scholarly journals SCD2-mediated monounsaturated fatty acid metabolism regulates cGAS-STING-dependent type I IFN responses in CD4+ T cells

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Toshio Kanno ◽  
Takahiro Nakajima ◽  
Satoru Yokoyama ◽  
Hikari K. Asou ◽  
Shigemi Sasamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Biosynthesis ◽  
Antiviral Response ◽  
Monounsaturated Fatty Acid ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Genes ◽  
Important Relationship

AbstractHost lipid metabolism and viral responses are intimately connected. However, the process by which the acquired immune systems adapts lipid metabolism to meet demands, and whether or not the metabolic rewiring confers a selective advantage to host immunity, remains unclear. Here we show that viral infection attenuates the expression of genes related to lipid metabolism in murine CD4+ T cells, which in turn increases the expression of antiviral genes. Inhibition of the fatty acid synthesis pathway substantially increases the basal expression of antiviral genes via the spontaneous production of type I interferon (IFN). Using a combination of CRISPR/Cas9-mediated genome editing technology and a global lipidomics analysis, we found that the decrease in monounsaturated fatty acid caused by genetic deletion of Scd2 in mice was crucial for the induction of an antiviral response through activation of the cGAS-STING pathway. These findings demonstrate the important relationship between fatty acid biosynthesis and type I IFN responses that enhances the antiviral response.

SCD2-mediated monounsaturated fatty acid metabolism regulates cGAS-STING-dependent type I IFN in CD4+ T cells

2021 ◽  
Author(s):  
Toshio Kanno ◽  
Takahiro Nakajima ◽  
Satoru Yokoyama ◽  
Hikari Asou ◽  
Shigemi Sasamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Biosynthesis ◽  
Viral Gene Expression ◽  
Monounsaturated Fatty Acid ◽  
Viral Gene ◽  
Type I ◽  
Type I Ifn ◽  
Viral Response

Abstract Intimate interactions exist between the host lipid metabolism and viral responses. However, how acquired immune systems adapt lipid metabolism to meet demands and whether or not the metabolic rewiring confers a selective advantage in host immunity remains unclear. We found that viral infection attenuated the expression of genes related to lipid metabolism in CD4+ T cells, which in turn increased the anti-viral gene expression. The inhibition of the fatty acid synthesis pathway substantially increased the basal expression of anti-viral genes via the spontaneous production of type I interferon. Using a combination of CRISPR/Cas9-mediated genome editing technology and a global lipidomics analysis, we found that the decreased monounsaturated fatty acid by genetic deletion of Scd2 was crucial for the induction of an anti-viral response through the activation of cGAS-STING pathway. These findings demonstrate the novel relationship between fatty acid biosynthesis and type I IFN responses that enhances the anti-viral response.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals The Matrix Protein of Nipah Virus Targets the E3-Ubiquitin Ligase TRIM6 to Inhibit the IKKε Kinase-Mediated Type-I IFN Antiviral Response

2016 ◽  
Vol 12 (9) ◽  
pp. e1005880 ◽  
Author(s):  
Preeti Bharaj ◽  
Yao E. Wang ◽  
Brian E. Dawes ◽  
Tatyana E. Yun ◽  
Arnold Park ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Matrix Protein ◽  
Nipah Virus ◽  
E3 Ubiquitin Ligase ◽  
Antiviral Response ◽  
Type I ◽  
Type I Ifn ◽  
The Matrix

Polyunsaturated fatty acid biosynthesis in human CD3+ T cells is temporally related to cell activation.

2021 ◽  
Author(s):  
Annette West ◽  
Karen Lilycrop ◽  
Philip Calder ◽  
Barbara Fielding ◽  
Johanna Von Gerichten ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Polyunsaturated Fatty Acid ◽  
Cell Activation ◽  
Fatty Acid Biosynthesis ◽  
Acid Biosynthesis

scholarly journals STING: a master regulator in the cancer-immunity cycle

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuanyuan Zhu ◽  
Xiang An ◽  
Xiao Zhang ◽  
Yu Qiao ◽  
Tongsen Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Negative Effects ◽  
Independent Manner ◽  
Adaptive Immune ◽  
Cancer Immunity

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

scholarly journals Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

2020 ◽  
Vol 117 (51) ◽  
pp. 32433-32442
Author(s):  
Ji-Yoon Lee ◽  
Miso Nam ◽  
Hye Young Son ◽  
Kwangbeom Hyun ◽  
Seo Young Jang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Cancer Cells ◽  
Polyunsaturated Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Intestinal Type ◽  
Biosynthesis Pathway ◽  
Gastric Cancer Cells ◽  
Regulated Necrosis

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

scholarly journals A Lymphotoxin/Type I IFN Axis Programs CD8+T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

2015 ◽  
Vol 195 (10) ◽  
pp. 4650-4659 ◽  
Author(s):  
Dennis Ng ◽  
Blandine Maître ◽  
Derek Cummings ◽  
Albert Lin ◽  
Lesley A. Ward ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Type I ◽  
Type I Ifn

Cyclophosphamide induces type I interferon and augments the number of CD44hi T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2024-2030 ◽  
Author(s):  
Giovanna Schiavoni ◽  
Fabrizio Mattei ◽  
Tiziana Di Pucchio ◽  
Stefano M. Santini ◽  
Laura Bracci ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Adoptive Immunotherapy ◽  
Messenger Rna ◽  
Type I ◽  
Type I Ifn ◽  
Term Survival ◽  
Spleen Lymphocytes

Abstract In a previous study, we reported that a single injection of cyclophosphamide (CTX) in tumor-bearing mice resulted in tumor eradication when the animals were subsequently injected with tumor-sensitized lymphocytes. Notably, CTX acted by inducing bystander effects on T cells, and the response to the combined CTX/adoptive immunotherapy regimen was inhibited in mice treated with antibodies to mouse interferon (IFN)–/β. In the present study, we have investigated whether CTX induced the expression of type I IFN, and we have characterized the CTX effects on the phenotype of T cells in normal mice. CTX injection resulted in an accumulation of type I IFN messenger RNA in the spleen of inoculated mice, at 24 to 48 hours, that was associated with IFN detection in the majority of the animals. CTX also enhanced the expression of the Ly-6C on spleen lymphocytes. This enhancement was inhibited in mice treated with anti–type I IFN antibodies. Moreover, CTX induced a long-lasting increase in in vivo lymphocyte proliferation and in the percentage of CD44hiCD4+ and CD44hiCD8+T lymphocytes. These results demonstrate that CTX is an inducer of type I IFN in vivo and enhances the number of T cells exhibiting the CD44hi memory phenotype. Since type I IFN has been recently recognized as the important cytokine for the in vivo expansion and long-term survival of memory T cells, we suggest that induction of this cytokine may explain at least part of the immunomodulatory effects observed after CTX treatment. Finally, these findings provide a new rationale for combined treatments with CTX and adoptive immunotherapy in cancer patients.

scholarly journals Supplementing Genistein for Breeder Hens Alters the Fatty Acid Metabolism and Growth Performance of Offsprings by Epigenetic Modification

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Zengpeng Lv ◽  
Hao Fan ◽  
Bochen Song ◽  
Guang Li ◽  
Dan Liu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Growth Performance ◽  
Fatty Acid Biosynthesis ◽  
Cholesterol Metabolism ◽  
Epigenetic Modification ◽  
Treated Group ◽  
Control Group ◽  
Histone H4 ◽  
Acyl Coenzyme A

The experiment was designed to clarify the effect and molecular mechanism of maternal genistein (GEN) on the lipid metabolism and developmental growth of offspring chicks. Laying broiler breeder (LBB) hens were supplemented with 40 mg/kg genistein (GEN), while the control group was fed with the low-soybean meal diet. The offspring chicks were grouped according to the mother generation with 8 replicates each. Hepatic transcriptome data revealed 3915 differentially expressed genes (DEGs, P adjusted < 0.05, fold change>1.5 or fold change<0.67) between chicks in the two groups. Maternal GEN activated the GH-IGF1-PI3K/Akt signaling pathway, which promoted the developmental processes and cellular amino acid metabolic processes, as well as inhibited the apoptotic process. GEN treatment significantly increased the weight gain, breast muscle percentage, and liver index in chicks. PANTHER clustering analysis suggested that maternal GEN enhanced the antioxidant activity of chicks by the upregulation of gene (SOD3, MT1, and MT4) expression. Accordingly, the activities of T-AOC and T-SOD in the liver were increased after GEN treatment. The overrepresentation tests revealed that maternal GEN influenced the glycolysis, unsaturated fatty acid biosynthesis, acyl-coenzyme A metabolism, lipid transport, and cholesterol metabolism in the chick livers. Hepatic cholesterol and long-chain fatty acid were significantly decreased after GEN treatment. However, the level of arachidonic acid was higher in the livers of the GEN-treated group compared with the CON group. Moreover, GEN treatment enhanced fatty acid β-oxidation and upregulated PPARδ expression in the chick liver. ChIP-qPCR analysis indicated that maternal GEN might induce histone H3-K36 trimethylation in the promoter region of PPARδ gene (PPARD) through Iws1, methyltransferases. It also induced histone H4-K12 acetylation at the PPARD promoter through MYST2, which activated the PPAR signaling pathways in the chick livers. In summary, supplementing LBB hens with GEN can alter lipid metabolism in the offspring chicks through epigenetic modification and improve the antioxidative capability as well as growth performance.

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