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A genome-wide CRISPR screen identifies the TNRC18 gene locus as a novel regulator of inflammatory signaling [CRISPR Screen]

ABSTRACT: Interleukin-1β (IL-1β) is dysregulated in chronic inflammatory diseases, yet the genetic factors influencing IL-1β production remain largely unknown. Myeloid-derived cells are the primary producers of IL-1β, which prompted a genome-wide CRISPR knockout screen in the human myeloid-derived U937 cell model treated with lipopolysaccharide (LPS) to mimic inflammatory conditions and sorted for high and low intracellular IL-1β levels. A total of 295 genes were identified as regulators of IL-1β production, including known mediators such as TLR4, JAK-STAT and IL-10 receptor. Notably, 57 out of the 295 genes overlapped with loci associated with human inflammatory diseases, including the TNRC18 gene locus associated with multiple diseases in the Finnish population. U937 cells engineered with the Finnish-enriched rs748670681 risk allele demonstrated decreased levels of mRNA for TNRC18 and an adjacent gene WIPI2, reduction in LPS-dependent gene activation and cytokine production, but elevation of interferon-responsive gene programs. Transcriptomic profiles for individual knockouts of TNRC18 and WIPI2 attributed the loss of LPS-dependent signaling primarily to TNRC18, which occurs through the modulation of H3K27 acetylation around inflammatory regulatory regions via TNRC18 and its protein interaction network. In contrast, the loss of WIPI2 is characterized by an exacerbation of interferon signaling. Collectively, these findings delineate the global regulatory mechanisms of IL-1β production and provide molecular insights to the role of the rs748670681 variant as a pleiotropic risk factor for inflammatory diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299544 | GEO | 2025/09/30

REPOSITORIES: GEO

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A genome-wide CRISPR screen identifies the TNRC18 gene locus as a novel regulator of inflammatory signaling [CUT&Tag]

Project description:Interleukin-1β (IL-1β) is dysregulated in chronic inflammatory diseases, yet the genetic factors influencing IL-1β production remain largely unknown. Myeloid-derived cells are the primary producers of IL-1β, which prompted a genome-wide CRISPR knockout screen in the human myeloid-derived U937 cell model treated with lipopolysaccharide (LPS) to mimic inflammatory conditions and sorted for high and low intracellular IL-1β levels. A total of 295 genes were identified as regulators of IL-1β production, including known mediators such as TLR4, JAK-STAT and IL-10 receptor. Notably, 57 out of the 295 genes overlapped with loci associated with human inflammatory diseases, including the TNRC18 gene locus associated with multiple diseases in the Finnish population. U937 cells engineered with the Finnish-enriched rs748670681 risk allele demonstrated decreased levels of mRNA for TNRC18 and an adjacent gene WIPI2, reduction in LPS-dependent gene activation and cytokine production, but elevation of interferon-responsive gene programs. Transcriptomic profiles for individual knockouts of TNRC18 and WIPI2 attributed the loss of LPS-dependent signaling primarily to TNRC18, which occurs through the modulation of H3K27 acetylation around inflammatory regulatory regions via TNRC18 and its protein interaction network. In contrast, the loss of WIPI2 is characterized by an exacerbation of interferon signaling. Collectively, these findings delineate the global regulatory mechanisms of IL-1β production and provide molecular insights to the role of the rs748670681 variant as a pleiotropic risk factor for inflammatory diseases.

2025-09-30 | GSE299545 | GEO

A genome-wide CRISPR screen identifies the TNRC18 gene locus as a novel regulator of inflammatory signaling

2025-09-30 | GSE299089 | GEO

Interleukin 1b triggers catabolism via a central nervous system-mediated pathway in mice and rat

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2011-11-03 | E-GEOD-26766 | biostudies-arrayexpress

Serine metabolism supports macrophage IL-1β production.

Project description:Serine is a substrate for nucleotides, NADPH and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1β mRNA expression, but not inflammasome activation. The mechanism involves a requirement for glycine, which is made from serine, to support macrophage glutathione (GSH) synthesis. Cell-permeable GSH, but not the one-carbon donor formate, rescues IL-1β mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1β levels and improved survival in an LPS-driven model of sepsis in mice. Our study reveals that serine metabolism is necessary for GSH synthesis to support IL-1β cytokine production.

2019-01-15 | GSE125036 | GEO

Interleukin 1b triggers catabolism via a central nervous system-mediated pathway in mice and rat

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Itaconate Negatively Regulates Innate Signaling through Modification of IRAK4, Degradation of NFκB, and the Modulation of Global Ubiquitination

Project description:A wide variety of electrophilic derivatives of the Kreb’s cycle-derived metabolite, itaconate, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 disrupting IRAK4 autophosphorylation and activation, drives the degradation of NFκB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as TNFα, IL6, and IL-1β in response to these innate activators. In contrast, the production of IFNβ, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

2024-07-16 | PXD053956 | JPOST Repository

Expression data from primary culture human myometrial cells

Project description:Inflammation plays a central role in many human diseases. Human parturition also resembles an inflammatory reaction, where progesterone (P4) and progesterone receptors (PRs) have already been demonstrated to suppress contraction-associated gene expression. In our previous studies, we have found that the progesterone actions, including progesterone-induced gene expression and progesterone’s anti-inflammatory effect, are mediated by PR, GR or both. In this study, we used microarrays to find P4 and IL-1β responsive genes and which IL-1β responsive genes were repressed by P4. These data may provide a broader view of gene networks and cellular functions regulated by P4 and IL-1βin human myometrial cells. In our future study, this will also help us understand the role of PR and GR in human parturition. Primary cultures of human myometrial cells were grown from myometrial biopsies obtained at the time of elective caesarean section. Cells were exposed to different stimuli, IL-1β (5ng/mL) and P4 (10 µM), either alone or in combination for 6 h, and then total RNA were extracted from each culture. Three comparisons were carried out including: 1. V vs. P4; 2. V vs. IL-1β; 3. IL-1β vs. IL-1β+P4.

2015-08-13 | E-GEOD-68171 | biostudies-arrayexpress

Differential production of Type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages

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2016-09-07 | GSE79809 | GEO

GABA regulates IL-1β production in macrophages

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2023-01-31 | MTBLS6337 | MetaboLights

Olfactory Receptor 2 in Monocytes Exacerbates Myocardial Ischemia-Reperfusion Injury via Drp1-Dependent Mitochondrial Fission Mediated by NR4A1

Project description:Myocardial ischemia-reperfusion (I/R) injury represents a major clinical challenge with limited therapeutic options. This study examines the role of Olfactory Receptor 2 (Olfr2) in monocytes during myocardial I/R injury. We utilized RNA sequencing to analyze monocytes isolated from the spleens of wild-type (WT) mice, investigating their response to low-dose LPS priming and subsequent treatment with octanal (Oct), a specific agonist of Olfr2. Principal component analysis (PCA) revealed distinct clustering among experimental groups, highlighting significant gene expression changes in pathways related to cAMP/PKA signaling and inflammasome activation. Notably, the low-dose LPS+Oct treatment induced substantial upregulation of genes such as Adcy, Pka, Nlrp3, Pycard, Casp4, Gsdmd, and Nr4a1. Moreover, monocytes subjected to low-dose LPS+Oct exhibited increased expression of pro-inflammatory cytokines (IL-1β, IL-12a, IL-18, and TNF), chemokines (CCL3, CCL4, CXCL1, CXCL2, and CXCL3), and demonstrated enrichment in pathways associated with oxidative stress, positive chemotaxis, and the production and secretion of inflammatory cytokines (IL-1β, IL-8, TNF).

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