Combined inhibition of IL-1, IL-33 and IL-36 signaling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of Systemic Sclerosis
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ABSTRACT:
PROVIDER: PRJNA1073269 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27869000_1.fastq.gz | Fastqsanger.gz | |||
| SRR27869000_2.fastq.gz | Fastqsanger.gz | |||
| SRR27869001_1.fastq.gz | Fastqsanger.gz | |||
| SRR27869001_2.fastq.gz | Fastqsanger.gz | |||
| SRR27869002_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: The IL-1 receptor accessory protein (IL1RAP) is an essential co-receptor required for signaling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). Methods: The expression of IL1RAP-associated signaling molecules was determined by data mining of publicly available RNAseq data as well as by imaging mass cytometry (IMC). Efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complimentary mouse models: chronic sclerodermatous graft-versus-host-disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. Results: SSc skin showed upregulation of IL1RAP and IL1RAP-related signaling molecules on mRNA and protein level compared to normal skin. IL-1, IL-33, and IL-36 all regulate distinct genes sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33, and IL-36 were completely blocked by treatment with an anti-IL1RAP-antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-, bleomycin- and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. Conclusion: This study provides first evidence for the therapeutic benefits of targeting of IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase 1 clinical trial.
2024-04-30 | GSE255031 | GEO
Project description:Interleukin-33 (IL-33) is a novel member of the IL-1 family of cytokines that plays diverse roles in the regulation of immune responses. IL-33 exerts its effects by binding to a heterodimeric receptor complex consisting of interleukin-1 receptor like 1 (IL1RL1) and an accessory receptor protein IL-1RAcP resulting in the production and release of proinflammatory cytokines. A detailed understanding of the signaling pathways activated by IL-33 remains elusive. To elucidate IL-33 mediated signaling, we performed a global quantitative phosphoproteomic analysis using stable isotope labeling by amino acids in cell culture. Employing anti-phosphotyrosine antibodies and titanium dioxide-based enrichment strategies, we identified 6,207 phosphorylation sites mapping to 2,013 phosphoproteins of which more than 185 phosphosites are regulated by IL-33 stimulation. Our findings will greatly expand the understanding of IL-33 signaling and provide novel therapeutic targets for IL-33/IL-33R-associated diseases in humans.
2015-01-29 | PXD000984 | Pride
Project description:IL-33 is a nuclear cytokine from the IL-1 family that plays important roles in health and disease. Under healthy conditions, IL-33 is constitutively expressed to high levels in the nucleus of producing cells in various human and mouse tissues. The extracellular function of IL-33 cytokine has been well documented, but it remains unclear whether intracellular nuclear IL-33 has additional functions in the nucleus. Here, we used a global proteomic approach based on quantification of 5000 individual proteins by high-resolution mass spectrometry to compare the extracellular and intracellular roles of IL-33 in primary human endothelial cells, a major source of IL-33 protein in human tissues. Large-scale analysis of protein expression was performed either after stimulation of the cells with the IL-33 mature form IL-3395-270 (during 6h or 24h) or after siRNA knockdown of intracellular IL-33 (two experiments, each with a different pool of distinct siRNAs, noted siRNA1 and siRNA2). In each case, proteins were fractionated by 1D SDS-PAGE in 12 gel bands, and label-free quantitative analysis was performed. The present dataset contains the files for the two experiments of knockdown of endogenous nuclear IL-33 expression: - RNA silencing strategy 1. Knockdown of endogenous nuclear IL-33 expression was performed with a pool of four distinct siRNAs (Dharmacon ON-TARGETplus SMARTpool IL-33 siRNAs) that have been specifically modified for efficient silencing of the target gene with reduced off-target effects. Cells transfected with these siRNA duplexes (si1) were compared with those transfected with the provided controls (CTsi1). Three independent biological replicates (noted _A, _B, _C) were prepared and analyzed for each condition, leading to 6 different samples. Each of them was fractionated into 12 gel bands analyzed by nanoLC-MS/MS, leading to 72 raw files. - RNA silencing strategy 2. The second knockdown strategy was based on the use of an independent pool of three siRNAs targeting IL-33, predesigned by another provider using new and critical siRNA design rules (Sigma MISSION Predesigned Il-33 siRNAs based on Rosetta siRNA design algorithm). Cells transfected with these siRNA duplexes (si2) were compared with those transfected with the provided controls (CTsi2). Three independent biological replicates (noted _A, _B, _C) were prepared and analyzed for each condition, leading to 6 different samples. Each of them was fractionated into 12 gel bands analyzed by nanoLC-MS/MS, leading to 72 raw files.
2016-10-12 | PXD004141 | Pride
Project description:Interleukin-33 (IL-33), a member of the IL-1 superfamily cytokines, is an endogenous danger signal and a nuclear-associated cytokine. It is one of the essential mediators of both innate and adaptive immune responses. Aberrant IL-33 signaling has been demonstrated to play a defensive role against various infectious and inflammatory diseases. Although the signaling responses mediated by IL-33 have been previously reported, the temporal signalingdynamicsare yet to be explored. Towards this end,we applied quantitative temporal phosphoproteomics analysis to elucidate pathways and proteins induced by IL-33 in THP1 monocytes. Employing TMT labeling-based quantitation and titanium dioxide (TiO2)-based phosphopeptide enrichment strategy followed by mass spectrometry analysis, we identified 14,515 phosphorylation sites mapping to 4,174 proteins across (0 min to 240 mins)time points.
2022-02-16 | PXD028673 | Pride
Project description:Determination of the molecular mechanism of IL33 on glioma cells Since IL-33 is known to associate with chromatin and regulate transcriptional activity and that nuclear expression of IL-33 increases glioma progression, we determined Nuclear IL-33 regulates the expression and secretion of inflammatory cytokines in glioma cells. Using these parameters 340 genes were induced by the ectopic expression of IL-33 and an additional 377 genes were downregulated. Gene ontology terms over-represented in the genes induced by IL-33 include three major clusters that associate with cytokine activity and inflammation
2020-08-21 | GSE153486 | GEO
Project description:IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we performed single-cell RNA-seq on an acute LPS mouse model of lung inflammation to provide insights into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. We identified neutrophils as a source of IL-36 which provides a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
2021-01-25 | GSE159161 | GEO
Project description:Impairment of microglial clearance activity contributes to beta-amyloid (Aβ) pathology in Alzheimer disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aβ pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33–responsive microglia (IL-33RM) express distinct transcriptome signature, highlighted by major histocompatibility complex class II genes, and restored homeostatic signature genes. IL-33–induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1–DNA interaction abolishes the microglial state transition and Aβ clearance induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33–induced functional state transition of microglia, resulting in enhanced Aβ clearance.
2020-05-01 | GSE147495 | GEO
Project description:Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells
2025-04-08 | GSE282699 | GEO
Project description:Glioma cells response Interleukin-33 (IL-33) [microarray]
| PRJNA642838 | ENA
Project description:Summary: Blocking IL-33 signaling ameliorates inflammation, tissue remodeling and preserves lung function in a model of persistent and exacerbating airway disease. Background: Severe inflammatory airway diseases are associated with inflammation that fails to resolve, leading to structural changes and an overall environment primed for exacerbations. Objective: We sought to identify and inhibit pathways that perpetuate this heightened inflammatory state, as this could lead to therapies that allow for a more quiescent lung, less predisposed to symptoms and exacerbations. Methods: Using prolonged exposure to house dust mite (HDM) in mice, we developed a mouse model of persistent and exacerbating airway disease characterized by a mixed inflammatory phenotype. Results: We show that lung IL-33 drives inflammation and remodeling beyond the type 2 response classically associated with IL-33 signaling. IL-33 blockade with an IL-33 neutralizing antibody normalized established inflammation, and improved remodeling of both the lung epithelium and lung parenchyma. Specifically, IL-33 blockade normalized persisting and exacerbating inflammatory endpoints, including eosinophilic, neutrophilic and ST2+ CD4+ T cell infiltration. Importantly, we identified a key role for IL-33 in driving lung remodeling, as anti-IL-33 also reestablished the presence of ciliated cells over mucus producing cells and lowered myofibroblast numbers, even in the context of continuous allergen exposure, resulting in improved lung function. Conclusion: Overall, this study shows that elevated IL-33 drives a self-perpetuating amplification loop that retains the lung in a state of lasting inflammation and remodeled tissue, primed for exacerbations. Thus, IL-33 blockade may ameliorate symptoms and prevent exacerbations by quelling persistent inflammation and airway remodeling.
2019-09-13 | GSE137324 | GEO