Citraconate preserves T cell stemness and antitumor immunity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE326246 | GEO | 2026/04/06
REPOSITORIES: GEO
Similar Datasets
Project description:Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as Arachidonate 5-Lipoxygenase (ALOX5) and ALOX5 Activating Protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6-day training, they exhibit enhanced TNF-α and IL-6 production to LPS. Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
2024-06-20 | GSE263024 | GEO
Project description:Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as Arachidonate 5-Lipoxygenase (ALOX5) and ALOX5 Activating Protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6-day training, they exhibit enhanced TNF-α and IL-6 production to LPS. Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
2024-06-20 | GSE263019 | GEO
Project description:To understand the underlying mechanism by which Alox15 gene is required by HSCs, we performed a comparative DNA microarray analysis using total RNA isolated from wild type Lin-Sca-1+c-Kit+, Alox5-/- Lin-Sca-1+c-Kit+. The result was validated by quantitative real-time PCR analysis of wild type Lin-Sca-1+c-Kit+ and Alox15-/- Lin-Sca-1+c-Kit+. Cancer stem cells are responsible for the initiation and maintenance of some types of cancer, and few effective target genes in these stem cells have been identified. Here we show that the arachidonate 15-lipoxygenase gene (Alox15) is essential for the survival of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL failed to induce CML in mice. This Alox15 deficiency caused the impairment of LSC function through affecting cell division and apoptosis, leading to eventual deletion of LSCs. Inhibition of Alox15 function by a chemical compound also impaired the function of LSCs, and cured CML mice. In addition, we show that Alox15 is required for the survival of human CD34+ CML stem cells. The defective CML phenotype in the absence of Alox15 is rescued by depleting P-selectin. The underlying mechanisms are also related to pathways involving PTEN, PI3K/AKT, and ICSBP. These results identify Alox15 as a potential target gene for eradicating LSCs in CML, providing a novel strategy for treating CML patients for cure. we compared the gene profile of HSCs between WT mice and Alox15-/- mice.
2011-05-17 | E-GEOD-29348 | biostudies-arrayexpress
Project description:The tumor microenvironment possesses multiple overlapping mechanisms that suppress anti-tumor immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumor immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secreted itaconate that can be taken up by CD8+ T cells and suppress their proliferation, cytokine production, and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed biosynthesis of aspartate and serine/glycine in CD8+ T cells to attenuate their proliferation. Moreover, stromal deletion of IRG1 in mice bearing allografted tumors resulted in decreased tumor growth, inhibited the immune suppressive activities of MDSCs, reduced levels of itaconate in tumors, promoted anti-tumor immunity of CD8+ T cells, and enhanced the anti-tumor activity of anti-PD-1 antibody treatment. Importantly, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in melanoma patients. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8+ T cells, but also establish IRG1 as a novel myeloid-selective target in immunometabolism to promote anti-tumor immunity and enhance the efficacy of immune checkpoint protein blockade.
2022-11-15 | GSE190028 | GEO
Project description:Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor, and initial management of AML continues to rely on standard induction chemotherapy for many patients. Given the importance of identifying new approaches to improve the efficiency of induction therapy in AML, we sought to identify resistance genes to induction therapy in AML and identified ALOX5 is a novel mediator of resistance to anthracycline based therapy. ALOX5 mRNA is expressed at high levels in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA and protein expression is increased in response to induction therapy. Genetic and pharmacologic perturbations of ALOX5 function in vitro and in vivo confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, while ALOX5 loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity. Specifically, the ALOX5 dependent resistance phenotype depends on its ability to synthesize LTB4 and bind to the LTB receptor (BLTR). Overall, our studies reveal a previously unrecognized role of LT’s in AML pathogenesis and chemoresistance, and provide a potential novel strategy to enhance the therapeutic efficacy of induction chemotherapy in AML.
2022-04-14 | GSE200614 | GEO
Project description:The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. Cells were treated with 0.5 μmol/L DZNep for 48 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip® Human Genome U133A Array (Affymetrix) following the manufacturer’s instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.
2011-07-04 | E-GEOD-26921 | biostudies-arrayexpress
Project description:To understand the underlying mechanism by which Alox15 gene is required by HSCs, we performed a comparative DNA microarray analysis using total RNA isolated from wild type Lin-Sca-1+c-Kit+, Alox5-/- Lin-Sca-1+c-Kit+. The result was validated by quantitative real-time PCR analysis of wild type Lin-Sca-1+c-Kit+ and Alox15-/- Lin-Sca-1+c-Kit+. Cancer stem cells are responsible for the initiation and maintenance of some types of cancer, and few effective target genes in these stem cells have been identified. Here we show that the arachidonate 15-lipoxygenase gene (Alox15) is essential for the survival of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL failed to induce CML in mice. This Alox15 deficiency caused the impairment of LSC function through affecting cell division and apoptosis, leading to eventual deletion of LSCs. Inhibition of Alox15 function by a chemical compound also impaired the function of LSCs, and cured CML mice. In addition, we show that Alox15 is required for the survival of human CD34+ CML stem cells. The defective CML phenotype in the absence of Alox15 is rescued by depleting P-selectin. The underlying mechanisms are also related to pathways involving PTEN, PI3K/AKT, and ICSBP. These results identify Alox15 as a potential target gene for eradicating LSCs in CML, providing a novel strategy for treating CML patients for cure.
2011-05-17 | GSE29348 | GEO
Project description:In our study, we demonstrated that downregulation of arachidonate 15-lipoxygenase (ALOX15B) promotes KRASmut-PDAC tumour growth. In order to elucidate the mechanisms underlying downregulation of ALOX15B promoting KRASmut-PDAC progression, quantitative proteomics mass-spectrometry(MS) analysis of differential proteins in KRAS-mutant tissues was performed
2024-12-02 | PXD058462 |
Project description:Itaconate is a metabolite naturally produced in large amounts in macrophages after exposure to immune stimulation. Following the discovery of itaconate’s immunoregulatory properties, several ester derivatives of this dicarboxylic acid were designed to further examine its role. We evaluated the metabolic, electrophilic, and immunologic profiles of macrophages treated with unmodified itaconate and a panel of itaconate derivatives. We found that only unmodified itaconate strongly enhances LPS-induced IFNb secretion after 12h pre-treatment. Thus, we compared the transcriptional profile of wild type and Irg1-/- cells, which are unable to produce itaconate, after 24h LPS stimulation. We find that cells lacking itaconate have impaired downstream type I interferon signaling, and that addition of itaconate Irg1-/- BMDMs restores this signaling back to levels comparable to wild type. This data highlights the role of itaconate as an immunoregulatory metabolite, and highlights the importance of using unmodified itaconate or genetic knockout models in future mechanistic studies.
2020-05-15 | GSE145950 | GEO
Project description:We previously demonstrated that Alox5 deficiency impairs the function of LSCs and prevents the initiation of BCR-ABL-induced CML. To identify the pathways in which Alox5 gene regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to further dissect this pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs derived from our mouse model for BCR-ABL-induced CML. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was up-regulated in Alox5-/- LSCs, suggesting that Msr1 might suppress the proliferation of LSCs. Using our CML mouse model, we show that Msr1 is down-regulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and ?-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of Msr1 function may be of significance in the development of novel therapeutic strategies targeting CML. To identify genes that are regulated by BCR-ABL in LSCs and LSCs without Alox5 gene, we compared the gene profile between wild type(WT) LSCs or Alox5-/- LSCs.
2011-05-17 | E-GEOD-29347 | biostudies-arrayexpress