Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718612 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14113943.fastq.gz | Fastqsanger.gz | |||
| SRR14113944.fastq.gz | Fastqsanger.gz | |||
| SRR14113945.fastq.gz | Fastqsanger.gz | |||
| SRR14113946.fastq.gz | Fastqsanger.gz | |||
| SRR14113947.fastq.gz | Fastqsanger.gz |
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Project description:T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction in cancer. We identify that CD36 limits anti-tumor CD8+ T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+ TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally ‘exhausted’ CD8+ TILs increased CD36 expression and CD36-deficient CD8+ TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL), induces lipid peroxidation in CD8+ TILs, and enhances p38 kinase phosphorylation. Moreover, we found that OxLDL inhibits CD8+ T cell functions in a CD36/p38-dependent manner. Furthermore, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+ TILs. These results define a key role for an oxidized lipid-CD36-p38 axis in promoting intratumoral CD8+ T cell dysfunction.
2021-03-31 | GSE171194 | GEO
Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.
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Project description:Human fungal pathogens must survive diverse reactive oxygen species (ROS) produced by host immune cells. ROS can oxidize a range of cellular molecules including proteins, lipids, and DNA. Formation of lipid radicals by ROS can be especially damaging, as it leads to a chain reaction of lipid peroxidation that causes widespread damage to the plasma membrane. Most previous studies on antioxidant pathways in fungal pathogens have been conducted with hydrogen peroxide, so the pathways used to combat organic peroxides and lipid peroxidation are not well understood. The most well-known peroxidase in Candida albicans, catalase, only acts on hydrogen peroxide. We therefore characterized a family of four glutathione peroxidases (GPxs) that were predicted to play an important role in reducing organic peroxides. One of the GPxs, Gpx3 is also known to activate the Cap1 transcription factor that plays the major role in inducing antioxidant genes in response to ROS. Surprisingly, we found that the only measurable role of the GPxs is activation of Cap1 and did not find a significant role for GPxs in the direct detoxification of peroxides. Furthermore, a CAP1 deletion mutant strain was highly sensitive to organic peroxides and oxidized lipids, indicating an important role for antioxidant genes upregulated by Cap1 in protecting cells from organic peroxides. We identified GLR1 (Glutathione reductase), a gene upregulated by Cap1, as important for protecting cells from oxidized lipids, implicating glutathione utilizing enzymes in the protection against lipid peroxidation. Furthermore, an RNA-sequencing study in C. albicans measuring the transcriptional response for exposure to an organic peroxide showed upregulation of antioxidant and protein damage pathways. Overall, our results identify novel mechanisms by which C. albicans responds to oxidative stress resistance which open new avenues for understanding how fungal pathogens resist ROS in the host.
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Project description:relative quantification of oxidized lipids in human cell line (fibrosacroma) using parallel reaction monitoring
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2019-05-27 | PXD008050 | Pride
Project description:Oxidized LDL induce macrophages to turn into foam cells in a CD36 dependent manner. The Goal of this study is to compare transcriptome profile by RNA-seq among WT/CD36 knockout macrophages treated with or without oxLDL. We detected re-organization of lipid metabolisms as well as immune activation by oxLDL.
2019-10-28 | GSE139439 | GEO
Project description:relative quantification of oxidized lipids in human cell line (fibrosacroma) using parallel reaction monitoring
2022-08-11 | MSV000090108 | GNPS
Project description:Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis. Twelve individual HAEC lines were treated in duplicate (in 35-mm dishes) for 4 h in media containing PAPC (40 μg/ml) or oxidized PAPC (OxPAPC) at 20 ug/ml or 40 μg/ml. Cytoplasmic RNA was isolated by using an RNAeasy kit (Qiagen) and analyzed on an Agilent 2100 Bioanalyzer (Agilent, Palo Alto, CA) to assess RNA integrity. Double-stranded cDNAs were synthesized from total RNA by using the cDNA Synthesis System (Invitrogen, Carlsbad, CA). Biotin-labeled cRNA was generated and used to probe Affymetrix (Santa Clara, CA) Human Genome U133 Plus 2.0 arrays according to the manufacturer’s recommendations (Affymetrix). The Microarray Suite 5.0 software (Affymetrix) was used to analyze image data and make the absolute call for each measurement. The array data were normalized with the median invariant method (31).
2011-06-13 | E-GEOD-29903 | biostudies-arrayexpress
Project description:Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.
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Project description:Postprandial dyslipidemia is a recognized risk factor for atherosclerosis. High-density lipoprotein (HDL)-mediated reverse cholesterol transport plays a crucial role in mitigating this risk by clearing postprandial lipids. This study aimed to investigate the impact of esculetin, a 4-Hydroxycoumarin, on postprandial cholesterol metabolism and excretion after a high-fat meal. Esculetin significantly elevated postprandial HDL cholesterol levels in serum and postprandial bile acid levels in bile, and altered serum metabolomics in mice fed a high-fat meal, indicating esculetin promotes HDL-driven cholesterol excretion after a high-fat meal. Furthermore, esculetin administration in mice led to an increase in the ratio and phagocytic activity of a subset of adipose tissue macrophages (ATMs) expressing high levels of CD36 and Tim4. Inhibition of CD36 by Sulfo-N-succinimidyl oleate (SSO) blocked esculetin-induced elevation of postprandial serum HDL and bile acid levels in bile. Additionally, esculetin demonstrated the ability to increase the uptake of oxidized LDL (ox-LDL) via CD36 in a macrophage cell line, which might involve alteration of the epigenetic landscape controlled by CCAAT enhancer-binding protein beta (C/EBPβ). Esculetin-induced increased uptake of ox-LDL and elevation of CD36 was inhibited in C/EBPβ-deficient cells. A relatively higher expression of C/EBPβ was observed in CD36+ ATMs, and esculetin increased the ratio of C/EBPβ+ CD36+ ATMs in mice fed a lipid-rich meal. Moreover, the direct interaction between esculetin and C/EBPβ were observed by Terahertz chemical microscope. Overall, these findings suggest esculetin promotes HDL-mediated postprandial cholesterol excretion by directly binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.
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