Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Pulmão , Interleucina-33/metabolismo , Interleucina-33/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Animais , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Camundongos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Transdução de Sinais , Humanos , Camundongos KnockoutAssuntos
Interleucina-33 , Necroptose , Proteínas Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores , Staphylococcus aureus , Animais , Camundongos , Interleucina-33/metabolismo , Interleucina-33/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Humanos , Proteínas Quinases/metabolismo , Pele/metabolismo , Pele/microbiologia , Pele/patologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/imunologia , Masculino , FemininoRESUMO
Epithelial-derived IL-33 (Interleukin-33), as a member of alarm signals, is a chemical substance produced under harmful stimuli that can promote innate immunity and activate adaptive immune responses. Type 2 inflammation refers to inflammation primarily mediated by Type 2 helper T cells (Th2), Type 2 innate lymphoid cells (ILC2), and related cytokines. Type 2 inflammation manifests in various forms in the lungs, with diseases such as asthma and chronic obstructive pulmonary disease chronic obstructive pulmonary disease (COPD) closely associated with Type 2 inflammation. Recent research suggests that IL-33 has a promoting effect on Type 2 inflammation in the lungs and can be regarded as an alarm signal for Type 2 inflammation. This article provides an overview of the mechanisms and related targets of IL-33 in the development of lung diseases caused by Type 2 inflammation, and summarizes the associated treatment methods. Analyzing lung diseases from a new perspective through the alarm of Type 2 inflammation helps to gain a deeper understanding of the pathogenesis of these related lung diseases. This, in turn, facilitates a better understanding of the latest treatment methods and potential therapeutic targets for diseases, with the expectation that targeting lL-33 can propose new strategies for disease prevention.
Assuntos
Interleucina-33 , Humanos , Interleucina-33/metabolismo , Interleucina-33/imunologia , Animais , Inflamação/imunologia , Imunidade Inata , Células Th2/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Asma/imunologiaRESUMO
Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.
Assuntos
Alarminas , Sistema Nervoso Central , Humanos , Alarminas/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/lesões , Inflamação/metabolismo , Citocinas/metabolismo , Proteína HMGB1/metabolismo , Interleucina-33/metabolismo , Interleucina-1alfa/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Allergic rhinitis (AR) is a multifactorial disease triggered by interactions between genes and the environment. Clinical evidence has shown that trans-resveratrol, a widely used drug, significantly ameliorates AR pathology. However, the precise mechanisms underlying this effect remain unclear. PURPOSE: This study aimed to elucidate the pharmacological mechanisms of action of trans-resveratrol in patients with AR who exhibit hypoxic symptoms. This will be achieved through microRNA sequencing and signaling pathway screening combined with basic experiments to determine the effects of Trans-resveratrol intervention in this patient population. METHODS: Network pharmacology was used to determine the therapeutic value of trans-resveratrol in AR. The micro-RNA miR-204-3p was pinpointed by sequencing. Quantitative reverse transcription polymerase chain reaction was used to quantify the expression levels. Haematoxylin and eosin, alcian blue-periodic acid-Schiff, and Masson's trichrome staining were used to assess the effects of hypoxia on nasal mucosa immunohistochemistry and immunofluorescence-localised target proteins. Egl nine homolog 3 (EGLN3) was screened using bioinformatics software. Protein expression was detected by western blotting. Cell growth and death were gauged via Cell Counting Kit-8 and terminal deoxynucleotidyl transferase dUTP nick end labelling staining, respectively. Cell migration was observed using a transwell assay. Enzyme-linked immunosorbent assay was used to measure interleukin (IL)33 levels in the cell supernatants. Flow cytometry was used to verify cell cycle and antigen levels. Electron microscopy was used to visualise the status of the nasal mucosa prior to in vivo expression analysis. RESULTS: Patients with hypoxic AR demonstrated more pronounced nasal mucosal remodelling than that in patients with common AR. Sequencing results indicated that these patients had a reduced expression of miR-204-3p. Through a combination utilizing of bioinformatics analysis and experimental validation, EGLN3 has been identified as a direct target of HIF-1α. The low expression level of miR-204-3p represses EGLN3, resulting in the accumulation of HIF-1α and the activation of the IL33/ST2 signaling pathway. These stimulate the proliferation, survival, and migration of HNEpCs, ultimately contributing to mucosa remodeling and AR progression. Trans-resveratrol notably downregulated the levels of HIF-1α and IL33/ST2, while simultaneously increasing the expression of EGLN3. CONCLUSIONS: Downregulation of miR-204-3p initiated a vicious cycle of hypoxic AR via EGLN3/HIF-1α/IL33/ST2. Trans-resveratrol reversed the pathological process of nasal mucosa remodeling of hypoxic AR by exhibiting anti-inflammatory and anti-angiogenic functions via the above signaling pathway. Our study uncovers the underlying mechanism by which hypoxia drives the progression of AR. It presents innovative strategies for addressing inflammatory and hypoxia-related diseases, bridging traditional and modern medicine, and highlighting the potential of natural compounds in clinical practice.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Interleucina-33 , MicroRNAs , Resveratrol , Rinite Alérgica , Transdução de Sinais , MicroRNAs/metabolismo , MicroRNAs/genética , Rinite Alérgica/tratamento farmacológico , Humanos , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-33/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Feminino , Masculino , Mucosa Nasal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Adulto , Progressão da DoençaRESUMO
Background: Insufficiently managed incisional (INC) pain severely affects patients' life quality and rehabilitation after a major operation. However, mechanisms underlying INC pain still remain poorly understood. Methods: A mouse model of INC pain was established by skin plus deep muscle incision. Biochemistry assay, in vivo reactive oxygen species (ROS) imaging, Ca2+ imaging combined with retrograde labelling, neuron tracing and nocifensive behavior test, etc. were utilized for mechanism investigation. Results: We found pro-nociceptive cytokine interleukin -33 (IL-33) ranked among top up-regulated cytokines in incised tissues of INC pain model mice. IL-33 was predominantly expressed in keratinocytes around the incisional area. Neutralization of IL-33 or its receptor suppression of tumorigenicity 2 protein (ST2) or genetic deletion of St2 gene (St2 -/-) remarkably ameliorated mechanical allodynia and improved gait impairments of model mice. IL-33 contributes to INC pain by recruiting macrophages, which subsequently release ROS in incised tissues via ST2-dependent mechanism. Transfer of excessive macrophages enhanced oxidative injury and reproduced mechanical allodynia in St2 -/- mice upon tissue incision. Overproduced ROS subsequently activated functionally up-regulated transient receptor potential ankyrin subtype-1 (TRPA1) channel innervating the incisional site to produce mechanical allodynia. Neither deleting St2 nor attenuating ROS affected wound healing of model mice. Conclusions: Our work uncovered a previously unrecognized contribution of IL-33/ST2 signaling in mediating mechanical allodynia and gait impairment of a mouse model of INC pain. Targeting IL-33/ST2 signaling could be a novel therapeutic approach for INC pain management.
Assuntos
Modelos Animais de Doenças , Hiperalgesia , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Macrófagos , Camundongos Knockout , Espécies Reativas de Oxigênio , Canal de Cátion TRPA1 , Animais , Interleucina-33/metabolismo , Interleucina-33/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Canal de Cátion TRPA1/metabolismo , Canal de Cátion TRPA1/genética , Macrófagos/metabolismo , Hiperalgesia/metabolismo , Pele/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Queratinócitos/metabolismo , Dor/metabolismoRESUMO
Bleomycin (BLM) induces lung injury, leading to inflammation and pulmonary fibrosis. Regulatory T cells (Tregs) maintain self-tolerance and control host immune responses. However, little is known about their involvement in the pathology of pulmonary fibrosis. Here we show that a unique Treg subset expressing trefoil factor family 1 (Tff1) emerges in the BLM-injured lung. These Tff1-expressing Tregs (Tff1-Tregs) were induced by IL-33. Moreover, although Tff1 ablation in Tregs did not change the pathological condition, selective ablation of Tff1-Tregs using an intersectional genetic method promoted pro-inflammatory features of macrophages in the injured lung and exacerbated the fibrosis. Taken together, our study revealed the presence of a unique Treg subset expressing Tff1 in BLM-injured lungs and their critical role in the injured lung to ameliorate fibrosis.
Assuntos
Bleomicina , Pulmão , Fibrose Pulmonar , Linfócitos T Reguladores , Fator Trefoil-1 , Bleomicina/efeitos adversos , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Camundongos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/imunologia , Fator Trefoil-1/genética , Fator Trefoil-1/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Camundongos Knockout , Masculino , Interleucina-33/metabolismo , Interleucina-33/genéticaRESUMO
PURPOSE OF THE STUDY: To observe the dynamic changes in monocyte subsets during septic lung injury and to assess the anti-inflammatory role of the sulfotransferase homolog 2 (ST2) receptor. MATERIALS AND METHODS: Dynamic changes of monocyte subsets from patients with septic lung injury and mice post-cecal ligation and puncture (CLP) were monitored. ST2 receptors on mice monocytes and concentrations of IL-33, IL-1ß, IL-12, and IL-27 from peripheral blood or culture supernatant were detected. RESULTS: CD14lowCD16- (Mo0) and CD14++CD16+ (Mo2) monocyte subsets were significantly expanded in patients with sepsis-related acute respiratory distress syndrome. In sepsis model mice, monocyte counts, particularly of Ly6Cint and CDLy6Cint+hi monocytes, were significantly increased. The mean optical density value of TNF-α after CLP mainly increased after 24 h, whereas that of IL-6 was significantly increased at all time points assessed after CLP. The levels of IL-1ß, IL-12, IL-27, and IL-33 increased to variable degrees at 6, 12, 24, and 48h after CLP, and ST2+ monocytes were significantly expanded in sepsis model mice compared to sham-operated mice. ST2 receptor blockade suppressed IL-1ß and IL-12 production in cell culture. CONCLUSIONS: Changes in monocyte subsets expressing the ST2 receptor play an important role in septic lung injury by modulating inflammatory cytokine secretion.
Assuntos
Citocinas , Monócitos , Sepse , Animais , Monócitos/metabolismo , Camundongos , Sepse/metabolismo , Masculino , Humanos , Citocinas/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Interleucina-33/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar Aguda/metabolismo , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Idoso , Interleucina-27/metabolismoRESUMO
Asthma is characterized by lung eosinophilia, remodeling, and mucus plugging, controlled by adaptive Th2 effector cells secreting IL-4, IL-5, and IL-13. Inhaled house dust mite (HDM) causes the release of barrier epithelial cytokines that activate various innate immune cells like DCs and basophils that can promote Th2 adaptive immunity directly or indirectly. Here, we show that basophils play a crucial role in the development of type 2 immunity and eosinophilic inflammation, mucus production, and bronchial hyperreactivity in response to HDM inhalation in C57Bl/6 mice. Interestingly, conditional depletion of basophils during sensitization did not reduce Th2 priming or asthma inception, whereas depletion during allergen challenge did. During the challenge of sensitized mice, basophil-intrinsic IL-33/ST2 signaling, and not FcεRI engagement, promoted basophil IL-4 production and subsequent Th2 cell recruitment to the lungs via vascular integrin expression. Basophil-intrinsic loss of the ubiquitin modifying molecule Tnfaip3, involved in dampening IL-33 signaling, enhanced key asthma features. Thus, IL-33-activated basophils are gatekeepers that boost allergic airway inflammation by controlling Th2 tissue entry.
Assuntos
Asma , Basófilos , Interleucina-33 , Pulmão , Camundongos Endogâmicos C57BL , Pyroglyphidae , Células Th2 , Animais , Basófilos/imunologia , Interleucina-33/metabolismo , Interleucina-33/imunologia , Células Th2/imunologia , Asma/imunologia , Asma/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Pyroglyphidae/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Transdução de Sinais , Interleucina-4/metabolismo , Interleucina-4/imunologiaRESUMO
Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease characterised by irreversible airways obstruction associated with chronic airways inflammation and remodelling, while the pathogenesis and the mechanistic differences between patients remain to be fully elucidated. We previously reported that alarmin cytokine IL-33 may contribute to the production of autoantibodies against respiratory epithelial cells. Here we expand the hypothesis that pulmonary autoimmune responses induced by airway microbiota also contribute to the progression of COPD. We focused on Edwardsiella tarda which we detected uniquely in the induced sputum of patients with acute exacerbations of COPD. Pernasal challenge of the airways of WT mice with supernatants of cultured E. tarda induced marked, elevated expression of IL-33 in the lung tissues. Immunisation of animals with supernatants of cultured E. tarda resulted in significantly elevated airways inflammation, the formation of tertiary lymphatic structures and significantly elevated proportions of T follicular helper T cells in the lung tissue and mediastinal lymph nodes. Interestingly, such challenge also induced production of IgG autoantibodies directed against lung tissue lysate, alveolar epithelial cell proteins and elastin fragment, while putrescine, one of metabolites generated by the bacterium, might play an important role in the autoantibody production. Furthermore, all of these effects were partly but significantly abrogated in mice with deletion of the IL-33 receptor ST2. Collectively, these data support the hypothesis that COPD is progressed at least partly by airways microbiota such as E. tarda initiating autoimmune attack of the airways epithelium mediated at least partly through the IL-33-ST2 axis.
Assuntos
Autoanticorpos , Edwardsiella tarda , Infecções por Enterobacteriaceae , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Pulmão , Doença Pulmonar Obstrutiva Crônica , Animais , Interleucina-33/imunologia , Interleucina-33/metabolismo , Autoanticorpos/imunologia , Edwardsiella tarda/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Infecções por Enterobacteriaceae/imunologia , Camundongos , Humanos , Pulmão/imunologia , Pulmão/patologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Feminino , Transdução de Sinais , MasculinoRESUMO
Interleukin (IL)-33 released from airway epithelial cells plays a vital role in shaping type 2 immune responses by binding to the ST2 receptor present in many immune cells, including mast cells (MCs). Intranasal administration of IL-33 in mice induces type 2 lung inflammation, an increase in lung MC progenitors, and transepithelial migration of leukocytes to the bronchoalveolar space. The aim of this study was to determine the contribution of MCs in IL-33-induced lung pathology. Four daily intranasal administrations of IL-33 reduced spirometry-like lung function parameters, induced airway hyperresponsiveness, and increased leukocytes in bronchoalveolar lavage fluid (BAL) in an ST2-dependent manner. MC-deficient (Cpa3cre/+) mice, which lack MCs, had intact spirometry-like lung function but slightly reduced airway hyperresponsiveness, possibly related to reduced IL-33 or serotonin. Strikingly, Cpa3cre/+ mice exposed to IL-33 had 50% reduction in BAL T-cells, and CXCL1 and IL-33 were reduced in the lung. Intranasal IL-33 induced CXCR2 expression in T-cells in a MC-independent fashion. Furthermore, IL-33-induced lung MCs were immunopositive for CXCL1 and localized in the epithelium of wild-type mice. These results suggest that MCs are required to sustain intact lung IL-33 and CXCL1 levels in mice with IL-33-induced airway inflammation, thereby facilitating T-cell accumulation in the bronchoalveolar space.
Assuntos
Líquido da Lavagem Broncoalveolar , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Mastócitos , Camundongos Knockout , Linfócitos T , Animais , Interleucina-33/metabolismo , Interleucina-33/imunologia , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Camundongos Endogâmicos C57BL , Pulmão/imunologia , Pulmão/patologia , Pneumonia/imunologia , Pneumonia/metabolismo , Receptores de Interleucina-8B/metabolismo , Quimiocina CXCL1/metabolismoRESUMO
Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-ß (LTß) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-ß receptor (LTßR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.
Assuntos
Linfócitos B , Eosinófilos , Interleucina-33 , Células Estromais , Animais , Eosinófilos/imunologia , Eosinófilos/metabolismo , Células Estromais/metabolismo , Células Estromais/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Interleucina-33/metabolismo , Camundongos , Receptor beta de Linfotoxina/metabolismo , Camundongos Endogâmicos C57BL , Linfonodos/imunologia , Comunicação Celular , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Transdução de Sinais , Receptores de Superfície CelularRESUMO
The interleukin (IL)-1 family is a major proinflammatory cytokine family, ranging from the well-studied IL-1s to the most recently discovered IL-33. As a new focus, IL-33 has attracted extensive research for its crucial immunoregulatory roles, leading to the development of notable monoclonal antibodies as clinical candidates. Efforts to develop small molecules disrupting IL-33/ST2 interaction remain highly desired but encounter challenges due to the shallow and featureless interfaces. The information from relative cytokines has shown that traditional binding site identification methods still struggle in mapping cryptic sites, necessitating dynamic approaches to uncover druggable pockets on IL-33. Here, we employed mixed-solvent molecular dynamics (MixMD) simulations with diverse-property probes to map the hotspots of IL-33 and identify potential binding sites. The protocol was first validated using the known binding sites of two IL-1 family members and then applied to the structure of IL-33. Our simulations revealed several binding sites and proposed side-chain rearrangements essential for the binding of a known inhibitor, aligning well with experimental NMR findings. Further microsecond-time scale simulations of this IL-33-protein complex unveiled distinct binding modes with varying occurrences. These results could facilitate future efforts in developing ligands to target challenging flexible pockets of IL-33 and IL-1 family cytokines in general.
Assuntos
Interleucina-33 , Simulação de Dinâmica Molecular , Solventes , Interleucina-33/química , Interleucina-33/metabolismo , Sítios de Ligação , Solventes/química , Humanos , Interleucina-1/química , Interleucina-1/metabolismo , Ligação Proteica , Proteína 1 Semelhante a Receptor de Interleucina-1/química , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismoRESUMO
INTRODUCTION: Osteoarthritis (OA) is a chronic inflammatory disease where pro-inflammatory cytokines, damage-associated molecular patterns and macrophages play a crucial role. However, the interaction of these mediators, the exact cause, and the treatment of knee osteoarthritis (KOA) are still unclear. Moreover, the interaction of interleukin (IL)-33, platelet-derived growth factor-BB (PDGF-BB), and matrix metalloproteinase-9 (MMP-9) with other factors in the pathogenesis of KOA has not been elaborately explored. METHOD: Therefore, in this study, we analyzed the expression of IL-33, PDGF-BB, and MMP-9 in the knee cartilage tissue of model mice, murine KOA was induced by using the destabilization of the medial meniscus (DMM) model. RESULTS: Compared with the sham operation control group, the expression levels of PDGF-BB, IL-33, and MMP-9 were increased significantly, and the pathological sections showed obvious cartilage damage. Additionally, we assessed the levels of IL-33 and MMP-9 expression in the knee joint of KOA model mice following intervention with PDGF-BB antibody, and we found that the expression level of MMP-9 was reduced following intervention with IL-33 antibody. When the effects of the three antibodies were compared in a mouse disease model, it was discovered that the IL-33 antibody could dramatically lower the relative expression level of MMP-9, resulting in the least amount of cartilage damage and improved protection. In conclusion, inhibiting IL-33 can significantly lower inflammatory factor levels in the knee joint, including IL-33 and MMP-9, and it can improve cartilage breakdown in osteoarthritis of the knee. CONCLUSION: Overall, the results indicate that IL-33 has a therapeutic function in the treatment of knee osteoarthritis and may be a novel target for treatment of the underlying causes of KOA. Additionally, PDGF-BB might be an upstream pathway of IL-33, and KOA's MMP-9 is an downstream pathway of IL-33.
Assuntos
Modelos Animais de Doenças , Interleucina-33 , Metaloproteinase 9 da Matriz , Osteoartrite do Joelho , Animais , Interleucina-33/metabolismo , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Becaplermina/metabolismo , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-sis/metabolismoRESUMO
BACKGROUND: Alarmins resulting from cell death or oxidative stress are involved in the development of Kawasaki disease (KD) vasculitis. In a previous study, we demonstrated the potential role of interleukin (IL)-33 as an alarmin in the development of KD vasculitis. Although edematous dissociation (necrotic change) of the tunica media is thought to be a major source of IL-33 in KD vasculitis, it has not yet been elucidated. METHODS AND RESULTS: We investigated the impact of IL-33 released from necrotic human coronary artery smooth muscle cells (HCASMCs) on human coronary artery endothelial cells (HCAECs) using a coculture assay. Subsequently, we evaluated the anti-inflammatory effects of anti-IL-33 and anti-suppression of tumorigenicity 2 (ST2) antibodies compared with conventional therapies of KD, such as high-dose IgG or anti-tumor necrosis factor (TNF)-α antibody. Primary necrosis of HCASMCs induced significant release of IL-33. In cocultures of necrotic HCASMCs with HCAECs, the necrotic HCASMCs significantly induced the production of various proinflammatory cytokines in the HCAECs. Anti-IL-33 and anti-ST2 antibodies exhibited unique inhibitory effects on the production of platelet-derived growth factor-BB or IL-12(p70) in HCAECs. CONCLUSIONS: There is potential involvement of edematous dissociation of the tunica media in the development of KD vasculitis. Furthermore, the distinctive anti-inflammatory effects of the anti-IL-33/ST2 axis drugs suggest novel therapeutic options for patients with refractory KD.
Assuntos
Vasos Coronários , Interleucina-33 , Síndrome de Linfonodos Mucocutâneos , Necrose , Síndrome de Linfonodos Mucocutâneos/patologia , Humanos , Vasos Coronários/patologia , Interleucina-33/metabolismo , Túnica Média/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/etiologia , Masculino , Células Cultivadas , Técnicas de CoculturaRESUMO
Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B highexpressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B highexpressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B highexpressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B highexpressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/ß-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/ß-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B highexpressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/ß-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.
Assuntos
Fibroblastos , Fibrose , Doenças Inflamatórias Intestinais , Interleucina-33 , Células Matadoras Naturais , Proteínas Wnt , Humanos , Fibroblastos/metabolismo , Animais , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-33/metabolismo , Interleucina-33/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Proteínas Wnt/metabolismo , Proteínas Wnt/genética , Camundongos , Via de Sinalização Wnt , Masculino , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Feminino , Colite/metabolismo , Colite/imunologia , GlicoproteínasRESUMO
Mast cells are multifaceted cells localized in tissues and possess various surface receptors that allow them to respond to inner and external threat signals. Interleukin-33 (IL-33) is a cytokine released by structural cells in response to parasitic infections, mechanical damage, and cell death. IL-33 can activate mast cells, causing them to release an array of mediators. This study aimed to identify the different cytokines released by human cord blood-derived mast cells (hCBMCs) in response to acute and prolonged stimulation with IL-33. For this purpose, a hCBMC model was established and stimulated with 10 ng and 20 ng of recombinant human IL-33 (rhIL-33) for 6 h and 24 h. Total RNA was hybridized using a high-density oligonucleotide microarray. A multiplex assay was performed to assess the released cytokines. Acute exposure to rhIL-33 increased the expression of IL-1α, IL-1ß, IL-6, and IL-13, whereas prolonged exposure increased the expression of IL-5 and IL-10, and cytokines were detected in the culture supernatant. WebGestalt analysis revealed that rhIL-33 induces pathways and biological processes related to the immune system and the acute inflammatory response. This study demonstrates that rhIL-33 can activate hCBMCs to release pro- and anti-inflammatory cytokines, eliciting distinct acute and prolonged responses unique to hCBMCs.
Assuntos
Citocinas , Sangue Fetal , Interleucina-33 , Mastócitos , Humanos , Interleucina-33/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Sangue Fetal/citologia , Citocinas/metabolismo , Células Cultivadas , Proteínas Recombinantes/farmacologia , Perfilação da Expressão GênicaRESUMO
Atopic dermatitis (AD) is associated with chronic inflammation and an altered skin barrier. Lipids of the stratum corneum of AD patients are known to differ substantially in composition from those of healthy subjects. A reconstructed human epidermis (RHE) model has been developed in vitro in order to mimic the characteristics of AD. In this study, using this model, we compared lipid profile modifications between control RHE and RHE treated with Th2 cytokines in order to mimic AD. We focused particularly on the lipid profile of the ceramide subclasses: non-hydroxy sphingosine (NS) and esterified ω-hydroxy sphingosine (EOS), which have been reported to be clearly modified in atopic skin. RHE lipids were extracted and analysed using high-performance liquid chromatography coupled to high-resolution mass spectrometry. The following lipid profile changes were observed in Th2-cytokine-treated RHE: (i) an increase in ceramide NS composed of an unsaturated fatty acid chain; (ii) an increase in saturated ceramide NS with small total carbon content (≤40 carbon atoms), whereas NS with a higher total carbon content (≥42 carbon atoms) was decreased; and (iii) a decrease in ceramide EOS. These results are in accordance with reported lipid profiles of human atopic skin in vivo. Moreover, the in vitro model represents a useful tool to better understand the pathogenesis of AD which may be used for future screening of new effective treatments.
Assuntos
Ceramidas , Citocinas , Dermatite Atópica , Epiderme , Células Th2 , Humanos , Ceramidas/metabolismo , Ceramidas/análise , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Citocinas/metabolismo , Esfingosina/análogos & derivados , Interleucina-4/metabolismo , Modelos Biológicos , Interleucina-33/metabolismo , Linfopoietina do Estroma do TimoRESUMO
BACKGROUND: Activation of the IL-33/ST2 axis leads to the production of proinflammatory cytokines and thus to the triggering of osteoclastogenesis, which is why it plays an important role in the immunopathogenesis of periodontitis. The aim of this study was to compare IL-33 levels in serum, plasma, saliva and gingival crevicular fluid (GCF) of subjects with chronic periodontitis (CP) in comparison with the control group (CG). METHODS: This systematic review and meta-analysis followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and was registered in the Open Science Framework (OSF): https://doi.org/10.17605/OSF.IO/YHUWA . Six electronic databases were used for study identification; PubMed, Google Scholar, ScienceDirect, Web of Science, Scopus and Dentistry & Oral Sciences Source from March 10, 2012 to April 30, 2024. The Joanna Briggs Institute (JBI) tool was used to assess the quality of the included cross-sectional articles and clinical trials. RESULTS: Of the 949 articles identified, 14 were included according to the inclusion and exclusion criteria. The total number of individuals studied in the included investigations was 814 of whom 445 had CP and 369 were healthy. The reported age range was from 20 to 50 years, with a mean age ± standard deviation of 40.29 ± 7.83 years. Four hundred and twenty-six (52%) patients were men and 388 (48%) were women. Meta-analysis revealed that there is an increase in IL-33 levels in plasma, saliva and GCF of subjects with CP compared to CG (p = * < 0.05). CONCLUSIONS: This study found a significant increase in IL-33 levels in different biological samples (plasma, saliva and GCF) of individuals with CP compared to CG, thus IL-33 has potential to be a biomarker in the diagnosis of periodontitis.