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Mesenchymal IL-33 licenses reparative macrophages to facilitate endovascular injury-induced neointimal hyperplasia [scRNA-Seq]

ABSTRACT: Immune remodeling is crucial for tissue repair, but the interaction between arterial macrophages and mesenchymal stromal cells (MSCs) in neointimal hyperplasia is not well understood. Herein, we identified Il33-expressing MSCs serve as the key regulators of arterial immune responses following endovascular injury via facilitating the recruitment of reparative macrophages. Using temporal-resolving scRNA-seq and multi-color flow cytometry, we revealed a distinct subset of LY6C-CD63+CD72+ reparative macrophages essential for vascular smooth muscle cell (VSMC) proliferation and neointimal formation. These ST2-expressing macrophages are recruited and activated by MSC-derived IL-33, which is upregulated via NFκB signaling following injury, and in turn amplify the osteopontin (OPN) production that drives VSMC proliferation. Furthermore, hydrogel-mediated local delivery of siRNAs targeting Il33 or Spp1 reduced neointimal hyperplasia, confirming the importance of the IL-33-ST2-OPN axis in pathological vascular remodeling. Our findings uncover a critical role of mesenchymal IL-33 in orchestrating immune cell recruitment and promoting VSMC proliferation, suggesting that targeting this pathway may offer therapeutic potential for preventing restenosis and other vascular diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE281009 | GEO | 2025/11/27

REPOSITORIES: GEO

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Mesenchymal IL-33 licenses reparative macrophages to facilitate endovascular injury-induced neointimal hyperplasia [RNA-Seq]

Project description:Immune remodeling is crucial for tissue repair, but the interaction between arterial macrophages and mesenchymal stromal cells (MSCs) in neointimal hyperplasia is not well understood. Herein, we identified Il33-expressing MSCs serve as the key regulators of arterial immune responses following endovascular injury via facilitating the recruitment of reparative macrophages. Using temporal-resolving scRNA-seq and multi-color flow cytometry, we revealed a distinct subset of LY6C-CD63+CD72+ reparative macrophages essential for vascular smooth muscle cell (VSMC) proliferation and neointimal formation. These ST2-expressing macrophages are recruited and activated by MSC-derived IL-33, which is upregulated via NFκB signaling following injury, and in turn amplify the osteopontin (OPN) production that drives VSMC proliferation. Furthermore, hydrogel-mediated local delivery of siRNAs targeting Il33 or Spp1 reduced neointimal hyperplasia, confirming the importance of the IL-33-ST2-OPN axis in pathological vascular remodeling. Our findings uncover a critical role of mesenchymal IL-33 in orchestrating immune cell recruitment and promoting VSMC proliferation, suggesting that targeting this pathway may offer therapeutic potential for preventing restenosis and other vascular diseases.

2025-11-27 | GSE281008 | GEO

The alarmin IL-33 amplifies an immune response in the degenerating retina

2015-12-17 | GSE74695 | GEO

The alarmin IL-33 amplifies an immune response in the degenerating retina

Project description:ST2 heterodimerizes with IL-1RAcp to form the receptor for IL-33, which is primarily associated with allergic inflammation by inducing Th2 responses. Recently, however, IL-33 was found to be expressed in the central nervous system and in retinal Muller cells which imply functions, as yet undescribed, beyond Th2 mediated inflammation. Muller cells support the health of the retina and photoreceptors and are also involved in inflammation in retinal degeneration. It is not known how IL-33/ST2 functions in this capacity. We recently found that ST2 ko mice are protected from CLE-induced photoreceptor loss, implying a detrimental effect of IL33/ST2 in CLE. We wish to perform microarray analysis using WT and ST2 KO mice in CLE model to better understand the mechanism by which IL-33/ST2 regulates retinal degeneration. CLE (Constant Light Exposure) is a model of retinal damage/degeneration in mice. Mice are exposed to bright light 24 hours a day for a period of time which damages retina photoreceptors. This damage is assessed by histology, optical coherence tomography (OCT), which measures retina thickness in vivo. In this experiment, the WT and ST2 KO mice (5 mice per genotype per time point) will be exposed to 1200-lux constant light for 0, 3, 10 days. The retinal RNA will be isolated and analyzed for differential gene expression by microarray.

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Gene expression profile of F4/80+ cells isolated from tumors implanted in wild type and St2-/- mouse

Project description:We report a novel mechanism of the interaction between perivascular cell and TAMs in promoting metastasis through the IL-33-ST2-dependent pathway. IL-33 was the highest up-regulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Il33-/- deficient mice showed impaired TAM recruitment and metastasis. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibited TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocked PDGF-BB-induced TAM recruitment and metastasis. High IL-33 in human cancers correlated with poor survival prognosis. These findings shed novel mechanisms of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

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Regulation of IL-33 alarmin production from lung epithelial cells via CLEC-2:Podoplanin interactions

Project description:Lung epithelial cells produce alarmins that promote allergic inflammation, however, the molecular mechanisms that regulate alarmin expression and production have not been fully elucidated. We constructed an integrated single-cell RNA-seq atlas of murine airways, lung, and vagal nerves, which we use to characterize novel lung cell subsets and infer intercellular interactions, including an interaction between podoplanin (PDPN) on alveolar epithelial cells and C-type Lectin-like Receptor-2 (CLEC-2/Clec1b) on alveolar macrophages that controls the expression of IL-33. Clec1b-/- mice spontaneously develop allergic airway inflammation with increased Il33 expression in alveolar epithelial type 2 (AT2) cells and airway-associated fibroblasts; this airway inflammation is ameliorated by co-deletion of the IL-33 receptor, Il1rl1 (ST2). Myeloid cell-specific deletion of Clec1b and acute blockade of endogenous CLEC-2:PDPN interactions in vivo also promote type 2 immune responses in airway inflammation. Organoid experiments reveal that the regulation of AT2 Il33 expression by CLEC-2:PDPN interactions is directly mediated by alveolar macrophages. Single-cell characterization of house dust mite (HDM)-induced asthma reveals a smaller population of Clec1b expressing alveolar macrophages and increased Il33 expression by AT2 cells. Thus, our study has identified the CLEC-2:PDPN pathway as an important regulator of epithelial alarmin production and induction of type 2 immunity.

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RNA-Sequencing of ST2+ Treg cells in response to IL-33 stimulation

Project description:The effects of IL-33 on ST2+ Treg cells were not studied thouroughly. We FACS-sorted in vitro expanded ST2+ Treg cells from C57BL/6 Foxp3-IRES-mRFP (B6 FIR) mice. We next used RNA-seq techonology to define how recombinant IL-33 (rIL-33) may impact mouse Treg by to assessing the transcriptome of IL-33-stimulated ST2+ Treg cells compared to that of untreated ST2+ Treg cells. Our data revealed that ST2+ Treg stimulated with rIL-33 for 6 hours exhibited increased expression of Il10 and Il13 compared to unstimulated ST2+ Treg cells.

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Gene expression profile of RAW264.7 monocytes treated with or without IL-33

Project description:Molecular mechanisms underlying the cancer stroma in metastasis is largely unknown. Here we show that cancer-associated fibroblasts (CAFs) produce high levels of IL-33 that acted on tumor-associated macrophages (TAMs) to induce the M1 to M2 transition. Genome profiling of metastasis-related genes in the IL-33-stimulated TAMs showed a > 200-fold increase of metalloproteinase 9 (MMP9). Signaling analysis demonstrated the IL-33-ST2-NFkB-MMP9-laminin pathway that mediates cancer metastasis. In mouse and human fibroblast-rich pancreatic cancers, genetic deletion of IL-33, ST2 and MMP9 markedly blocked metastasis. Pharmacological inhibition of NFkB and MMP9 also blocked cancer metastasis. Deletion of IL-33, ST2 and MMP9 restored laminin, a key basement membrane component associated to tumor microvessels. Together, our data provide novel mechanistic insights on the IL-33-NFkB-MMP9-laminin axis that mediates the CAF-TAM-committed cancer metastasis. Thus, targeting the CAF-TAM-vessel interaction provides an outstanding therapeutic opportunity for cancer treatment.

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IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [shotgun sequencing]

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IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [scRNA-seq]

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