Pathological new bone formation is the main cause of disability in ankylosing spondylitis (AS), and so far, it lacks a targeted therapy. Macrophages are central orchestrators of inflammation progression and tissue remodeling, but their contribution to pathological new bone formation has largely not been explored. Here, it is identified that TREM2+ macrophages predominated within the sites of new bone formation and adjacent to osteogenic precursor cells. In vivo, both depletion of macrophages and knockout of Trem2 significantly reduced pathological new bone formation in a collagen antibody-induced arthritis (CAIA) model. Specifically, TREM2+ macrophages promoted osteogenic differentiation of ligament-derived progenitor cells (LDPCs) by secreting CREG1, a secretory glycoprotein involved in cell differentiation and normal physiology. CREG1-IGF2R-PI3K-AKT signaling pathway is involved in TREM2+ macrophage-mediated pathological new bone formation. In addition, it is found that IL-33 promoted TREM2+ macrophage differentiation through phosphorylation of STAT6. Targeting the above signalings alleviated new bone formation in the CAIA model. The findings highlight the critical role of IL-33-induced TREM2+ macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.

The absence of a biologic marker for hypertensive nephrosclerosis (HN) remains a challenge. This study aimed at exploring the relationship between sST2 and early HN and examining their interaction in glomerular mesangial cells. The serum sST2 levels of healthy controls (HC; n=9), patients with HN (n=15), and patients with lupus nephritis (LN; n=27) were measured using ELISA. The association between the serum sST2 levels and clinicopathologic characteristics, including kidney function and mesangial proliferation, were assessed. The expression of ST2 and fibrotic markers in glomerular mesangial cells in hypertensive conditions was evaluated using a 5/6 nephrectomy rat model. To mimic intraglomerular hypertension, human primary glomerular mesangial cells (hPGMCs) were subjected to a 3-mmHg pressure using a newly developed mechanical pressurizing device. The cells were then treated with anti-ST2 antibody (0.5 and 1 μg/mL) to examine inflammation, apoptosis, and necrosis. The serum sST2 levels were significantly higher in the HN and LN groups than in the HC group. Increased expression of ST2 and fibrotic markers in glomerular mesangial cells was observed in the hypertension-induced animal model. In the in vitro study, pressure-stimulated hPGMCs exhibited increased population of early and late apoptosis, which were markedly reduced after treatment with anti-ST2 antibody (1.0 μg/mL). ST2 indicates the early pathologic changes of hypertensive kidney damage and may serve as a mesangial cell-specific marker for HN in terms of determining kidney function and pathologic findings. Thus, ST2 blockade could be a novel therapeutic approach for HN.

Thymic stromal lymphopoietin (TSLP) and IL-33 are alarmins implicated in EoE pathogenesis by activating multiple cells including mast cells (MCs). Whether TSLP or IL-33 have a role in EoE and whether their activities are distinct requires further investigation.

Experimental EoE was induced in wild type (WT) Il33 -/- and Crlf2 -/- mice. TSLP or IL-5 were neutralized using antibodies. Esophageal histopathology was determined by H&E, anti-Ki67, anti-CD31 and anti-MBP staining. Esophageal RNA was subjected to RNA sequencing. Bone marrow-derived MCs were activated with TSLP and IL-13 was determined (ELISA).

TSLP and IL-33 were overexpressed in human and experimental EoE. Human and mouse esophageal MCs displayed the highest level of Crlf2 (TSLPR) compared to other immune cells. Crlf2 -/- mice were nearly-completely protected from EoE, and TSLP neutralization resulted in decreased basal cell proliferation, eosinophilia, lamina propria thickening and vascularization. Induction of experimental EoE in Il33 -/- mice resulted in reduced eosinophilia but no alterations in tissue remodeling were observed compared to WT mice. RNA sequencing revealed that TSLP regulates the expression of key genes associated with human EoE (e.g. eotaxins, Il19, Klk5, Flg, Il36rn, Il1r2) and suggest a role for TSLP in regulating IL-1 signaling, barrier integrity and epithelial cell differentiation. Experimental EoE was characterized by a MC-associated gene signature and elevated MCs. Activation of MCs with TSLP resulted in secretion of IL-13.

TSLP and IL-33 have non-redundant functions in experimental EoE. This study highlights TSLP as an upstream regulator of IL-13 and a potential therapeutic target for EoE.

Inflammatory bowel disease (IBD), a chronic and relapsing-remitting condition, is inadequately managed by conventional therapies that often lack targeting specificity and carry significant side effects, particularly failing to address intestinal barrier repair and microbial balance. Probiotics, with their strong colonization capabilities, present a novel approach to drug delivery. Various engineering strategies have been developed to enhance the targeting ability of probiotics to inflammation sites, enabling precise delivery or in situ synthesis of therapeutic molecules to expand their multifunctional potential. This review discusses the recent advancements in bacterial modifications, including surface physico-chemical and biological coating, genetic engineering, outer membrane vesicles, minicells, and bacterial ghosts, all of which can enhance therapeutic localization. We also outline critical preclinical considerations, such as delivery frequency, systemic distribution, immune evasion, and gene contamination risks, for clinical translation. These engineered bacteria and bacterial derivatives hold great promise for personalized and sustained IBD treatments, providing a new frontier for therapy tailored to the complex inflammatory environment of IBD.

Modulating mechanotransduction by inhibiting yes-associated protein (YAP) in mice yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that one-time treatment with verteporfin, a YAP inhibitor, immediately after wounding is sufficient to prevent scarring and to drive wound regeneration in pigs. By performing single-cell RNA sequencing (scRNA-seq) on porcine wounds in conjunction with spatial proteomic analysis, we found perturbations in fibroblast dynamics with verteporfin treatment and the presence of putative pro-regenerative/profibrotic fibroblasts enriched in regenerating/scarring pig wounds, respectively. We also identified differences in enriched myeloid cell subpopulations after treatment and linked this observation to increased elaboration of interleukin-33 (IL-33) in regenerating wounds. Finally, we validated our findings in a xenograft wound model containing human neonatal foreskin engrafted onto nude mice and used scRNA-seq of human wound cells to draw parallels with fibroblast subpopulation dynamics in porcine wounds. Collectively, our findings provide support for the clinical translation of local mechanotransduction inhibitors to prevent human skin scarring, and they clarify a YAP/IL-33 signaling axis in large animal wound regeneration.

Emerging studies reveal that neurotransmitters and neuropeptides play critical roles in regulating anti-helminth immune responses, hinting at the potential of intrinsic enteric neurons (iENs) in orchestrating intestinal immunity. Whether and how iENs are activated during infection and the potential neuroimmune interactions involved remain poorly defined. Here, we found that helminth infection activated a subset of iENs. Single-nucleus RNA sequencing (snRNA-seq) of iENs revealed alterations in the transcriptional profile of interleukin (IL)-13R+ intrinsic primary afferent neurons (IPANs), including the upregulation of the neuropeptide β-calcitonin gene-related peptide (CGRP). Using genetic mouse models and engineered viral tools, we demonstrated that group 2 innate lymphoid cell (ILC2)-derived IL-13 was required to activate iENs via the IL-13R, leading to iEN production of β-CGRP, which subsequently inhibited ILC2 responses and anti-helminth immunity. Together, these results reveal a previously unrecognized bi-directional neuroimmune crosstalk in the intestine between a subset of iENs and ILC2s, which influences pathogen clearance.

The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms.

The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21-/- mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses.

The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21-/- mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21-/- asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK.

To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.

Extracellular vesicles (EVs) secreted by umbilical cord-derived mesenchymal stem cells (UC-MSCs) hold significant promise as therapeutic agents in regenerative medicine. This study investigates the effects of UC-MSC-derived EVs on dermal fibroblast function, and their potential in wound healing applications. EVs were characterized by nanoparticle tracking analysis and transmission electron microscopy, revealing a mean size of 118.6 nm, consistent with exosomal properties. Dermal fibroblasts were treated with varying concentrations of EVs (25-100 µg/mL), and their impacts on cellular metabolism, mitochondrial activity, reactive oxygen species (ROS) production, wound closure, inflammatory cytokine secretion, growth factor production, and extracellular matrix (ECM) gene expression were evaluated. At lower concentrations (25-50 µg/mL), EVs significantly enhanced fibroblast metabolic and mitochondrial activity. However, higher concentrations (≥75 µg/mL) increased ROS levels, suggesting potential hormetic effects. EVs also modulated inflammation by reducing pro-inflammatory cytokines (IL-6, TNF-α) while promoting pro-regenerative cytokines (IL-33, TGF-β). Treatment with 50 µg/mL of EVs optimally stimulated wound closure and growth factor secretion (VEGF, BDNF, KGF, IGF), and upregulated ECM-related gene expression (type I and III collagen, fibronectin). These findings demonstrate that UC-MSC-derived EVs exert multifaceted effects on dermal fibroblast function, including enhanced cellular energetics, stimulation of cell migration, regulation of inflammation, promotion of growth factor production, and increased ECM synthesis. This study highlights the potential of EVs as a novel therapeutic strategy for wound healing and tissue regeneration, emphasizing the importance of optimizing EV concentration for maximal therapeutic efficacy.

Effective tissue response to infection and injury essentially relies on the fine-tuned induction and subsequent resolution of inflammation. Recent research highlighted multiple functions of dermal white adipose tissue (dWAT) beyond its traditional role as an energy reservoir. However, in contrast to other fat depots, there are only limited data about putative immune-regulatory functions of dWAT. Therefore, we investigated the impact of dWAT in the control of an acute skin inflammation. Skin inflammation triggers the activation of dWAT. In turn, soluble mediators of activated dWAT stimulate the expression of numerous genes controlling skin inflammation, including the T helper 2 cell cytokines Il4 and Il13, in myeloid cells in vitro. Consistently, myeloid cells isolated from inflamed skin showed a significant upregulation of Il-4/13 expression compared with those isolated from healthy skin. Mechanistically, we demonstrate that IL-33 released from activated dWAT is responsible for IL-4/13 stimulation in myeloid cells. Interestingly, obesity attenuates IL-33 secretion in dWAT during inflammation, resulting in decreased Il-4 and Il-13 expressions in myeloid cells. Our data reveal an IL-33-IL-4/13 signaling cascade initiated from dWAT in a T helper 2-independent context of inflammation that may contribute to limitation of inflammation. This cascade seems to be disturbed in individuals with obesity with prolonged inflammation.

Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.

Neointimal hyperplasia is one of the persistent complications after vascular interventions, and is the major cause of treatment failure. Interleukin-33 (IL-33) emerges as a crucial factor in many biological processes and plays an important role in vascular diseases. Adventitial injection is catching attention for its effectiveness and fewer side effects. We hypothesize that targeting IL-33 by adventitial injection can be a therapeutic method to inhibit neointimal hyperplasia.

IL-33 expression was examined in human vein graft. The hydrogel was fabricated by the interaction of hyaluronic acid, sodium alginate, and CaCO3; and phosphate buffered saline (PBS) or IL-33 antibody or recombinant IL-33 was mixed within the hydrogel uniformly. A rat aortic wire injury-induced neointimal hyperplasia model was developed; rats were divided into three groups and received an adventitial injection of a hydrogel loaded with PBS or IL-33 antibody or recombinant IL-33 after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with PBS, IL-33 antibody, or IL-33 was also used in a mouse carotid artery ligation neointimal hyperplasia model.

There was a high expression of IL-33 in human vein graft neointima. Hydrogel can be successfully injected into the aortic wall and is encapsulated by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection and was partly degraded at day 21. There was a significantly thinner neointimal thickness and less proliferation and inflammation in the IL-33 antibody group compared to the control group. On the contrary, the IL-33 group has a thicker neointima, increased proliferation, and inflammation. The mouse carotid artery ligation model showed similar results.

IL-33 plays a role in arterial neointimal hyperplasia in both human and rodent models; adventitial injection of hydrogel loaded with IL-33 antibody can effectively decrease neointimal thickness. Neutralizing IL-33 by IL-33 antibody may be a potential therapeutic method to inhibit intimal hyperplasia after vascular interventions.

Interleukin-33 (IL-33) is a pleiotropic cytokine of the IL-1 family that plays a key role in innate and adaptive immune responses and contributes to tissue homeostasis. Its role in adipose tissue function has been extensively studied, as adipose tissue serves as an important mediator of metabolic dysfunction. In adipose tissue, IL-33 is primarily produced by stromal cells. Its production is regulated by factors, such as androgens, aging, sympathetic innervation, and various inflammatory stimuli that affect the proliferation and differentiation of IL-33-producing stromal cells. Many studies have elucidated the mechanisms by which IL-33 interacts with the immune system components, local nerve fibers, and adipocytes to influence energy balance, with important consequences in obesity, cold-induced thermogenesis, and aging-related metabolic dysfunction. Here, we detail our current understanding of the molecular events that regulate the production of IL-33 within adipose tissue and discuss its role in regulating adipose function.

Myocardial infarction (MI) is one of the leading causes of mortality and morbidity worldwide. MI-damaged vascular structures are difficult to completely restore due to the heart's low regenerative capacity. Given interleukin-33 (IL-33) as a potent endothelial activator promoting angiogenesis, this study investigated the role of IL-33 in angiogenesis and cardiac repair after MI. A mouse model of MI was established. IL-33 improved cardiac function and induced an increase in vascular density after MI. Besides, IL-33 promoted human endothelial cells proliferation, migration, and differentiation under both normoxic and hypoxic conditions, consistently with increased angiogenesis in vivo. Mechanistic studies demonstrated that IL-33 could promote angiogenesis by activating eNOS and AKT, and stimulating NO production in vivo and in vitro. Given that injection of exogenous IL-33 induced an inflammatory response, we employed a multifunctional biomimetic nanoparticle drug delivery system to deliver IL-33, thereby enhancing its targeting to the heart for fibrotic therapy and reducing inflammation. In conclusion, our results indicate that IL-33 promotes endothelial angiogenesis after MI through AKT/eNOS/NO signaling pathway. PM&EM/IL-33 nanoparticles may hold promising therapeutic potential for protecting cardiac ischemic injury and mitigating inflammation.

Urticaria is a debilitating skin condition affecting up to 20% of the global population, characterized by erythematous, maculopapular lesions and significant quality of life impairment. This study focused on the role of interleukin 33 (IL-33) and its polymorphisms, particularly SNP rs1929992, in chronic spontaneous urticaria (CSU). Using demographic, clinical, and laboratory data from CSU patients and controls, we estimated allele and genotype frequencies, Hardy-Weinberg equilibrium condition, and serum IL-33 levels, using unconditional binomial logistic regression for association analysis. Results revealed that CSU patients had significantly higher frequencies of the minor allele of IL-33 rs1929992 compared to controls (31.25% vs. 17.35%, p = 0.024), and carriers of the GA genotype exhibited increased odds of CSU (adjusted OR = 2.208, p ≤ 0.001). Additionally, serum IL-33 levels were markedly elevated in CSU patients, particularly those with the GA genotype. The findings suggest that the IL-33 SNP is associated with an increased susceptibility to CSU, emphasizing its potential as a diagnostic and therapeutic biomarker. This study underscores the genetic and immunological underpinnings of CSU, paving the way for personalized treatment approaches.

Mast cells are regarded as effectors in immune defense against parasites and venoms and play an essential role in the pathology of allergic diseases. More recently, mast cells have been shown to receive stimuli derived from type 2 immunity, tissue damage, stress, and inflammation. Mast cells then rapidly convert these diverse signals into appropriate, organ-specific protective reflexes that can limit inflammation or reduce tissue damage. In this review, we consider functions of mast cells in sensations-such as pain, itch, and nausea-arising from tissue insults and inflammation and the ensuing protective responses. In light of emerging data highlighting the involvement of mast cells in neuroimmune communication, we also propose that mast cells are "signal converters" linking immunological and tissue states with nervous system responses.

The skin serves as the first protective barrier for nonspecific immunity and encompasses a vast network of skin-associated immune cells. Atopic dermatitis (AD) is a prevalent inflammatory skin disease that affects individuals of all ages and races, with a complex pathogenesis intricately linked to genetic, environmental factors, skin barrier dysfunction as well as immune dysfunction. Individuals diagnosed with AD frequently exhibit genetic predispositions, characterized by mutations that impact the structural integrity of the skin barrier. This barrier dysfunction leads to the release of alarmins, activating the type 2 immune pathway and recruiting various immune cells to the skin, where they coordinate cutaneous immune responses. In this review, we summarize experimental models of AD and provide an overview of its pathogenesis and the therapeutic interventions. We focus on elucidating the intricate interplay between the immune system of the skin and the complex regulatory mechanisms, as well as commonly used treatments for AD, aiming to systematically understand the cellular and molecular crosstalk in AD-affected skin. Our overarching objective is to provide novel insights and inform potential clinical interventions to reduce the incidence and impact of AD.

Obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, and there is a critical need for novel interventions. Interleukin-33 (IL-33), an anti-inflammatory cytokine that regulates metabolism, is a promising biomarker for these conditions. The goal of this systematic review and meta-analysis is to examine the role of IL-33 in obesity and T2D, assessing its potential in predicting disease progression. A systematic search was performed on Scopus, Web of Science, and PubMed up until May 30, 2023. Each study was assessed for quality and sources of bias using the relevant critical appraisal checklists. Meta-analyses were conducted to compare IL-33 levels in individuals with obesity and T2D versus healthy controls (HC), and in obesity alone versus HC. Eighteen studies were included in the systematic review, and nine qualified for meta-analyses. The analyses showed insufficient evidence to suggest a significant difference in IL-33 levels between individuals with T2D and HC (mean difference, MD = -79.95, 95% CI [-241.38; 81.48]), with substantial heterogeneity across the studies observed (I2 = 97.1%, τ2 = 33,549.15). Similarly, there was insufficient evidence to suggest a significant difference between nondiabetic individuals with obesity and HC (MD = -7.31, 95% CI [-25.74; 11.13]), and heterogeneity was noted (I2 = 86.2%, τ2 = 342.45). There is insufficient evidence to indicate significant differences in IL-33 levels in individuals with T2D or obesity compared with HC. The results suggest a need for improved IL-33 measurement methods to reduce heterogeneity, enhancing understanding of the role of IL-33 in obesity and T2D, and informing future research and therapeutic strategies.NEW & NOTEWORTHY Our research finds an inconclusive relationship between IL-33 serum levels in individuals with type 2 diabetes (T2D) and nondiabetic individuals with obesity. In addition, we note a potential gender association with IL-33 serum levels. Further studies with larger cohorts are required to assess the significance of serum IL-33 in T2D and obesity. Urgent standardization is needed in IL-33 quantification and reporting methods for reliable comparisons.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a significant threat to global public health. Immunopathological damage plays a role in driving pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure in severe COVID-19. Therefore, dissecting the pulmonary immune response to SARS-CoV-2 infection is critical to understand disease pathogenesis and identify immune pathways targetable by therapeutic intervention. Considering that the type 2 cytokine IL-13 enhances COVID-19 disease severity, therapeutic targeting of upstream signals that drive type 2 immunity may confer further protection. In this study, we investigate the role of the IL-33/ST2 signaling axis, a potent inducer of type 2 immunity in the lung, in a mouse model of COVID-19. Upon infection with mouse-adapted SARS-CoV-2 MA10, ST2 -/- mice had significantly improved weight loss and survival (69.2% vs 13.3% survival; P = 0.0005), as compared to wild-type mice. In a complementary pharmacologic approach, IL-33/ST2 signaling was inhibited using HpBARI_Hom2, a helminth derived protein that binds to mouse ST2 and blocks IL-33 signaling. In SARS-CoV-2 MA10 infection, HpBARI_Hom2-treated mice had significantly improved weight loss and survival (60% vs 10% survival; P = 0.0035), as compared to inert control-treated mice. These data demonstrate that loss of IL-33/ST2 signaling confers protection during acute SARS-CoV-2 MA10 infection, implicating the IL-33/ST2 signaling axis as an enhancer of COVID-19 disease severity. The protection conferred by pharmacologic blockade of IL-33/ST2 signaling was independent of viral control, as HpBARI_Hom2-treated mice had no reduction in viral titers. This finding suggests an immunopathogenic role for IL-33/ST2 signaling. One potential mechanism through which IL-33/ST2 signaling may drive severe disease is through enhancement of type 2 immune pathways including IL-5 production, as pulmonary IL-5 concentrations were found to depend on IL-33/ST2 signaling in acute SARS-CoV-2 MA10 infection.

NLRP3 inflammasome-mediated inflammatory responses play pivotal functions in innate immunity. However, its homeostatic regulation still needs to be better understood. Here we explore the effect and potential mechanism of IL-33 on NLRP3 inflammasome upon Toxoplasma gondii infection through a series of molecular biology and immunological experiments, including western blot, qRT-PCR, and ELISA. We demonstrated that T. gondii infection induces the expression of IL-33, and IL-33-deficient (IL-33-/-) mice exhibit longer survival time than wild-type (WT) mice upon T. gondii infection. IL-33 deficiency promotes the expression of NLRP3 and ASC and the secretion of IL-1β, while exogenous IL-33 inhibits NLRP3 inflammasome. Furthermore, T. gondii infection results in the M2 polarization of macrophages, exacerbated by exogenous IL-33, which also promotes the proliferation of T. gondii. These findings showed that IL-33 deficiency attenuates T. gondii infection by promoting NLRP3 inflammasome, advancing the understanding of the role of IL-33 in inflammation.

Group 2 innate lymphoid cells (ILC2s) are key players in type 2 immunity, but whether they can be directly activated by microbial ligands remain uncertain. In this study, we observed a positive correlation between blood endotoxin (LPS) levels and circulating ILC2s in allergic patients. In vitro, LPS robustly induced ILC2 proliferation and production of type 2 effector cytokines. RNA-seq revealed a type 2 immune-responsive profile in LPS-stimulated ILC2s. Notably, ILC2s lost their LPS-mediated growth and activation capacity when treated with TLR4 receptor antagonists and inhibitors of the NF-κB and JAK pathways, though this effect was not observed with IL-33 receptor blocking antibodies. Genetically, ILC2s from TLR4 knockout (KO) mice, but not from ST2 KO mice, were unresponsive to LPS. Collectively, these findings suggest a direct, non-canonical activation mechanism of ILC2s via the LPS-TLR4-NF-κB/JAK signaling axis.

ST2 belongs to the interleukin 1 receptor family and is expressed in immune cells including certain CD4+ T cells and mast cells. Binding of ST2 with interleukin 33 (IL-33) induces downstream signaling that activates NF-κB pathway. Although the ST2/IL-33 axis exerts immune tolerance via expansion of regulator T cells, the same axis also activates a subset of immune cells to produce proinflammatory cytokines in host defense or in tissue repair. Here, we reported the development of ST2 inhibitors with improved inhibitory activities against ST2 and metabolic stability based on a previous lead, iST2-14e. Using the human mast cell line (LAD2), we showed that ST2 inhibitors mitigated ST2 upregulation and reduced IL-1β released through degranulation, demonstrating that small-molecule ST2 inhibitors effectively attenuated the ST2/IL-33 signaling in human mast cells. Further optimization of the compounds may lay the foundation for developing ST2 inhibitors for the treatment of mast cells mediated diseases.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions. Tozorakimab is a high-affinity human monoclonal antibody that neutralizes interleukin-33, a broad-acting alarmin cytokine that is over-expressed in keratinocytes of patients with AD.

This Phase 2a study (FRONTIER-2; NCT04212169) evaluated the safety and efficacy of tozorakimab in adults with moderate-to-severe AD.

FRONTIER-2 was a randomized, placebo-controlled, parallel-group, double-blind study conducted from 9 December 2019 to 20 September 2022 at 32 centres across six countries. Patients were randomized 3:1:1:3 to receive placebo, tozorakimab 60 mg, tozorakimab 300 mg or tozorakimab 600 mg by subcutaneous injection once every 4 weeks for four doses. The primary endpoint was percentage change from baseline to Week 16 in the Eczema Area and Severity Index (EASI) score in patients treated with tozorakimab versus placebo. Secondary outcomes included EASI-75 responders (patients achieving ≥75% reduction from baseline in EASI score), Investigator's Global Assessment (IGA) responders (patients achieving an IGA score of 0 or 1), pharmacokinetics, immunogenicity and safety.

Overall, 148 patients were randomized. There was no statistically significant difference in the primary endpoint (60 mg difference of 1.3 [90% confidence interval (CI): -13.7, 16.2], p = 0.888; 300 mg: difference of 5.9 [90% CI: -10.4, 22.1], p = 0.549; 600 mg: difference of - 1.7 [90% CI: -13.4, 10.0], p = 0.807). The proportion of EASI-75 and IGA 0/1 responders at Week 16 was numerically higher in the tozorakimab 600 mg group than in the placebo group (EASI-75: 18.2% vs. 7.1%, p = 0.094; IGA 0/1: 9.1% vs. 1.8%, p = 0.113). Serum pharmacokinetics were dose-dependent, immunogenicity incidence was low and tozorakimab was well tolerated.

FRONTIER-2 did not show a statistically significant difference in the primary endpoint for tozorakimab compared with placebo. However, numerical increases in responder rates were observed.

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.

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.

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.

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.

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.

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.

Calcitonin gene-related peptide (CGRP), a neuropeptide involved in nociceptor neuronal function, plays a critical role in mediating neuroinflammation and pain. In this study, we find that bladder group 2 innate lymphoid cells (ILC2s) function as primary producers of CGRP in the early phase of bacterial cystitis, contributing to increased inflammation, altered voiding behavior, and heightened pelvic allodynia. Furthermore, we demonstrate that interleukin (IL)-33, a cytokine secreted by urothelial cells, upregulates CGRP production by ILC2s in the bladder during uropathogenic Escherichia coli (UPEC) infection. Moreover, our research reveals that monocytes expressing high levels of receptor activity-modifying protein 1 (RAMP1), a CGRP receptor, mediate the pro-inflammatory effects of CGRP-producing ILC2s. In summary, our results underscore the significance of the immune cell-derived neuropeptides in the pathology of UPEC infection, suggesting a promising therapeutic approach targeting the IL-33-ILC2-CGRP axis for managing lower urinary tract symptoms in bacterial cystitis.

Inflammation is an essential factor in pulmonary complications of diabetes. Bone marrow (BM)-derived C-kit+ cells have immunomodulatory properties and their transplantation is suggested as a promising strategy for ameliorating diabetes complications. This study evaluated the effect of BM-derived C-kit+ cells on the inflammation signaling pathway in lung tissue of type 2 diabetic male rats. Ten rats were used to extract C-kit cells, and 48 male Wistar rats weighing 180 ± 20 g were randomly divided into four equal groups: (1) Control (Cont), (2) Diabetic (D), (3) Diabetic + C-kit+ cells (D + C-kit pos) intravenously injected 50-µl phosphate buffer saline (PBS) containing 300,000 C-kit+ cells, and (4) Diabetic + C-kit- cells (D + C-kit neg), intravenously injected C-kit- cells. Diabetes induction increased IL-33, ST-2, CD127, and IL-2 levels and decreased IL-10. C-kit+ cell therapy significantly decreased IL-33 and CD127 and increased IL-10. In addition, lung histopathological changes significantly improved in the C-kit+ group compared to the diabetic group. These findings suggest that C-kit+ cells may have a potential therapeutic role in mitigating diabetes-induced respiratory complications via ameliorating the inflammation and histopathological changes in lung tissue.

Mucus and its movements are essential to epithelial tissue immune defenses against pathogens, including fungal pathogens, which can infect respiratory, gastrointestinal or the genito-urinary tracts. Several epithelial cell types contribute to their immune defense. This review focuses on the respiratory tract because of its paramount importance, but the observations will apply to epithelial cell defenses of other mucosal tissue, including the gastrointestinal and genito-urinary tracts. Mucus and its movements can enhance or degrade the immune defenses of the respiratory tract, particularly the lungs. The enhancements include inhaled pathogen entrapments, including fungal pathogens, pollutants and particulates, for their removal. The detriments include smaller lung airway obstructions by mucus, impairing the physical removal of pathogens and impairing vital transfers of oxygen and carbon dioxide between the alveolar circulatory system and the pulmonary air. Inflammation, edema and/or alveolar cellular damage can also reduce vital transfers of oxygen and carbon dioxide between the lung alveolar circulatory system and the pulmonary air. Furthermore, respiratory tract defenses are affected by several fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, dendritic cells, various innate lymphoid cells including the natural killer cells, T cells, γδ T cells, mucosal-associated invariant T cells, NKT cells and mast cells. These mediators include the inflammatory and frequently immunosuppressive prostaglandins and leukotrienes, and the special pro-resolving mediators, which normally resolve inflammation and immunosuppression. The total effects on the various epithelial cell and immune cell types, after exposures to pathogens, pollutants or particulates, will determine respiratory tract health or disease.

Benign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology is believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using a mouse steroid hormone imbalance model identified a specific increase in macrophages that migrated and accumulated in the prostate lumen where they differentiated into lipid-laden foam cells in mice implanted with testosterone and estradiol pellets, but not in sham animals. The current study focused on further characterizing the cellular heterogeneity of the prostate in this model as well as identifying the specific transcriptomic signature of the recruited foam cells. Moreover, we aimed to identify epithelia-derived signals that drive macrophage infiltration and luminal translocation. Male C57BL/6J mice were implanted with slow-release testosterone and estradiol pellets (T + E2) or sham surgery was performed and the ventral prostates were harvested two weeks later for scRNA-seq analysis. We identified Ear2 + and Cd72 + macrophages that were elevated in response to steroid hormone imbalance, whereas a Mrc1 + resident macrophage population did not change. In addition, an Spp1 + foam cell cluster was almost exclusively found in T + E2 mice. Further markers of foam cells were also identified, including Gpnmb and Trem2, and GPNMB was confirmed as a novel histological marker with immunohistochemistry. Foam cells were also shown to express known pathological factors Vegf, Tgfb1, Ccl6, Cxcl16 and Mmp12. Intriguingly, a screen for chemokines identified the upregulation of epithelia-derived Cxcl17, a known monocyte attractant, in T + E2 prostates suggesting that it might be responsible for the elevated macrophage number as well as their translocation to the lumen. Our study identified macrophage subsets that responded to steroid hormone imbalance as well as further confirmed a potential pathological role of luminal foam cells in the prostate. These results underscore a potential pathological role of the identified prostate foam cells and suggests CXCL17-mediated macrophage migration as a critical initiating event.

Mycobacterium bovis (M. bovis) Bacillus Calmette-Guerin (BCG) strain used in immunotherapy of bladder cancer (onco-BCG) due to its acid tolerance can be a candidate for prevention or reversion of deleterious effects towards gastric cell barrier initiated by gastric pathogen Helicobacter pylori (Hp) with high resistance to commonly used antibiotics. Colonization of gastric mucosa by Hp promotes oxidative stress, apoptosis resulting in the gastric barrier damage. The aim of this study was to examine the ability of onco-BCG bacilli to control the Hp driven gastric damage using the model of Cavia porcellus primary gastric epithelial cells or fibroblasts in vitro. These cells were treated with Hp surface antigens (glycine acid extract-GE or lipopolysaccharide-LPS) alone or with onco-BCG bacilli and evaluated for cell apoptosis and proliferation in conjunction with the level of soluble lipid peroxidation marker (s4HNE). The cell migration was determined by "wound healing assay", while cytokine response of cells, including interleukin (IL)-33, IL-1β, IL-8 and tumor necrosis factor alpha (TNF-α), by the ELISA. The apoptosis of cells pulsed in vitro with Hp surface components present in GE or with LPS was reduced after exposure of cells to mycobacteria. Similarly, the cell regeneration which was diminished by Hp LPS has been improved in response to mycobacteria. This study reveals that vaccine mycobacteria may reduce gastric barrier damage induced by Hp infection.

The disease of osteoporosis is characterized by impaired bone structure and an increased risk of fractures. There is a significant impact of cytokines and hormones on bone homeostasis and the diagnosis of osteoporosis. As defined by the World Health Organization (WHO), osteoporosis is defined as having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young and healthy women (T score < -2.5 SD). Cytokines and hormones, particularly in the remodeling of bone between osteoclasts and osteoblasts, control the differentiation and activation of bone cells through cytokine networks and signaling pathways like the nuclear factor kappa-B ligand (RANKL)/the receptor of RANKL (RANK)/osteoprotegerin (OPG) axis, while estrogen, parathyroid hormones, testosterone, and calcitonin influence bone density and play significant roles in the treatment of osteoporosis. This review aims to examine the roles of cytokines and hormones in the pathophysiology of osteoporosis, evaluating current diagnostic methods, and highlighting new technologies that could help for early detection and treatment of osteoporosis.

One of the many warm-blooded hosts that toxoplasmosis-causing intracellular protozoan parasite Toxoplasma gondii can infect is humans. Cytokines are crucial to stimulate an effective immune response against T. gondii. Interleukin-33 (IL-33) is a unique anti-inflammatory cytokine that suppresses the immune response. The levels of cytokine gene expression are regulated by genetics, and the genetic polymorphisms of these cytokines play a functional role in this process. Single nucleotide polymorphisms (SNPs) are prognostic indicators of illnesses. This study aimed to determine whether toxoplasmosis interacts with serum levels of IL-33 and its SNP in miscarriage women as well as whether serum levels and IL-33 gene expression are related in toxoplasmosis-positive miscarriage women. Two hundred blood samples from patients and controls were collected from AL-Alawiya Maternity Teaching Hospital and AL-Yarmouk Teaching Hospital in Baghdad, Iraq from 2021 to 2022 in order to evaluate the serum level of IL-33 using ELISA test. For the SNP of IL-33, the allelic high-resolution approach was utilized, and real time-PCR was performed to assess gene expression. The results showed that compared to healthy and pregnant women, recurrent miscarriage with toxoplasmosis and recurrent miscarriage women had lower IL-33 concentrations. Additionally, there were significant differences among healthy women, pregnant women, and women with repeated miscarriage who experienced toxoplasmosis. Furthermore, no differences between patients and controls were revealed by gene expression data. The results revealed that recurrent miscarriage, pregnancy, and healthy women all had a slightly higher amount of the IL-33 gene fold. Additionally, the SNP of IL-33 data demonstrated that there was no significant genetic relationship between patients and controls. Recurrent miscarriage women with toxoplasmosis have showed significant differences from pregnant women in the genotypes GG and AA as well as the alleles A and G. There were notable variations between recurrent miscarriage with and without toxoplasmosis in terms of the genotypes AA and AC. The genotypes GG, AA, and allele A in recurrent miscarriage women with toxoplasmosis and recurrent miscarriage women is a protective factor. Taking together, there was a statistically significant negative correlation between toxoplasmosis and IL-33 gene expression, which calls for more quantitative investigation in order to fully comprehend the interaction of mRNA and protein.

Several reports have highlighted the dichotomous nature of the Interleukin-33 (IL-33) system in cardiac and lung disease, where this cytokine can exert both protective effects and drive pro-inflammatory responses in a context-specific manner. This State-of-the-Art review focuses on preclinical mechanistic studies of the IL-33 system in development of allograft rejection in heart and lung transplantation. We address the scope of potential cellular sources of IL-33 and pathways for cellular release that may impact the study of this cytokine system in transplant models. We then highlight soluble IL-33 receptor as a biomarker in cardiac allograft rejection and detail preclinical models that collectively demonstrate a role for this cytokine in driving type-2 immune programs to protect cardiac allografts. We contrast this with investigation of IL-33 in lung transplantation, which has yielded mixed and somewhat conflicting results when comparing human studies with preclinical models, which have implicated the IL-33 system in both allograft tolerance and acceleration of chronic rejection. We summarize and interpret these results in aggregate and provide future directions for study of IL-33 in heart and lung transplantation.

Recent advancements in mucosal immunology have unveiled a complex network of intercellular connections within diverse tissues, shedding light on the unique properties of different cell types. Central to this intricate network is the cytokine IL-33, which has gained significant attention for its critical role in various diseases, from allergy to cancer, triggering type 2 immune responses, among others. Recent research has challenged the prior assumptions attributing IL-33 expression to epithelial cells, highlighting stromal cells as the predominant source in adipose tissue and the lungs. However, in the complex landscape of the intestine, where IL-33 plays a crucial role in mediating immune surveillance and tolerance and is implicated in many gut-related disorders, its primary source, regulation, and main characteristics need more exploration. This study identifies stromal cells as the primary IL-33-expressing cell type in the small intestine. By investigating their transcriptome and intrinsic signaling pathways, we have uncovered a possible role of IL-33+ stromal cells in maintaining the stem cell niche and their potential crosstalk with neurons relevant to the regulation of axonogenesis. Importantly, our experiments have demonstrated that vasoactive intestinal peptide stimulation of a primary intestinal stromal cell culture significantly amplifies IL-33 expression on mRNA and protein level. Therefore, our study represents a significant leap forward in understanding the plethora of interactions IL-33+ intestinal stromal cells maintain in the intestine, paving the way for future investigations into stromal-neuro crosstalk in the gut. These findings hold great promise for developing targeted therapeutic strategies aimed at harnessing the potential of IL-33 across a spectrum of diseases.

Development of type 2 diabetes mellitus (T2DM) is associated with low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via the production of type 2 cytokines. Here, we demonstrate that CB2, a G-protein-coupled receptor (GPCR) and member of the endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB2 engagement on VAT ILC2s in a T2DM model. Our results show that CB2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin resistance. Our mechanistic studies reveal that the therapeutic effects of CB2 are mediated through activation of the AKT, ERK1/2, and CREB pathways on ILC2s. The results reveal that the CB2 agonist can serve as a candidate for the prevention and treatment of T2DM.

Regulatory T cells (Tregs) within the visceral adipose tissue (VAT) play a crucial role in controlling tissue inflammation and maintaining metabolic health. VAT Tregs display a unique transcriptional profile and T cell receptor (TCR) repertoire, and closely interact with adipocytes, stromal cells, and other immune components within the local VAT microenvironment. However, in the context of obesity, there is a notable decline in VAT Tregs, resulting in heightened VAT inflammation and insulin resistance. A comprehensive understanding of the biology of VAT Tregs is essential for the development of Treg-based therapies for mitigating obesity-associated metabolic diseases. Recent advancements in lineage tracing tools, genetic mouse models, and various single cell "omics" techniques have significantly progressed our understandings of the origin, differentiation, and regulation of this unique VAT Treg population at steady state and during obesity. The identification of VAT-Treg precursor cells in the secondary lymphoid organs has also provided important insights into the timing, location, and mechanisms through which VAT Tregs acquire their distinctive phenotype that enables them to function within a lipid-rich microenvironment. In this review, we highlight key recent breakthroughs in the VAT-Treg field while discussing pivotal questions that remain unanswered.

Interleukin 33 (IL-33) is a crucial inflammatory factor that functions as an alarm signal in endometriosis (EMs). Epithelial-mesenchymal transition (EMT), a process related to inflammatory signals, intracellular reactive oxygen species (ROS) production, and lipid peroxidation, have been proposed as potential mechanisms that contribute to the development and progression of EMs. IL-33 is highly upregulated in the ectopic milieu. Moreover, ectopic endometrial cells constitutively express interleukin-33 receptor ST2 (IL-33R). However, the role of IL-33/ST2 in the EMT of EMs remains largely unknown. In this study, we aimed to mechanistically determine the role of IL-33/ST2 in EMs-associated fibrosis.

We established a non-lethal oxidative stress model to explore the conditions that trigger IL-33 induction. We performed α-smooth muscle actin (α-SMA) protein detection, cell counting kit-8 (CCK-8) assays, and scratch assays to analyze the impact of IL-33 on primary endometrial stromal cells (ESCs) proliferation and invasion. Clinical samples from patients with or without EMs were subjected to immunohistochemical (IHC) and and immunofluorescence(IF) staining to assess the clinical relevance of IL-33 receptor ST2 and EMT-related proteins. Furthermore, we used the ectopic human endometrial epithelial cell line 12Z and normal human epithelial cell line EEC to evaluate the effects of IL-33 on Wnt/β-catenin signaling. The effect of IL-33 on EMT-associated fibrosis was validated in vivo by intraperitoneal injections of IL-33 and antiST2.

We observed that ectopic milieu, characterized by ROS, TGF-β1, and high level of estrogen, triggers the secretion of IL-33 from ectopic ESCs. Ectopic endometrial lesions exhibited higher level of fibrotic characteristics and ST2 expression than that in the normal endometrium. Exogenous recombinant human (rhIL-33) enhanced ESC migration and survival. Similarly, 12Z cells displayed a higher degree of EMT characteristics with elevated expression of CCN4 and Fra-1, downstream target genes of the WNT/β-catenin pathway, than that observed in EECs. Conversely, blocking IL-33 with neutralizing antibodies, knocking down ST2 or β-catenin with siRNA, and β-catenin dephosphorylation abolished its effects on EMT promotion. In vivo validation demonstrated that IL-33 significantly promotes EMs-related fibrosis through the activation of Wnt/β-catenin signaling.

Our data strongly support the vital role of the IL-33/ST2 pathway in EMs-associated fibrosis and emphasize the importance of the EMT in the pathophysiology of fibrosis. Targeting the IL-33/ST2/Wnt/β-catenin axis may hold promise as a feasible therapeutic approach for controlling fibrosis in EMs.