Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+T cells

Abstract Fatty acid synthesis (FAS) or oxidation (FAO) are important regulatory pathways in immune response. In fact, FAS plays a pivotal role in antigen presentation and T cells activation and FAO leads to fatty acid degradation which has been previously shown to regulate hematopoietic stem cell maintenance. Here we hypothesized that FAS can be a new target to suppress T cell alloimmune responses in solid organ or stem cell transplantations. Therefore, we tested if the FAS inhibitor C75 could suppress T cell alloreactivity without impairing normal hematopoiesis. The immuno-suppressive (IS) effect of moderate FAS inhibition was demonstrated in mixed leukocyte cultures (MLC) where C75 at 10 mkg/ml significantly reduced T cell proliferation and prevented the expansion of CD3+CD25+ and CD3+CD69+ T cells. In T cells stimulated by alloantigen, C75 also induced the downregulation of NF-kB gene expression and the upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene involved in ubiquitination and degradation of NF-kB protein. When compared to other standard IS agents, such as anti-thymocyte globulin (ATG), Cyclosporine A, Rapamycin or inhibitor of FAO Etomoxir, C75 showed similar anti-T cell activity. The same dose of C75 (10 mkg/ml) did not cause apoptotic death of human CD34+ cells in vitro, nor affected CD34+ cell clonogenicity in vitro. In fact, C75 increased the number of BFU-E and CFU-GM colonies (P < 0.05). We observed that the expression of de novo DNA methyltrasferases DNMT3A and DNMT3B, which are important regulators of stem cell renewal, was strongly reduced in CD34+ cells co-cultured for 3 days with allogeneic T cells. On the contrary, in the presence of C75 the expression of DNMT3A and DNMT3B was not different from baseline control. To test the in-vivo effect of C75 we utilized a xenograft model of stem cell rejection where 2 x 105 human CD34+ cells and HLA incompatible T lymphocytes were injected in immunodeficient nonobese diabetic/ltsz-scid/scid - IL2 receptor gamma chain knockout (NSG) mice at 1:1 ratio. Four weeks after transplantation, control NSG mice showed complete rejection of huCD45+CD34+ cells and the expansion of T cells in the marrow and spleen. NSG mice treated with intra-peritoneum injections of C75 every 3 days for 2 weeks, instead, showed 10-15% human CD45+ myeloid cells in the marrow and spleen at week 4 after transplant, suggesting at least a partial effect on preventing rejection of incompatible stem cells. We showed here that moderate FAS inhibition may represent a novel immunosuppressive strategy and our findings will prompt preclinical investigations exploiting the effect of FAS inhibitors alone or in combination with standard IS agents in models of allogeneic transplantation or bone marrow failure. Disclosures No relevant conflicts of interest to declare.

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Study on the Mechanism of Cold Tolerance of the Strain Shewanella putrefaciens WS13 Through Fatty Acid Metabolism

Nanoscience and Nanotechnology Letters ◽

10.1166/nnl.2019.3055 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1718-1723 ◽

Cited By ~ 1

Author(s):

Li Chen ◽

Hao Yu ◽

Shengping Yang ◽

Yunfang Qian ◽

Jing Xie

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Cold Tolerance ◽

Fatty Acid Synthesis ◽

Unsaturated Fatty Acids ◽

Saturated Fatty Acids ◽

Acid Synthesis ◽

Shewanella Putrefaciens ◽

Synthesis Process ◽

Key Enzymes

In order to investigate the cold tolerance mechanism of Shewanella, the whole genome of strain Shewanella putrefaciens WS13 was used to study the comparative genome related to cold tolerance of Shewanella . By comparing and analyzing the key enzymes involved in the process of lipid synthesis with those of other psychrophilic and non-psychrophilic bacteria, the results showed that in S. putrefaciens WS13, the genes fabA, fabB, fabD, fabF, fabG, fabH and fabZ, as the key enzymes of fatty acid synthesis, were found in the target strain, but the gene fabI did not exist in the type II fatty acid synthesis pathway. However, due to the absence of the key enzyme fabI gene, the synthesis process of saturated fatty acids will be blocked, and the pathway of unsaturated fatty acid synthesis still exists, which leads to the bacteria Shewanella start to synthesize a large number of unsaturated fatty acids, thus increasing the synthesis of unsaturated fatty acids and reducing the synthesis of saturated fatty acids. It is precisely because unsaturated fatty acids have lower phase transition temperature than that saturated fatty acids have, which can increase the fluidity of biofilm, so that Shewanella has better cold adaptability than that other bacteria have. It is a complex biological process for microorganisms to adapt to the environment, and the biosynthesis of fatty acids is only one aspect. However, the mechanism of cold adaptation of Shewanella in other aspects remains to be further discussed.

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Regulation of Acetyl-Coenzyme A Carboxylase and Acetyl-Coenzyme A Synthetase in Spinach Chloroplasts

Zeitschrift für Naturforschung C ◽

10.1515/znc-1984-3-412 ◽

1984 ◽

Vol 39 (3-4) ◽

pp. 268-275 ◽

Cited By ~ 23

Author(s):

Andreas Sauer ◽

Klaus-Peter Heise

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthesis ◽

Coenzyme A ◽

Acid Synthesis ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Acetyl Coenzyme A ◽

Key Enzymes ◽

Spinach Chloroplasts ◽

Triton X

In analogy to chloroplast fatty acid synthesis from acetate the key enzymes of acetate fixation, acetyl-CoA synthetase and acetyl-CoA carboxylase, in rapidly Triton X-100 lysed spinach chloroplasts show an activation by light and deactivation in the dark. The stim ulation of acetyl-CoA carboxylase by dithiothreitol in darkened chloroplasts points to an involvement of reducing equivalents in the light activation of this enzyme. But more than by alterations of the activation state per se, these enzymes appear to be effected by changes in their catalytic activity due to differences in the proton-, Mg2+- and adenine nucleotide levels of the chloroplast stroma. Thus the pH dependence of both enzymes, as immediately extracted from Triton X-100 lysed chloroplasts, resembles that recently found for lipid incorporation of acetate into intact spinach chloroplasts in the light with an identical pH optim um of about pH 8.5 for the acetyl-CoA carboxylase. Moreover, in the same extracts both enzyme activities show the already postulated requirement for MgATP and free Mg and are com petitively inhibited by free ATP and ADP with respect to MgATP. But on account of the fact, that the extractable acetyl-CoA synthetase as opposed to the carboxylase activities exceed by far the lipid incorporation rates of acetate by illuminated chloroplasts before disruption, acetyl-CoA synthetase will be excluded as rate limiting step in fatty acid synthesis from acetate. From key enzymes of acetate fixation only the carboxylase appears to be involved therefore in the light regulation of acetate incorporation into long-chain fatty acids

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Indoleamine 2,3-dioxygenase, by degrading L-tryptophan, enhances carnitine palmitoyltransferase I activity and fatty acid oxidation, and exerts fatty acid-dependent effects in human alloreactive CD4+ T-cells

International Journal of Molecular Medicine ◽

10.3892/ijmm.2016.2750 ◽

2016 ◽

Vol 38 (5) ◽

pp. 1605-1613 ◽

Cited By ~ 10

Author(s):

Theodoros Eleftheriadis ◽

Georgios Pissas ◽

Maria Sounidaki ◽

Konstantina Tsogka ◽

Nikolaos Antoniadis ◽

...

Keyword(s):

T Cells ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Cd4 T Cells ◽

Carnitine Palmitoyltransferase ◽

Acid Oxidation ◽

Indoleamine 2,3 Dioxygenase ◽

Carnitine Palmitoyltransferase I

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De Novo Fatty Acid Synthesis During Mycobacterial Infection Is a Prerequisite for the Function of Highly Proliferative T Cells, But Not for Dendritic Cells or Macrophages

Frontiers in Immunology ◽

10.3389/fimmu.2018.00495 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 12

Author(s):

Philipp Stüve ◽

Lucía Minarrieta ◽

Hanna Erdmann ◽

Catharina Arnold-Schrauf ◽

Maxine Swallow ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Mycobacterial Infection ◽

Acid Synthesis

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RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211067133 ◽

2021 ◽

pp. 0271678X2110671

Author(s):

Yueman Zhang ◽

Fengshi Li ◽

Chen Chen ◽

Yan Li ◽

Wanqing Xie ◽

...

Keyword(s):

T Cells ◽

Fatty Acid ◽

T Cell ◽

Fatty Acid Synthesis ◽

Acid Synthesis ◽

Conditional Knockout ◽

Metabolic Reprogramming ◽

Stroke Recovery ◽

Post Stroke ◽

Soluble Rage

The metabolic reprogramming of peripheral CD4+ T cells that occurs after stroke can lead to imbalanced differentiation of CD4+ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4+ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4+ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4+ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4+ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.

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