Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms
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ABSTRACT:
PROVIDER: PRJNA1230560 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32544500_1.fastq.gz | Fastqsanger.gz | |||
| SRR32544500_2.fastq.gz | Fastqsanger.gz | |||
| SRR32544502_1.fastq.gz | Fastqsanger.gz | |||
| SRR32544502_2.fastq.gz | Fastqsanger.gz |
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Project description:"Trained immunity" of innate immune cells occurs through a two-step response pattern where an initial pathogenic or sterile inflammatory trigger is followed by an augmented response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further showed that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, which is independent of its enzymatic activity; and a second mechanism that requires its SET domain and is associated with both elevated H3K9 methylation changes and repression of interferon response pathway gene promoters. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon these pathways to limit complications of chronic inflammation.
2025-06-25 | GSE290872 | GEO
Project description:Hydroxychloroquine inhibits trained immunity
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Project description:scRNAseq of monocytes from in vitro Trained immunity experiments stimulated by β-glucan (BG), uric acid (UA), muramyl dipeptide (MDP), oxidized low-density lipoprotein (oxLDL), or RPMI-Control, and respective samples restimulated with Lipopolysaccharide (LPS).
2021-09-30 | E-MTAB-9702 | biostudies-arrayexpress
Project description:We demonstrate that hydroxychloroquine inhibits trained immunity at the functional and epigenetic level and is accompanied by reduced expression of interferon-stimulated genes. Trained immunity comprises a functional adaptation induced by epigenetic reprogramming which facilitates the anti-viral innate immune response.
2020-10-21 | GSE159678 | GEO
Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
2024-11-04 | GSE280787 | GEO
Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
2024-11-04 | GSE280903 | GEO
Project description:Venous thromboembolism is common in individuals with chronic inflammatory diseases, but the pathogenic basis for this increased thrombotic risk remains poorly understood. Myeloid cell ‘trained immunity’ describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a novel maladaptive consequence of trained immunity. LPS stimulation of murine bone marrow-derived macrophages trained previously with either β-glucan or free haem exhibited significantly enhanced procoagulant and antifibrinolytic gene expression and activity compared to macrophages stimulated with LPS alone. The β-glucan training-mediated increase in activated myeloid cell procoagulant activity was mediated by enhanced acid sphingomyelinase-mediated tissue factor (TF) functional decryption. Furthermore, pre-treatment with methyltransferase and acetyltransferase inhibitors to erase epigenetic marks associated with innate immune memory diminished trained macrophage TF gene expression in β-glucan-trained macrophages. Functional analysis of splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Remarkably, monocyte procoagulant activity increased proportionately with time since β-glucan administration, before plateauing at 4 weeks. Furthermore, haematopoietic progenitor cells and bone marrow interstitial fluid isolated from β-glucan-trained mice possessed enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent novel therapeutic vulnerabilities in immunothrombotic disease development, opening new avenues for targeted intervention.
2025-03-07 | GSE273173 | GEO
Project description:Trained Immunity Causes Myeloid Cell Hypercoagulability
| PRJNA1140546 | ENA
Project description:As the primary driving forces of gastrulation, convergence and extension (C&E) movements lead to a medio-lateral narrowing and an anterior-posterior elongation of the embryonic body axis. Histone methylation as a post-translational modification plays a critical role for early embryonic development, but its functions on C&E movements remaine largely unknown. Here, we uncover that knockdown of setdb2, a SET domain-containing protein possessing potential histone H3K9 methyltransferase activity, induces abnormal C&E movements. Then, we perform genome-wide gene expression profiling of zebrafish in 6h control embryos and setdb2 morphant embryos to address the downstream target of setdb2 gene.
2014-06-20 | E-MTAB-2207 | biostudies-arrayexpress
Project description:Histone H3 lysine 9 tri-methyltransferases (H3K9me3) are related to transcriptional gene silencing. Although SETDB2 has H3K9me3 activity, it is unknown whether SETDB2 is linking to carcinogenesis. Here, we studied alterations and functions of SETDB2 in gastric cancers (GCs). In human clinical samples, overexpression of SETDB2 protein was observed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts, and significantly associated with poor prognosis of the patients (P<0.05). SETDB2 protein was significantly detected in late stage of GCs. Moreover, SETDB2 protein was strongly expressed in four (30.8%) of 13 GC cell lines, and knockdown of SETDB2 led to decrease the cell proliferation, migration and invasion. According to the microarray analysis on a GC cell line after knockdown of SETDB2, the expression of WWOX and CADM1 tumor suppressor genes was significantly up-regulated. ChIP analysis showed that the H3K9me3 levels at the promoter regions of WWOX and CADM1 genes were closely regulated by the SETDB2 in GC cells. We also found that SETDB2 bound to the promoter regions after SETDB2 overexpression. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, through H3K9me3, and hence overexpression of SETDB2 may contribute to gastric progression. Transfection of SETDB2 siRNA into MKN74 cells were performed by electroporation. After 48hrs, cells were harvested. Total RNA was used for cDNA microarray.
2016-02-21 | E-GEOD-76135 | biostudies-arrayexpress