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Results for “Interleukin-33”

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PubMed2018

E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor.

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.

Animals↗
PubMed2026

The alarmin interleukin-33 modulates platelet proteome, function, and biogenesis.

Platelets, traditionally recognized for their involvement in hemostasis and wound healing, also play a central role in immune regulation and inflammation. Their function and production adapt in response to inflammatory cues such as cytokines and danger-associated molecular patterns. Interleukin-33 (IL-33), an alarmin released during tissue damage, particularly in lung inflammation, has been implicated in influencing platelet biology, though its exact effects remain poorly understood. To clarify IL-33's role, we examined its impact on platelet production, proteome, adhesion, secretion, and aggregation using platelets from IL-33-deficient (IL-33 knockout [IL-33KO]) mice and IL-33 stimulation in vivo. Our results reveal that although platelets themselves do not express IL-33, platelets isolated from IL-33KO mice display altered proteomic signatures and reduced adhesion to fibrinogen, podoplanin, and laminin, alongside impaired thrombus formation under shear stress. IL-33 administration in vivo led to proteomic remodeling characterized by increased expression of inflammatory proteins, as well as changes in platelet morphology, including increased size, typically associated with de novo production. Using lung intravital microscopy, we visualized platelet fragmentation within the lung vasculature in real time, and observed enhanced fragmentation following IL-33 stimulation. Interestingly, ST2, the receptor for IL-33, is expressed in subsets of mouse and human megakaryocytes and hematopoietic progenitors, particularly those involved in a noncanonical pathway of thrombopoiesis that enables the rapid replenishment of platelets during inflammation, infection, and aging. Together, these findings identify IL-33 as a pivotal regulator of platelet function and production, linking inflammatory signaling to the dynamic regulation of thrombopoiesis.

Interleukin-33↗
PubMed2026

The Staphylococcus aureus serine protease-like protein B is a potent allergen in a murine asthma model.

BACKGROUND: Asthma is associated with Staphylococcus aureus colonization. Two hypotheses were proposed to explain this phenomenon: (1) the allergic environment in asthma favors S. aureus colonization and (2) S. aureus colonization creates a pro-allergic environment. Since several S. aureus virulence factors, such as the serine protease-like protein (Spl) B, elicit a type 2 biased immune response, we asked whether the pathogen itself can cause asthma. OBJECTIVE: Test the ability of recombinant SplB of S. aureus to sensitize mice and induce allergic airway inflammation (AAI). METHODS: Mice were treated with repeated intratracheal inoculations of either catalytically active SplB or an inactive mutant. AAI was assessed by evaluating airway hypersensitivity, immune cell infiltration, cytokines, mucus production, fibrosis, and specific serum IgE. We compared the outcome between wild-type and gene-deficient C57BL/6J mice, including recombination-activating gene knockout mice (Rag2-/-), interleukin-33 knockout mice (Il33-/-), and protease-activated receptor 2 knockout mice (F2rl1-/-). RESULTS: Intratracheal exposure to SplB sensitized the mice and caused eosinophilic airway inflammation and hyperresponsiveness. The development of asthma required both the proteolytic activity of SplB and a functional adaptive immune system. The soluble protease sensor IL-33 was necessary for eosinophil tissue invasion, whereas the membrane-bound protease sensor PAR2 was not. CONCLUSION: The serine protease SplB of S. aureus is a potent allergen. Based on this finding we propose a third mechanism to explain the relationship between S. aureus colonization and asthma: S. aureus can release allergens, such as SplB, that sensitize individuals and lead to the development of asthma.

Allergy↗
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↗
PubMed2026

Negative regulation of human IL-33 in endothelium during allergic airway inflammation.

Lung IL-33 is involved in pathogen defense, barrier homeostasis, and development of allergic responses. We previously identified a 5 kb noncoding region within a GWAS-defined segment that regulates expression of human IL33 (hIL33) but is absent in the murine locus. To understand how this region affects IL-33 expression in vivo, we engineered 2 BAC-transgenic strains in which 166 kb of the human genome upstream of the hIL33 locus, along with a fluorescent reporter, was inserted into the murine genome, both with and without the 5 kb region. Comparison to a murine Il33 (mIl33) reporter strain revealed species-specific tropism; hIL33 reporter was mostly expressed in the endothelium, while mIl33 reporter was expressed in type 2 alveolar epithelium. hIL33 reporter expression in tracheal basal epithelium, submucosal glands, and lung microvasculature required the 5 kb region. Surprisingly, allergen and exogenous IL-33 downregulated hIL33 reporter in lung endothelium only when the 5 kb region was present. Similar IL-33-dependent downregulation of IL33 transcripts was observed in human endothelial cell lines, validating that our hIL33 reporter strain recapitulated human endothelial biology. Together, these data reveal the importance of the asthma-associated human 5 kb region in regulating human IL33 expression in a cell type- and context-dependent manner.

Interleukin-33↗