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

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.

C75 Fatty Acid Synthesis (FAS) Inhibitor Has Potent Immunosuppressive Activity

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2156-2156 ◽  
Author(s):  
Vitalyi Senyuk ◽  
Dolores Mahmud ◽  
Annie L. Oh ◽  
Pritesh R. Patel ◽  
Damiano Rondelli
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Fatty Acid ◽  
T Cell ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Nsg Mice ◽  
Human Cd34 ◽  
Cd34 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.

scholarly journals 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

Immunology ◽  
2015 ◽  
Vol 146 (2) ◽  
pp. 292-300 ◽  
Author(s):  
Theodoros Eleftheriadis ◽  
Georgios Pissas ◽  
Georgia Antoniadi ◽  
Vassilios Liakopoulos ◽  
Ioannis Stefanidis
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Cd4 T Cells ◽  
Acid Synthesis ◽  
General Control ◽  
Key Enzymes ◽  
Indoleamine 2,3 Dioxygenase

scholarly journals Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1419 ◽  
Author(s):  
Moris Sangineto ◽  
Rosanna Villani ◽  
Francesco Cavallone ◽  
Antonino Romano ◽  
Domenico Loizzi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Synthesis ◽  
Cell Signalling ◽  
Acid Synthesis ◽  
Environmental Adaptation ◽  
Metabolic Reprogramming ◽  
Therapeutic Approaches

Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death.

scholarly journals Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection

2017 ◽  
Vol 200 (2) ◽  
pp. 643-656 ◽  
Author(s):  
Samad A. Ibitokou ◽  
Brian E. Dillon ◽  
Mala Sinha ◽  
Bartosz Szczesny ◽  
Añahi Delgadillo ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Chronic Infection ◽  
Acid Synthesis ◽  
Effector T Cells ◽  
Early Inhibition

Abstract 46: The Influence of Age and Stroke on Gut Inflammation and Microbiota

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Javiera B Bravo-Alegria ◽  
Pedram Honarpisheh ◽  
Monica Spychala ◽  
Louise D McCullough ◽  
Venugopal R Venna
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
The Elderly ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Γδ T Cell ◽  
Fecal Transplant ◽  
Post Stroke ◽  
Young Mice

Introduction: Earlier work by our laboratory and other groups has identified that aging leads to changes in both the immune system and the microbiome. The elderly have high mortality and more disability after a stroke, a finding that is recapitulated in murine model. Recently, pro-inflammatory γδ T cells have received increasing attention as a major contributor to gut immune responses. These cells may be a link in the bidirectional communication between the microbiome and the central nervous system. We hypothesize that fecal transplant of aged biome into young animals will enhance inflammation, γδ T cell numbers, and worsen functional recovery after stroke in young mice. Methods: Young C57BL/6 male mice, were randomized and subjected to sham surgery/right middle cerebral artery occlusion (MCAO-60min) followed by reperfusion. All mice received streptomycin treatment at 24h and 48h after MCAO. Subsequently, mice were gavaged with biome from either young or aged animals at 72 and 96 h post-stroke. Behavioral and functional outcomes were evaluated. Animals were sacrificed 15 days after stroke. Brain atrophy was quantified, and Flow Cytometry (FACS) and immunohistochemistry was performed on gut tissue and spleen to determine if stroke or the aged biome influence γδ T cells. Results: Young mice transplanted with aged biome take a longer time to regain their pre-stroke body weight. These mice have higher post-stroke hyperactivity compared with mice treated with young biome, as measured by average velocity (p<.006) and total distance traveled (p<.006) in the Open Field. Young mice given aged biome had poorer grip strength, as well as a depressive phenotype, when compared with mice transplanted with young biome. FACS analysis shows higher levels of γδ T cell in the gut with stroke and with fecal transplant of aged biome (sham vs. stroke p=0.0443; young vs. aged biome p=0.0199). Conclusion: Collectively our findings suggests that the gut microbiome plays an important role in post-stroke recovery. Understanding the underlying mechanisms may identify novel therapeutic targets for the treatment of stroke patients.

scholarly journals Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Kensuke Shima ◽  
Inga Kaufhold ◽  
Thomas Eder ◽  
Nadja Käding ◽  
Nis Schmidt ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chlamydia Trachomatis ◽  
Fatty Acid Synthesis ◽  
Tricarboxylic Acid Cycle ◽  
Acid Synthesis ◽  
Tricarboxylic Acid ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Content Type ◽  
Acid Cycle

ABSTRACT Infection with the obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide. Since no vaccine is available to date, antimicrobial therapy is the only alternative in C. trachomatis infection. However, changes in chlamydial replicative activity and the occurrence of chlamydial persistence caused by diverse stimuli have been proven to impair treatment effectiveness. Here, we report the mechanism for C. trachomatis regulating host signaling processes and mitochondrial function, which can be used for chlamydial metabolic reprogramming during treatment with β-lactam antimicrobials. Activation of signal transducer and activator of transcription 3 (STAT3) is a well-known host response in various bacterial and viral infections. In C. trachomatis infection, inactivation of STAT3 by host protein tyrosine phosphatases increased mitochondrial respiration in both the absence and presence of β-lactam antimicrobials. However, during treatment with β-lactam antimicrobials, C. trachomatis increased the production of citrate as well as the activity of host ATP-citrate lyase involved in fatty acid synthesis. Concomitantly, chlamydial metabolism switched from the tricarboxylic acid cycle to fatty acid synthesis. This metabolic switch was a unique response in treatment with β-lactam antimicrobials and was not observed in gamma interferon (IFN-γ)-induced persistent infection. Inhibition of fatty acid synthesis was able to attenuate β-lactam-induced chlamydial persistence. Our findings highlight the importance of the mitochondrion-fatty acid interplay for the metabolic reprogramming of C. trachomatis during treatment with β-lactam antimicrobials. IMPORTANCE The mitochondrion generates most of the ATP in eukaryotic cells, and its activity is used for controlling the intracellular growth of Chlamydia trachomatis. Furthermore, mitochondrial activity is tightly connected to host fatty acid synthesis that is indispensable for chlamydial membrane biogenesis. Phospholipids, which are composed of fatty acids, are the central components of the bacterial membrane and play a crucial role in the protection against antimicrobials. Chlamydial persistence that is induced by various stimuli is clinically relevant. While one of the well-recognized inducers, β-lactam antimicrobials, has been used to characterize chlamydial persistence, little is known about the role of mitochondria in persistent infection. Here, we demonstrate how C. trachomatis undergoes metabolic reprogramming to switch from the tricarboxylic acid cycle to fatty acid synthesis with promoted host mitochondrial activity in response to treatment with β-lactam antimicrobials.

scholarly journals Fatty acid metabolic reprogramming promotes C. elegans development

2021 ◽  
Author(s):  
Xuwen Cao ◽  
Yusu Xie ◽  
Beining Xue ◽  
Hanwen Yang ◽  
L. Rene Garcia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Fast Growth ◽  
Metabolic Reprogramming ◽  
Wild Type ◽  
Fatty Acid Elongase ◽  
C Elegans ◽  
Metabolic Remodeling ◽  
Pharyngeal Muscles

AbstractAcetylcholine signaling has been reported to play essential roles in animal metabolic regulation and disease affected by diets. However, the underlying mechanisms that how diets regulate animal physiology and health are not well understood. Here we found that the acetylcholine receptor gene eat-2 was expressed in most of the pharyngeal muscles, which is in accordance to our previous report that EAT-2 received synaptic signals not only from pharyngeal MC neurons. The expression of fatty acid synthesis genes was significantly increased in both eat-2 and tmc-1 fast-growth mutants on CeMM food environment, compared to the wild-type. Excitingly, dietary fatty acids such as 15-methyl-hexadecanoic acid (C17ISO), palmitic acid (PA, C16:0) and stearic acid (SA, C18:0) supplementation, significantly accelerated wild-type worm development on CeMM, indicating that the fatty acid synthesis reprogramming is an essential strategy for C. elegans to regulate its development and growth on CeMM diet. Furthermore, we found that fatty acid elongase gene elo-6 knock-out significantly attenuated eat-2 mutant’ fast growth, while overexpression of elo-6 could rescue the eat-2; elo-6 double mutant’ slow development, which suggested that elo-6 played a major role in the above metabolic remodeling. Taken together, our report indicates that diets regulate neuromuscular circuit and modulate C. elegans development via fatty acid metabolic reprogramming. As most of the key genes and metabolites found in this study are conserved in both invertebrate and vertebrate animals, we believed that our results might provide essential clues to the molecular mechanisms underlying interactions among animal nutrition sensation, metabolism reprogramming and developmental regulation.Significance StatementDiets and nutritional composition affect animal development and human health, however the underlying mechanisms remain elusive. We demonstrate that the acetylcholine receptor gene eat-2 is expressed in most of pharyngeal muscles, and the expression of fatty acid synthesis genes is significantly increased in both eat-2 and tmc-1 fast-growth mutants on the synthetic chemical defined CeMM food environment. Dietary supplementation of several fatty acids significantly speed up animal development. Furthermore, we demonstrate that the fatty acid elongase gene elo-6 knock-out attenuates eat-2 mutant’ fast growth, and overexpression of wild-type elo-6 promotes the eat-2; elo-6 double mutant’ slow development. Our findings describe that acetylcholine signaling coordinate nutrition sensation and developmental regulation through fatty acid metabolic remodeling.

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