of this study is to elucidate the causal association between asthma and alopecia areata (AA) through the application of Mendelian randomization (MR) analysis, leveraging summary data from genome-wide association studies (GWAS). Additionally, it explores potential mediating factors. MATERIALS AND METHODS: Mendelian randomization (MR) analysis was employed to investigate the causal relationship between asthma and AA using genetic instrumental variables (IVs) for asthma, 91 circulating inflammatory proteins, and AA extracted from large-scale GWAS. The primary analytical approach utilized the inverse-variance weighted (IVW) method, supplemented by weighted median and MR-Egger methods to assess robustness. Tests for heterogeneity and pleiotropy were conducted to ensure result reliability. Furthermore, the study examined the mediating role of circulating inflammatory proteins in the asthma-AA relationship. RESULTS: The findings revealed an increased risk of AA among asthma patients (odds ratio (OR) = 14.070; 95% confidence interval (CI) = 1.410-140.435; P = 0.024). Interleukin-33 (IL-33) emerged as a significant mediator in the asthma-AA relationship, explaining 13.1% of the mediation effect. Bidirectional Mendelian randomization analyses did not establish a causal effect of AA on asthma occurrence. CONCLUSION: This study, utilizing Mendelian Randomization, elucidates the causal link between asthma and AA, highlighting the mediating role of IL-33. These findings underscore the importance of considering AA risk in asthma management and offer insights for potential therapeutic strategies targeting IL-33. Future research should explore additional biomarkers and mediating mechanisms between asthma and AA to enhance treatment approaches and patient quality of life.
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Alopecia Areata , Asma , Estudio de Asociación del Genoma Completo , Interleucina-33 , Análisis de la Aleatorización Mendeliana , Humanos , Alopecia Areata/genética , Asma/genética , Asma/epidemiología , Asma/sangre , Interleucina-33/genética , Interleucina-33/sangre , Análisis de Mediación , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS.
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Síndrome de Liberación de Citoquinas , Interleucina-1 , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-1/antagonistas & inhibidores , Interleucina-1/inmunología , Interleucina-1/genética , Interleucina-1/metabolismo , Animales , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteínas de Unión al Calcio/genética , Interleucina-18/genética , Interleucina-18/inmunología , Síndrome de Activación Macrofágica/inmunología , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Proteínas Adaptadoras de Señalización CARDRESUMEN
A new, more effective vaccine against tuberculosis (TB) is urgently needed to curtail the current TB problem. The only licensed vaccine, BCG, has been shown to have highly variable protective efficacy in several clinical trials ranging from zero to 80 % against TB disease. We have previously reported that BCG formulated in dimethyl dioctadecyl-ammonium bromide (DDA) with D-(+)-Trehalose 6,6'-Dibehenate (TDB) adjuvant (BCG + Adj) is significantly more protective than BCG alone following murine aerosol Mycobacterium tuberculosis infection. Here we investigate the immunological basis for this improved efficacy by examining expression of different immune markers and cytokines in the lungs of vaccinated mice after M. tuberculosis aerosol challenge. We found significantly greater numbers of pulmonary IL-17A-expressing CD4+ T cells in mice immunized with BCG+Adj as compared to nonvaccinated and BCG-immunized mice at one-month post-challenge and that the enhanced protection was abrogated in IL-17A-deficient mice. Furthermore, we found significantly higher levels of IL-17A, IL-12p40 and IL-33 expression in the lungs of BCG + Adj immunized animals relative to nonvaccinated mice after M. tuberculosis challenge. These results demonstrate that the DDA/TDB adjuvant increases expression of IL-17A in response to the BCG vaccine and that these augmented IL-17A levels enhance control of M. tuberculosis infection.
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Background: One of the critical cases of recurrent pregnancy loss is immunological factors, whereas obtaining effective prevention or treatment is necessary for cognition of reasons. Objective: In this study, we tried to evaluate some immunological factors related to recurrent pregnancy loss. Materials and Methods: This case-control study was conducted on 66 women at the age of 18-35 yr who were referred to the Clinic of Gynecology and Obstetrics, Ali Ibn Abi Taleb hospital, Zahedan, Iran, from August-December 2019. Interleukin 33 (IL-33) serum levels were measured using enzyme-linked immunosorbent assay. Immunoglobulin G, Immunoglobulin A, Immunoglobulin M (IgM), and C-reactive protein levels were measured by serology and hematology methods. Results: The mean age of total participants was 30.8 ± 3.80 yr. The mean serum IL-33 in the case group was 318.5 ± 254.1 pg/ml and was lower than the control group (354.2 ± 259.9 pg/ml), which was not statistically significant (p = 0.52). The level of C-reactive protein in the case and control was not significantly different (p = 0.27), and Immunoglobulin A and Immunoglobulin G in the case and control were also not significantly different (p = 0.46, and p = 0.16, respectively), but there were significant differences (p = 0.003) between the level of the IgM in the case and control groups. Conclusion: No statistically significant difference was observed in the IL-33 serum level, for at least 4-6 months after the last abortion in the case group and the final live birth in the control group. In contrast, serum levels of IgM were statistically significant. Finally, the need for more studies is felt according to the different results of the previous studies in this field.
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Interleukin (IL)-33, a member of the IL-1 cytokine family, plays a vital role in immune system regulation and inflammation, with oxidative stress being implicated in its expression. During the search for compounds from natural sources with potential as therapeutic agents for allergic diseases via IL-33 signal modulation, we discovered significant IL-33 inhibitory activity in the methanol extract of Canavalia gladiata (sword bean) pods. Through chromatographic separation and liquid chromatography-mass spectrometry, we isolated 11 compounds (1-11) from the methanol extract. Furthermore, we assessed the inhibitory effects of these substances on IL-33/ST2 signaling in processes related to inflammatory and autoimmune diseases using an enzyme-linked immunosorbent assay. Among them, compounds 7, 10, and 11 exhibited substantial IL-33 inhibitory efficacy, with values reaching 78%, 86%, and 79% at 100 µM, respectively. Remarkably, compounds 7, 10, and 11 demonstrated significant and dose-dependent inhibition of IL-33 signaling at concentrations of 10, 50, and 100 µM. Computational molecular docking and dynamic simulations further elucidated the underlying mechanisms. These findings have promising pharmacological implications for allergy prevention and treatment associated with flavonoid glycosides derived from C. gladiata.
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Background: Toxoplasma gondii, a neurotropic protozoan, infects up one to third of the world population. The parasite can invade a wide variety of nucleated cells but preferably glial cells. Glia maturation factor ß (GMFß), a 17KD protein expressed at high levels in the central nervous system is predominantly related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple sclerosis. We aimed to determine the expression level of GMFß and its relation to other pro-inflammatory factors (IL33, SDF1, and CCL2) on T. gondii infected human neuroblastoma cell line. Methods: The human neuroblastoma (SK_NMC C535) cell line was infected by 5×106 (1:1 ratio). The supernatant was collected after cell lysis and centrifugation. Total RNA was extracted using the Yekta Tajhiz RNA extraction kit. cDNA was synthesized based on RevertAid First Strand cDNA Synthesis Kit manufacturer's protocol (Parstous, cDNA synthesis kit, Iran). The specificity of each primer pair (GMFß, IL33, SDF1, and CCL2) was provided by NCBI BLAST. Gene expression level was measured using Real-Time PCR. All experiments were conducted at the Hamadan University of Medical Sciences, western Iran in 2022. Results: The GMFß increased significantly up to 1.35-fold (P=0.007). The increase in GMFß expression in neuroblastoma cells was consistent with the increase in pro-inflammatory factors (CCL2 (0.47), IL33 (0.152) and, SDF1 (1.33)). Conclusion: GMFß upregulation can be a novel indicator of the destruction of nerve cells.
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Allergic rhinitis (AR) is a prevalent upper airway chronic inflammatory disease in children worldwide. The role of bioactive lipids in the regulation of AR has been recognized, but the underlying serum lipidomic basis of its pathology remains unclear. We utilized ultra-performance liquid chromatography (UPLC)-Q-Exactive Orbitrap/mass spectrometry (MS) to investigate the serum lipidomic profiles of children with AR. The lipidomic analysis identified 42 lipids that were differentially expressed (p < 0.05, fold change > 2) between the AR (n = 75) and normal control groups (n = 44). Specifically, the serum levels of diacylglycerol (DG), triacylglycerol (TG), fatty acid (FA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine, phosphatidyl-ethanolamine, and cardiolipins were significantly higher in the AR group. The diagnostic potential of the identified lipids was further evaluated using receiver operating characteristic curve analysis. The analysis revealed that five lipids, including FA 30:7, LPC O-18:1, LPC 18:0, LPC 16:0, and DG 34:0, had area under the curve values greater than 0.9 (p < 0.05). Furthermore, serum levels of IgE and IL-33, markers of AR severity, were found to have a significant positive correlation (p < 0.05) with DGs, LPCs, TGs, and FAs in AR patients. This study revealed the lipid disorders associated with AR and its severity, providing new insights into the pathological process of AR.
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Lipidómica , Lípidos , Rinitis Alérgica , Humanos , Niño , Lipidómica/métodos , Masculino , Femenino , Rinitis Alérgica/sangre , Lípidos/sangre , Cromatografía Líquida de Alta Presión/métodos , Biomarcadores/sangre , Preescolar , Interleucina-33/sangre , Índice de Severidad de la Enfermedad , Inmunoglobulina E/sangre , Adolescente , Espectrometría de Masas/métodosRESUMEN
Canine atopic dermatitis (CAD) is a chronic and inflammatory skin condition with a multifaceted origin, involving genetic factors, skin barrier abnormalities, immune responses, and hypersensitivity to various allergens. Interleukin 33 (IL-33), released by keratinocytes upon cellular injury, plays a crucial role in atopic dermatitis pathogenesis by inducing Th2 lymphocyte-mediated immune responses. This study aimed to evaluate IL-33 expression in dogs with atopic dermatitis and compare it to a control group. Forty-nine dogs were included, with 39 having atopic dermatitis, subdivided into groups based on clinical characteristics, and ten in the control group. Lesion and pruritus scores were assessed, and incisional biopsies were analyzed for dermatopathological characteristics. IL-33 expression was evaluated using immunohistochemistry, the analyses were blinded, based on the measurement of immunostaining areas using Image Pro-Plus software, version 4.5, relying on a semi-automatic color segmentation method, where the tissue immunostaining area for each biomarker was artificially delimited and quantified. Statistically significant differences in IL-33 immunostaining were found among groups (P=0.0005). Lichenified dogs (group 4) exhibited higher immunostaining compared to erythema (group 3) (P=0.0006), alesional pruritus (group 2) (P=0.0261), and the control group (group 1) (P=0.0079). IL-33 immunostaining increased with lesion progression, strongly correlating with lesion scores (P<0.0001), particularly in patients with chronic lesions characterized by erythema and lichenification. These findings suggest IL-33's significant role in canine atopic dermatitis pathogenesis and its association with lesion and inflammation scores during the chronic phase. This suggests potential therapeutic interventions targeting IL-33 or its receptors, though further studies are needed to explore these possibilities.
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Dermatitis Atópica , Enfermedades de los Perros , Inmunohistoquímica , Interleucina-33 , Perros , Animales , Interleucina-33/genética , Interleucina-33/inmunología , Dermatitis Atópica/veterinaria , Dermatitis Atópica/inmunología , Enfermedades de los Perros/inmunología , Masculino , Femenino , Inmunohistoquímica/veterinaria , Piel/inmunología , Piel/patología , Prurito/veterinaria , Prurito/inmunologíaRESUMEN
BACKGROUND: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 ≤ 2.44 µmol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts. CONCLUSION: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.
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Chronic obstructive pulmonary disease (COPD) is a main global epidemic increasing as population age and affecting approximately 10% of subjects over 45 years. COPD is a heterogeneous inflammatory disease with several endo-phenotypes and clinical presentations. Although neutrophilic inflammation is canonically considered a hallmark of COPD, eosinophilic inflammation can also be present in a subgroup of patients. Several other immune cells and cytokines play a key role in orchestrating and perpetuating the inflammatory pathways in COPD, making them attractive targets for treating this disorder. Recent studies have started to evaluate the possible role of type 2 (T2) inflammation and epithelial-derived alarmins (TSLP and IL-33) in COPD. Two phase III randomized clinical trials (RCTs) showed a modest reduction in exacerbations in COPD patients with eosinophilic phenotype treated with mepolizumab (anti-IL-5) or benralizumab (anti-IL-5Rα). A phase III RCT showed a 30% reduction in exacerbations in COPD patients with ≥ 300 eosinophils/µL treated with dupilumab (anti-IL-4Rα). These results suggest that blocking a single cytokine (e.g., IL-5) or its main target (i.e., IL-5Rα) is less promising than blocking a wider spectrum of cytokines (i.e., IL-4 and IL-13) in COPD. TSLP and IL-33 are upstream regulators of T2-high and T2-low immune responses in airway inflammation. Several ongoing RCTs are evaluating the efficacy and safety of anti-TSLP (tezepelumab), anti-IL-33 (itepekimab, tozorakimab), and anti-ST2 (astegolimab) in patients with COPD, who experience exacerbations. In conclusion, targeting T2 inflammation or epithelial-derived alarmins might represent a step forward in precision medicine for the treatment of a subset of COPD.
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Citocinas , Medicina de Precisión , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Citocinas/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Alarminas , Interleucina-33 , Ensayos Clínicos Fase III como Asunto , Interleucina-5/antagonistas & inhibidores , Linfopoyetina del Estroma TímicoRESUMEN
OBJECTIVE: A link between periodontitis and chronic obstructive pulmonary disease (COPD) has been identified, and interleukin-33 (IL-33) may play an important role in the common inflammatory mechanisms of these diseases. This study analyzed the associations of the serum IL-33 level with the occurrence and severity of periodontitis and COPD. METHODS: A total of 161 participants were divided into four groups: healthy volunteers, periodontitis patients, COPD patients, and patients with both COPD and periodontitis. Associations between serum IL-33 levels were measured by enzyme-linked immunosorbent assay, and clinical factors as well as the risks and severity of periodontitis and COPD were analyzed. RESULTS: Serum IL-33 levels were lower in all patient groups than in healthy controls. A trend toward lower IL-33 levels was observed among patients with both diseases compared with patients with either disease alone. The serum IL-33 level was also inversely associated with the severity of periodontitis and COPD. The serum IL-33 level was negatively associated with risks of periodontitis and COPD, indicating that IL-33 is likely involved in the pathophysiologic mechanism of the relationship between COPD and periodontitis. CONCLUSION: This study advances our understanding of the association between COPD and periodontitis and provides new bases for COPD prevention and treatment.
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Interleucina-33 , Periodontitis , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/sangre , Interleucina-33/sangre , Masculino , Femenino , Persona de Mediana Edad , Periodontitis/sangre , Periodontitis/complicaciones , Anciano , Índice de Severidad de la Enfermedad , Adulto , Estudios de Casos y Controles , Biomarcadores/sangreRESUMEN
Perioperative neurocognitive disorders (PND) are cognitive dysfunctions that usually occur in elderly patients after anesthesia and surgery. Microglial overactivation is a key underlying mechanism. Interleukin-33 (IL-33) is a member of the IL-1 family that orchestrates microglial function. In the present study, we explored how IL-33, which regulates microglia, contributes to cognitive improvement in a male mouse model of PND. An exploratory laparotomy was performed to establish a PND model. The expression levels of IL-33 and its receptor ST2 were evaluated using Western blot. IL-33/ST2 secretion, microglial density, morphology, phagocytosis of synapse, and proliferation, and dystrophic microglia were assessed using immunofluorescence. Synaptic plasticity was measured using Golgi staining and long-term potentiation. The Morris water maze and open field test were used to evaluate cognitive function and anxiety. Hippocampal expression of IL-33 and ST2 were elevated on postoperative day 3. We confirmed that IL-33 was secreted by astrocytes and neurons, whereas ST2 mainly colocalized with microglia. IL-33 treatment induced microgliosis after anesthesia and surgery. These microglia had larger soma sizes and shorter and fragmented branches. Compared to the Surgery group, IL-33 treatment reduced the synaptic phagocytosis of microglia and increased microglial proliferation and dystrophic microglia. IL-33 treatment also reversed the impaired synaptic plasticity and cognitive function caused by anesthesia and surgery. In conclusion, these results indicate that IL-33 plays a key role in regulating microglial state and synaptic phagocytosis in a PND mouse model. IL-33 treatment has a therapeutic potential for improving cognitive dysfunction in PND.
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Interleucina-33 , Ratones Endogámicos C57BL , Microglía , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Interleucina-33/metabolismo , Masculino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Complicaciones Cognitivas Postoperatorias/metabolismo , Fagocitosis/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/tratamiento farmacológico , Modelos Animales de Enfermedad , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
PURPOSE: Oral diseases act as a silent epidemic, and the pathogenetic role of interleukin-33/suppression of tumorigenicity-2 axis (IL-33/ST2) remains unclear due to a lack of literature. This review has attempted to highlight the importance of this axis in oral diseases, which may be helpful in developing therapeutic modalities required to halt disease progression. MATERIALS AND METHODS: A thorough search was conducted using various databases. Original research articles that assessed both IL-33 and ST2 levels in oral diseases using different techniques were included in the review. The risk of bias for each study was analyzed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool and Review Manager 5.4 was used to output the results. RESULTS: In the qualitative data synthesis we included 13 published articles. The most commonly used method was serum estimation, while methods with optimistic results were saliva, real-time quantitative polymerase chain reaction and immunohistochemistry. The predominant mechanism of action was nuclear factor kappa B signaling and type 2 immune response. However, salivary gland epithelial cell activation, activation of mast cells, type 1 immune response, and upregulated angiogenesis are crucial in mediating IL-33/ST2 signaling in oral diseases. CONCLUSIONS: Accumulating evidence demonstrates that the IL-33/ST2 axis is a fundamental pathogenetic mechanism of oral diseases of inflammatory, autoimmune, or neoplastic origin.
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Objective: Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. HSP is a multifactorial inflammatory disease, but its pathogenesis is still unclear. The pathogenicity of familial Mediterranean fever gene (MEFV) variants in HSP remains controversial. The objective of this study was to evaluate relationships between MEFV variants and susceptibility to HSP and their associations with clinical outcomes. We also investigated levels of IL-33 and soluble suppression of tumorigenicity 2 (sST2) in children with HSP and their clinical significance. Methods: We selected 100 children with HSP as the case group. The control group consisted of 50 children who visited the hospital for physical health examinations. All subjects were screened for MEFV gene exon mutations, and levels of IL-33 and sST2 were measured. Results: The frequency of MEFV variants was significantly greater in HSP patients than in healthy controls. The variant with the highest frequency was E148Q. The frequency of the C allele of the MEFV variant E148Q was 32 % in HSP patients and 18 % in controls (P-adjust = 0.04). Patients with the MEFV E148Q variant had more frequent joint involvement and recurrent purpura and higher levels of IL-33 and C-reactive protein (CRP). Levels of IL-33 and sST2 in children with HSP were significantly higher than those in the control group, and the sST2/IL-33 ratio in children with HSP was unbalanced (P-adjust <0.05). Logistic regression analysis revealed the presence of E148Q and an unbalanced sST2/IL-33 ratio to be independent risk factors for HSP. Conclusion: The results of this study suggest that the MEFV variant E148Q is associated with HSP susceptibility in Chinese children and that carriers of the variant may have more severe clinical manifestations and greater inflammatory responses. E148Q and the sST2/IL-33 ratio may play important roles in the pathogenesis of HSP.
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Perimenstrual worsening of asthma occurs in up to 40% of women with asthma, leading to increased acute exacerbations requiring clinical care. The role of sex hormones during these times remains unclear. In the current study, we used a translational approach to determine whether progesterone exacerbates allergic inflammation in the traditional chicken egg ovalbumin (OVA) model in BALB/c mice. Simultaneously, we used peripheral blood mononuclear cells (PBMC) from healthy human donors to assess the effects of progesterone on circulating group 2 innate lymphoid cells (ILC2). Briefly, lungs of ovariectomized (OVX) or sham-operated female (F-Sham) controls were implanted with a progesterone (P4, 25 mg) (OVX-P4) or placebo pellet (OVX-Placebo), followed by sensitization and challenge with ovalbumin (OVA). Progesterone increased total inflammatory histologic scores, increased hyper-responsiveness to methacholine (MCh), increased select chemokines in the bronchoalveolar lavage (BAL) and serum, and increased ILC2 and neutrophil numbers, along the airways compared with F-Sham-OVA and OVX-Placebo-OVA animals. Lung ILC2 were sorted from F-Sham-OVA, OVX-Placebo-OVA and OVX-P4-OVA treated animals and stimulated with IL-33. OVX-P4-OVA lung ILC2 were more responsive to interleukin 33 (IL-33) compared with F-Sham-OVA treated, producing more IL-13 and chemokines following IL-33 stimulation. We confirmed the expression of the progesterone receptor (PR) on human ILC2, and showed that P4 + IL-33 stimulation also increased IL-13 and chemokine production from human ILC2. We establish that murine ILC2 are capable of responding to P4 and thereby contribute to allergic inflammation in the lung. We confirmed that human ILC2 are also hyper-responsive to P4 and IL-33 and likely contribute to airway exacerbations following allergen exposures in asthmatic women with increased symptoms around the time of menstruation.NEW & NOTEWORTHY There is a strong association between female biological sex and severe asthma. We investigated the allergic immune response, lung pathology, and airway mechanics in the well-described chicken egg ovalbumin (OVA) model with steady levels of progesterone delivered throughout the treatment period. We found that progesterone enhances the activation of mouse group 2 innate lymphoid cells (ILC2). Human ILC2 are also hyper-responsive to progesterone and interleukin 33 (IL-33), and likely contribute to airway exacerbations following allergen exposures in women with asthma.
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Asma , Pulmón , Linfocitos , Ratones Endogámicos BALB C , Ovalbúmina , Progesterona , Progesterona/farmacología , Animales , Femenino , Linfocitos/inmunología , Linfocitos/metabolismo , Humanos , Asma/inmunología , Asma/patología , Asma/metabolismo , Ratones , Ovalbúmina/inmunología , Pulmón/patología , Pulmón/inmunología , Pulmón/metabolismo , Inmunidad Innata/efectos de los fármacos , Interleucina-33/metabolismo , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Hipersensibilidad/metabolismo , Inflamación/patología , Inflamación/inmunología , Inflamación/metabolismo , Modelos Animales de EnfermedadRESUMEN
The cellular and molecular mechanisms of atherosclerosis are still unclear. Type 2 innate lymphocytes (ILC2) exhibit anti-inflammatory properties and protect against atherosclerosis. This study aimed to elucidate the pathogenesis of atherosclerosis development using atherosclerosis model mice (ApoE KO mice) and mice deficient in IL-33 receptor ST2 (ApoEST2 DKO mice). Sixteen-week-old male ApoE KO and ApoEST2 DKO mice were subjected to an 8-week regimen of a high-fat, high-sucrose diet. Atherosclerotic foci were assessed histologically at the aortic valve ring. Chronic inflammation was assessed using flow cytometry and real-time polymerase chain reaction. In addition, saturated fatty acids (palmitic acid) and IL-33 were administered to human aortic endothelial cells (HAECs) to assess fatty acid metabolism. ApoEST2 DKO mice with attenuated ILC2 had significantly worse atherosclerosis than ApoE KO mice. The levels of saturated fatty acids, including palmitic acid, were significantly elevated in the arteries and serum of ApoEST2 DKO mice. Furthermore, on treating HAECs with saturated fatty acids with or without IL-33, the Oil Red O staining area significantly decreased in the IL-33-treated group compared to that in the non-treated group. IL-33 potentially prevented the accumulation of saturated fatty acids within atherosclerotic foci.
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Aterosclerosis , Ácidos Grasos , Interleucina-33 , Ratones Noqueados , Animales , Interleucina-33/metabolismo , Interleucina-33/genética , Aterosclerosis/metabolismo , Masculino , Ratones , Ácidos Grasos/metabolismo , Humanos , Modelos Animales de Enfermedad , Ácido Palmítico/farmacología , Apolipoproteínas E/genética , Apolipoproteínas E/deficiencia , Dieta Alta en Grasa , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Células Endoteliales/metabolismo , Ratones Noqueados para ApoE , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Aorta/metabolismo , Aorta/patología , Inmunidad InnataRESUMEN
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/ß-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/ß-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.
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Adipogénesis , Interleucina-33 , Vía de Señalización Wnt , Animales , Ratones , Adipocitos/metabolismo , Adipogénesis/genética , beta Catenina/metabolismo , Diferenciación Celular , Interleucina-33/metabolismo , Obesidad/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismoRESUMEN
The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33. Recent advancements in therapeutic strategies, specifically the utilization of biologics targeting pivotal cytokines (IL-4, IL-5, and IL-13), are discussed, offering insights into both challenges and opportunities. Acknowledging the pivotal role of innate type-2 cytokines in orchestrating immune responses positions them as promising therapeutic targets. The evolving landscape of research and development in this field not only propels immunological knowledge forward but also holds the promise of more effective treatments in the future.
RESUMEN
The cellular response to endoplasmic reticulum (ER) stress accompanies plasma cell maturation and is one of triggers and cofactors of the local inflammatory response. Chemical chaperones, low-molecular substances that eliminate pathological ER stress, are proposed as means of treating pathologies associated with ER stress. The aim of this study was to evaluate the effect and mechanisms of influence of chemical chaperones on the humoral response in a low-dose model of allergy. The allergic immune response was induced in BALB/c mice by repeated administration of ovalbumin at a dose of 100 ng for 6 weeks. Some animals were injected with both the antigen and the chemical chaperones, TUDCA (tauroursodeoxycholic acid) or 4-PBA (4-phenylbutyrate). Administration of TUDCA, but not 4-PBA, suppressed production of allergen-specific IgE (a 2.5-fold decrease in titer). None of the chemical chaperones affected the production of specific IgG1. The effect of TUDCA was associated with suppression of the switch to IgE synthesis in regional lymph nodes. This phenomenon was associated with suppressed expression of genes encoding cytokines involved in type 2 immune response, especially Il4 and Il9, which in turn could be caused by suppression of IL-33 release. In addition, TUDCA significantly suppressed expression of the cytokine APRIL, and to a lesser extent, BAFF. Thus, TUDCA inhibition of the allergy-specific IgE production is due to suppression of the release of IL-33 and a decrease in the production of type 2 immune response cytokines, as well as suppression of the expression of the cytokines APRIL and BAFF.
Asunto(s)
Hipersensibilidad , Interleucina-33 , Ácido Tauroquenodesoxicólico , Animales , Ratones , Hipersensibilidad/tratamiento farmacológico , Inmunoglobulina E , Citocinas , AlérgenosRESUMEN
BACKGROUND: Group 2 innate lymphoid cells (ILC2s) represent one of the main tissue-specific innate lymphoid cell populations, which are key drivers of cytokine secretion in their occupational niche. However, the precise involvement of ILC2s in cancer immunity and their potential impact on immunotherapeutic approaches remain poorly understood. METHODS: The proportion of ILC2s originating from various tissue sources were quantified through flow cytometry, along with the determination of CD4+ T cell and CD8+ T cell percentages. Flow cytometry was also employed to assess IFN-γ production and programmed cell death protein-1 (PD-1) expression in T cells. Immunohistochemistry was utilized to detect IL-33 expression in tumor tissues, while immunofluorescence was employed to confirm the infiltration of ILC2s in both murine and human tumor tissues. RESULTS: In this study, we provide evidence that intra-tumoral ILC2s in lung adenocarcinoma (LUAD) exist in a quiescent state. However, the activation of intra-tumoral ILC2s is induced by IL-33 specifically in a natural ILC2s (nILC2, ST2+KLRG1-) phenotype. Considering the pivotal role of PD-1 in cancer immunotherapy and its immunoregulatory functions, we investigated the synergistic effects of IL-33 and anti-PD-1 and found that their combination enhances anti-tumor immunity and improves the efficacy of immunotherapy. Moreover, this combination leads to the upregulation of activated mature ILC2s (mILC2, ST2+KLRG1+) phenotype, thereby highlighting the activated ILC2s as a novel enhancer of the immunoregulatory properties of anti-PD-1. CONCLUSIONS: Collectively, these findings underscore the significance of ILC2s and their contribution to the anti-tumor response in the context of cancer immunotherapy. Consequently, the simultaneous targeting of ILC2s and T cells represents a potentially promising and widely applicable strategy for immunotherapeutic interventions.