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PubMed2026

ICAM-1 Hypomethylation Predicts Poor Prognosis in Patients With Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a high short-term mortality rate. Therefore, early and accurate prognostic prediction is crucial for precise clinical management. This study aims to investigate the expression patterns of intercellular adhesion molecule-1 (ICAM-1) and its predictive value for the short-term prognosis of patients with HBV-ACLF. The Methylight method was used to quantitatively detect ICAM-1 promoter methylation level in peripheral blood mononuclear cells (PMBCs) of 286 participants. Meanwhile, the mRNA and plasma expression levels of ICAM-1 were determined using RT-qPCR and ELISA, respectively. The ICAM-1 promoter methylation levels in PBMCs of HBV-ACLF patients were significantly lower than those in chronic hepatitis B (CHB) patients and healthy controls (HCs), whereas the mRNA and plasma expression levels of ICAM-1 were markedly elevated. The ICAM-1 methylation levels in HBV-ACLF patients correlated with specific clinical parameters. Among HBV-ACLF patients, ICAM-1 methylation levels were significantly lower in the non-survivor groups at both 28 and 90 days. The study further revealed that ICAM-1 methylation level serves as an independent influencing factor for the prognosis of HBV-ACLF patients at 28 and 90 days. Based on ROC curve and Kaplan-Meier curves, ICAM-1 methylation levels demonstrated excellent performance in predicting 28- and 90-day mortality in patients with HBV-ACLF. In conclusion, patients with HBV-ACLF exhibit hypomethylation of the ICAM-1 promoter. The combination of ICAM-1 promoter methylation level and MELD score can effectively enhance the predictive ability for the short-term prognosis of HBV-ACLF patients.

Humans↗

PubMed2024

Serum lncRNA ITGB2-AS1 and ICAM-1 as novel biomarkers for rheumatoid arthritis and osteoarthritis diagnosis.

BACKGROUND: The complete circulating long non-coding RNAs (lncRNAs) signature of rheumatoid arthritis (RA) and osteoarthritis (OA) is still uncovered. The lncRNA integrin subunit beta 2 (ITGB2)-anti-sense RNA 1 (ITGB2-AS1) affects ITGB2 expression; however, there is a gap in knowledge regarding its expression and clinical usefulness in RA and OA. This study investigated the potential of serum ITGB2-AS1 as a novel diagnostic biomarker and its correlation with ITGB2 expression and its ligand intercellular adhesion molecule-1 (ICAM-1), disease activity, and severity in RA and primary knee OA patients. SUBJECTS: Forty-three RA patients, 35 knee OA patients, and 22 healthy volunteers were included. RESULTS: Compared with healthy controls, serum ITGB2-AS1 expression was upregulated in RA patients but wasn't significantly altered in knee OA patients, whereas serum ICAM-1 protein levels were elevated in both diseases. ITGB2-AS1 showed discriminative potential for RA versus controls (AUC = 0.772), while ICAM-1 displayed diagnostic potential for both RA and knee OA versus controls (AUC = 0.804, 0.914, respectively) in receiver-operating characteristic analysis. In the multivariate analysis, serum ITGB2-AS1 and ICAM-1 were associated with the risk of developing RA, while only ICAM-1 was associated with the risk of developing knee OA. A panel combining ITGB2-AS1 and ICAM-1 showed profound diagnostic power for RA (AUC = 0.9, sensitivity = 86.05%, and specificity = 91.67%). Interestingly, serum ITGB2-AS1 positively correlated with disease activity (DAS28) in RA patients and with ITGB2 mRNA expression in both diseases, while ICAM-1 positively correlated with ITGB2 expression in knee OA patients. CONCLUSION: Our study portrays serum ITGB2-AS1 as a novel potential diagnostic biomarker of RA that correlates with disease activity. A predictive panel combining ITGB2-AS1 and ICAM-1 could have clinical utility in RA diagnosis. We also spotlight the association of ICAM-1 with knee OA diagnosis. The correlation of serum ITGB2-AS1 with ITGB2 expression in both diseases may be insightful for further mechanistic studies.

Humans↗

PubMed2025

Cellular Adhesion Molecules and Adverse Outcomes in Chronic Heart Failure: Findings From the DAPA-HF Randomized Clinical Trial.

IMPORTANCE: Vascular cell adhesion molecule 1 (VCAM-1) and intracellular cell adhesion molecule 1 (ICAM-1) are responsible for immune cell-cell interactions. Systemic levels of VCAM-1 are associated with incident heart failure (HF). OBJECTIVES: To determine if VCAM-1 and ICAM-1 levels are associated with progression of established HF. DESIGN, SETTING, AND PARTICIPANTS: Participants enrolled in the biomarker substudy of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) randomized clinical trial had VCAM-1 and ICAM-1 levels measured at baseline and 12 months. The DAPA-HF trial was conducted at 410 sites in 20 countries. Patients with HF and reduced ejection fraction (HFrEF) in New York Heart Association (NYHA) class II to IV with elevated natriuretic peptides were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Data were analyzed from January 2023 to January 2025. INTERVENTIONS: Dapagliflozin, 10 mg, once daily vs placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite of a worsening HF event or cardiovascular death. The associations between VCAM-1 and ICAM-1 levels at baseline and the primary outcome, its components, and all-cause death were analyzed using Cox proportional hazards regression models adjusted for known prognostic variables including estimated glomerular filtration rate (eGFR), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT), as well as high-sensitivity C-reactive protein. RESULTS: A total of 3051 participants (mean [SD] age, 67.2 [10.5] years; 2386 male [78.2%]) were included in this study. Mean (SD) follow-up time was 17.6 (5.2) months. The median (IQR) baseline VCAM-1 level was 997 (816.7-1218.8) ng/mL. Compared with patients with lower concentrations of VCAM-1, those with higher concentrations of VCAM-1 were older (mean [SD] age T3 vs T1, 69.7 [9.7] years vs 64.1 [10.7] years; P < .001), in worse NYHA class (T3 vs T1, NYHA class III/IV 35.6% [362 of 1017] vs 26.5% [269 of 1017]; P < .001), and had higher NT-proBNP (median [IQR] T3 vs T1, 2018 [1126-3753] pg/mL vs 1118 [693-1830] pg/mL) and hs-TnT (median [IQR] T3 vs T1, 24.7 [17.1-37.5] ng/L vs 16.6 [11.6-24.9] ng/L) concentrations, and lower eGFR (mean [SD] T3 vs T1, 58.4 [17.6] mL/min/1.73 m2 vs 71.7 [18.0] mL/min/1.73 m2). Patients in tertile 3 of VCAM-1, compared with tertile 1, had the highest risk of each outcome (eg, adjusted hazard ratio [HR] for primary outcome 1.40; 95% CI, 1.11-1.77; P = .004). ICAM-1 level was not associated with an elevated risk of any outcome. The benefit of dapagliflozin vs placebo in reducing the risk of the primary outcome was consistent across VCAM-1 tertiles: HR, 0.76 (95% CI, 0.54-1.06), 0.82 (95% CI, 0.59-1.12), and 0.77 (95% CI, 0.61-0.98) for tertiles 1, 2 and 3, respectively (P for interaction = .93). There was no significant change in VCAM-1 level with dapagliflozin at 52 weeks. CONCLUSIONS AND RELEVANCE: Results of this substudy of the DAPA-HF randomized clinical trial demonstrate that higher VCAM-1 levels, possibly reflecting a distinct inflammatory/immune pathophysiological pathway in HFrEF, were associated with worse outcomes, even after adjustment for conventional prognostic variables. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03036124.

Aged↗

PubMed2026

Effects of CPAP on endothelial activation and fibrinolytic balance in coronary artery disease with obstructive sleep apnea: The RICCADSA randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) promotes endothelial activation and a prothrombotic milieu through intermittent hypoxia, oxidative stress, and systemic inflammation, mechanisms closely linked to atherosclerosis progression. The vascular effects of continuous positive airway pressure (CPAP) therapy in patients with established coronary artery disease (CAD) remain incompletely understood. OBJECTIVE: To evaluate the longitudinal effects of CPAP treatment on endothelial adhesion molecules and fibrinolytic balance in patients with CAD and OSA. METHODS: In this randomized controlled analysis from the RICCADSA trial, 210 revascularized CAD patients with moderate-to-severe OSA were assigned to CPAP (n = 104) or no-CPAP (n = 106) and had available biomarker measurements at baseline and 12 months. Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) were assessed. Linear mixed-effects models were used to examine longitudinal changes and time-by-treatment interactions adjusted for cardiometabolic covariates. RESULTS: For ICAM-1, no significant time-by-treatment interaction was observed. For PAI-1, a borderline time-by-treatment interaction suggested a numerically smaller increase in the CPAP group compared with no-CPAP (p = 0.09). CPAP treatment was associated with a significantly greater reduction in VCAM-1 over time compared with no-CPAP (time-by-treatment interaction p = 0.045 in adjusted models). CONCLUSIONS: CPAP treatment was associated with selective modulation of vascular biomarkers in patients with CAD and OSA, characterized by attenuation of endothelial activation reflected by reduced VCAM-1 levels, while fibrinolytic imbalance appeared largely resistant to intervention. These findings support pathway-specific vascular responses to CPAP and provide mechanistic insight into residual atherosclerotic risk in this high-risk population.

Aged↗

PubMed2026

Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial.

AIMS: The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. METHODS: This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age ≥ 50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. RESULTS: RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p = 0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p = 0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p < 0.01 and - 9, 95%CI [-14.3; -5.2] p < 0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p = 0.01 and 16.2, 95%CI [7.2;24.3], p < 0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p ≥ 0.11 and p ≥ 0.09, respectively). CONCLUSION: Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.

Aged↗

PubMed2025

The effect of penile tourniquet and continuous artificial erection on penile erectile tissues: An experimental study.

INTRODUCTION: Penile tourniquet (PT) is known to cause ischemic injury, which worsens with prolonged application. Artificial erection (AE), formed by intracorporal saline injection mostly under PT, has been practiced for decades to evaluate penile curvature, yet its effect on erectile tissues has never been investigated. In this study, we examined a modified approach, continuous artificial erection (CAE), and investigated its effects on erectile tissues. OBJECTIVE: This study aims to investigate the histopathological and immunohistochemical effects of CAE on penile erectile tissues. STUDY DESIGN: Thirty-five rats were randomized into five groups. Four experiment groups received 20 or 40 min of isolated PT (20T and 40T) or PT with CAE (20T&E and 40T&E). CAE was achieved through continuous intracavernosal saline injection. Penectomy was performed three weeks post-procedure in the experiment groups and directly in the control group. Erectile tissue samples were evaluated using light microscopy for histopathological parameters including inflammation, neovascularization and fibrosis, and by immunohistochemistry. Endothelial function was assessed by eNOS and e-selectin staining, while ICAM-1 staining was used to assess chronic inflammation. RESULTS: 40T showed the highest levels of inflammation, fibrosis, and endothelial dysfunction. 20T had significantly less inflammation than 40T, with a non-significant increase in fibrosis and alteration of endothelial markers. 40T&E displayed the second-highest fibrosis rate (adjusted p > 0.05), while 20T&E showed complete absence of fibrosis. Both 40T&E and 20T&E preserved strong eNOS and e-selectin expression, identical to controls. ICAM-1 expression in 20T&E was also consistent with the control group. The most significant difference in erectile tissue damage was noted between 40T and 20T&E. CONCLUSION: This is the first study to evaluate the effects of AE on erectile tissues. Findings of this experimental model support that, CAE does not increase the tissue damage that is already caused by PT, but rather reduces it, likely through the washout of blood elements contributing to reperfusion injury. CAE possibly provides a protective effect on erectile tissues by preserving endothelial function, reducing inflammation and fibrosis, especially under 20 minutes of duration. These findings may support that AE maneuvers such as "artificial erection test" and CAE are potentially safe, while further studies are needed to assess the detailed effects of CAE.

Male↗

PubMed2019

Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells - Novel qualification markers for chronic disease risk factors and conditional DAMPs.

To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).

Acetylation↗

PubMed2026

Effects of Acute Low- and Moderate-Dose Alcohol on Chronic Disease-Related Biomarkers in Healthy Light and Heavy Drinkers.

BACKGROUND: Alcohol consumption is a major contributor to global chronic disease, with growing evidence indicating health risks even at low levels of intake. However, mechanistic understanding of these risks relies heavily on preclinical models and observational data, leaving a critical gap in controlled experimental evidence regarding how alcohol perturbs human biological systems in vivo. METHODS: The present study utilized plasma samples from a randomized, placebo-controlled trial to evaluate the effects of low-dose (0.35 g/kg) and moderate-dose (0.60 g/kg) alcohol on disease-relevant biomarkers in 32 healthy adults (mean age = 25.0 ± 3.8 years; 21 female/11 male), characterized by light (n = 15) or heavy (n = 17) drinking. This design enabled evaluation of effects across dose, timescale, and drinking history, as well as assessment of their interactions. Plasma was collected at prebeverage baseline and hourly for 4 h afterward. Immunoassays quantified 10 disease-related biomarkers: adiponectin, angiogenin, D-dimer, high-sensitivity C-reactive protein (hsCRP), Intercellular Adhesion Molecule-1 (ICAM-1), Lipocalin-2 (LCN2), Matrix Metalloproteinase-7 (MMP-7), Matrix Metalloproteinase-9 (MMP-9), soluble Receptor for Advanced Glycation End-products (sRAGE), and Triggering Receptor Expressed on Myeloid cells 2 (TREM2). RESULTS: Main effects of group indicated that even in this young healthy sample, heavy drinking status was associated with higher levels of adiponectin, angiogenin, ICAM-1, LCN2, and sRAGE, a profile suggesting altered vascular and metabolic activity. Acute alcohol administration induced changes in sRAGE and hsCRP. Specifically, moderate-dose alcohol triggered an increase in the immunoglobulin sRAGE, which may reflect an acute compensatory response to inflammation and/or oxidative stress. Compared to placebo, hsCRP was lower in the low-dose alcohol condition; however, this finding should be interpreted in light of CRP biology. MMP-7, MMP-9, and LCN2 showed time-dependent fluctuations that were independent of experimental condition, highlighting the critical importance of placebo-controlled designs to account for diurnal/postprandial variation in immune biomarkers. CONCLUSION: Findings provide translational evidence that alcohol is associated with multisystem biomarker changes relevant to chronic disease and that alcohol-related biomarker perturbations vary by dose and chronicity.

Humans↗

PubMed2025

HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact. METHODS: Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell-cell interactions, and pathological responses of key immune populations. RESULTS: HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1. CONCLUSIONS: These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex-cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.

Humans↗

PubMed2026

Multiplexed perturbation enables scalable pooled screens.

CRISPR-based genetic perturbation screens have revolutionized the ability to link genes to cellular phenotypes with unprecedented precision and scale; however, conventional pooled CRISPR screens require large cell numbers to achieve adequate sgRNA representation, posing technical and financial challenges. Here, we investigate the impact of co-delivery of multiple guide RNAs via high multiplicity of infection (MOI) in pooled CRISPR interference screens as a strategy to enhance screening efficiency while reducing cell numbers. We systematically evaluate screen performance across varying MOIs, assessing the effects of multiplexing on knockdown efficiency, sgRNA representation and potential interference of multiple sgRNA phenotypes. Our data demonstrate that sgRNA multiplexing (MOI 2.5-10) can maintain screen performance while enabling significant reductions in cell number requirements. We further apply these optimized conditions to conduct a genome-wide CRISPR screen for regulators of the intracellular adhesion molecule ICAM-1, successfully identifying new candidates using as few as half a million cells. This study provides a framework for adopting multiplexed sgRNA strategies to streamline CRISPR screening applications in resource-limited settings.

Humans↗

PubMed2005

SUMO modification of the Ets-related transcription factor ERM inhibits its transcriptional activity.

A variety of transcription factors are post-translationally modified by SUMO, a 97-residue ubiquitin-like protein bound covalently to the targeted lysine. Here we describe SUMO modification of the Ets family member ERM at positions 89, 263, 293, and 350. To investigate how SUMO modification affects the function of ERM, Ets-responsive intercellular adhesion molecule 1 (ICAM-1) and E74 reporter plasmids were employed to demonstrate that SUMO modification causes inhibition of ERM-dependent transcription without affecting the subcellular localization, stability, or DNA-binding capacity of the protein. When the adenoviral protein Gam1 or the SUMO protease SENP1 was used to inhibit the SUMO modification pathway, ERM-dependent transcription was de-repressed. These results demonstrate that ERM is subject to SUMO modification and that this post-translational modification causes inhibition of transcription-enhancing activity.

Adenoviridae↗

PubMed2002

Activation of Rac1 by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression.

Hemodynamic shear stress is a fundamental determinant of vascular remodeling and atherogenesis. Changes in focal adhesions, cytoskeletal organization and gene expression are major responses of endothelial cells to shear stress. Here, we show that activation of the small GTPase Rac is essential for gene expression and for providing spatial information for shear stress-induced cell alignment. Fluorescence resonance energy transfer (FRET) localizes activated Rac1 in the direction of flow. This directional Rac1 activation is downstream of shear-induced new integrin binding to extracellular matrix. Additionally, Rac1 mediates flow-induced stimulation of nuclear factor kappaB (NF-kappaB) and the subsequent expression of intercellular cell adhesion molecule 1 (ICAM-1), an adhesion receptor involved in the recruitment of leukocytes to atherosclerotic plaque. These studies provide a unifying model linking three of the main responses to shear stress that mediate both normal adaptation to hemodynamic forces and inflammatory dysfunction of endothelial cells in atherosclerosis.

Animals↗

PubMed2026

IL-33 Drives Inflammatory Changes and Extracellular Trap Formation in Eosinophils Involving Oxidised LDL and Complement Pathways.

BACKGROUND: IL-33 levels are elevated in the airways of patients with eosinophilic diseases, and IL-33 receptor expression on eosinophils is upregulated in type 2-high environments. However, the role of IL-33 in the regulation of human eosinophils remains unclear. OBJECTIVE: To elucidate the inflammatory effects of IL-33 on the cellular function of human eosinophils. METHODS: Blood eosinophils were stimulated with IL-33, TNF-α, oxidised low-density lipoprotein (oxLDL) and complement fragments (C3a and C5a). Multi-omics analyses, including transcriptomics and proteomics, were performed. Extracellular trap formation (ETosis) was assessed by SYTOX nucleic acid staining and was visualised by immunofluorescence and transmission electron microscopy. RESULTS: Multi-omics analyses revealed an IL-33- and TNF-α-induced inflammatory gene signature characterised by the upregulation of cell surface markers (oxLDL receptor 1, CD22, CD4 and ICAM-1) and inflammatory mediators (C3, CCL3/4 and IL1A/B). CD22 upregulation was specific to IL-33 stimulation. Eosinophils derived from nasal polyps exhibited a gene expression profile similar to that of IL-33-stimulated eosinophils. Functional assays demonstrated that oxLDL and complement fragments differentially prolonged eosinophil survival and altered the expression of adhesion molecules. OxLDL- and complement fragment-induced gene signatures were partly detected in eosinophils derived from nasal polyps. Furthermore, IL-33 triggered ETosis via NADPH oxidase, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. CONCLUSIONS: IL-33, in conjunction with oxLDL and the complement cascade, induces inflammatory changes in eosinophils, promoting an ETosis-prone phenotype. These pathways represent potential therapeutic targets in refractory eosinophilic diseases.

Humans↗