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Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.

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Fatty acid oxidation controls CD8+ tissue-resident memory T cell survival in gastric adenocarcinoma

Cancer Immunology Research ◽

10.1158/2326-6066.cir-19-0702 ◽

2020 ◽

pp. canimm.0702.2019 ◽

Cited By ~ 4

Author(s):

Run Lin ◽

Hui Zhang ◽

Yujie Yuan ◽

Qiong He ◽

Jianwen Zhou ◽

...

Keyword(s):

Fatty Acid ◽

T Cell ◽

Cell Survival ◽

Fatty Acid Oxidation ◽

Gastric Adenocarcinoma ◽

Acid Oxidation ◽

Memory T Cell ◽

T Cell Survival

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ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

10.1101/823690 ◽

2019 ◽

Author(s):

Cayla N Rodia ◽

Diana Li ◽

Nicholas S Tambini ◽

Zania K Johnson ◽

Evan R Jellison ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

T Cell ◽

Fatty Acid Oxidation ◽

Lipoprotein Metabolism ◽

Lipid Lowering ◽

Acid Oxidation ◽

List Type ◽

Dss Colitis ◽

Mitochondrial Fatty Acid

AbstractObjectiveCellular metabolism is a key regulator of CD4+Foxp3+ regulatory T cell (Treg) homeostasis, but the foundational studies in this area use free fatty acid treatment as a proxy for plasma triglycerides. In vivo, plasma triglyceride is the main source of fatty acids for cells, not free fatty acids.Design/ResultsUsing apolipoprotein C-III transgenic and LDLr-/- mice, we report that the loss of lipoprotein triglycerides transport in these models results in protection from DSS-colitis and accumulation of intestinal Tregs and plasma IL-10. Total loss of apoC-III increases colitis severity. Tregs exposed to apoC-III increase lipolysis and fatty acid oxidation and apoC-III inhibits Bodipy-triglyceride uptake. Therapeutic treatment of WT mice with apoC-III-containing lipoproteins protects mice from colitis.ConclusionOur data suggest that therapies that reduce apoC-III could have negative effects in patients who are at risk of IBD, and conversely, that apoC-III could be a new therapeutic target to stimulate intestinal Tregs and IL-10 for the management of IBD. These data identify apoC-III and lipoprotein metabolism as a novel regulator of tolerance in the intestine.Summary Box* What is already known about this subject: ▪The relative capacity to use either glucose or FFA to generate acetyl CoA for mitochondrial fatty acid oxidation is a critical driver of Treg and T cell activity and proliferation.▪ApoC-III is a known regulator of triglyceride and fatty acid metabolism in cells via LPL and LDLr endocytosis pathways▪ApoC-III is reduced in Crohn’s and Colitis patients.* What are the new findings: ▪We show that Tregs express triglyceride transporters, and that LDLr expression is enriched in Tregs from the mesenteric lymph nodes.▪We show that T cells are capable of endocytosing triglyceride from lipoproteins, and this process is inhibited by apoC-III.▪Tregs from apoC-IIITg are metabolically unique from WT Tregs and they upregulate the genes of lipolysis, and have an increase in basal respiration.▪The inhibition of TAG endocytosis, using 2 different models (LDLrKO and apoC-III-transgenic mice), protects mice from colitis and stimulates the accumulation of Tregs and IL-10 in the gut.▪Intraperitoneal delivery of apoC-III on chylomicrons protects WT mice from DSS colitis.* How might it impact on clinical practice in the foreseeable future?▪Due to the protective role apoC-III plays in these mouse models of colitis, IBD risk should be carefully considered before prescribing patient anti-apoC-III lipid-lowering therapies.

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136. SPECIFICITY STUDIES ON THE IMMUNOSUPPRESSIVE AND CYTOTOXIC ACTIVITIES OF LYSOPHOSPHATIDYLCHOLINES (LPCs) OF GONADAL ORIGIN

Reproduction Fertility and Development ◽

10.1071/srb09abs136 ◽

2009 ◽

Vol 21 (9) ◽

pp. 55

Author(s):

M. Crane ◽

L. M. Foulds ◽

J. A. Muir ◽

M. P. Hedger

Keyword(s):

Fatty Acid ◽

T Cell ◽

Chain Length ◽

T Cell Activation ◽

Cell Activation ◽

Serum Proteins ◽

Lytic Activity ◽

Cytotoxic Activities ◽

Immunosuppressive Activity ◽

Activated T Cells

The immunosuppressive activity of ovarian follicular fluid and testicular interstitial fluid is due to the presence of several LPCs, but the specificity of this inhibition is a potential source of controversy, as these molecules also possess lytic activity. In the following study, we compared the immunosuppressive and cytotoxic activities of the two most abundant gonadal LPCs, 1-palmitoyl-sn-glycero-3-phosphocholine (16:0aLPC) and 1-oleoyl-sn-glycero-3-phosphocholine (18:1aLPC), together with a number of related lysophospholipids (LPs), using a T-cell activation inhibition assay and an ovarian granulosa cell viability assay. Both the immunosuppressive and cytotoxic activities of the LPCs were blocked by serum (>5%) and serum albumin (>5mg/ml) in vitro. In the absence of serum proteins, the most immunosuppressive LPCs were 16:0aLPC, 18:0aLPC, 18:1aLPC and platelet activating factor (PAF; 1-O-palmitoyl-2-O-acetyl-sn-glycero-3-phosphocholine) with IC50 values of 1.2-4.3 μM. Curiously, PAF was the LPC most cytotoxic to granulosa cells (IC50 10 μM). The other immunosuppressive LPCs exhibited cytotoxicity within the range of 40-50 μM, i.e. at doses 10–50-fold higher than their immunosuppressive concentrations. Comparison of LPs of different structures indicated that optimal immunosuppression is related to a phosphocholine, but not serine, ethanolamine or phosphate group, at sn-3, and an ester- or ether-linked fatty acid of chain length C16-C18 at sn-1. Acetylation of sn-2, as in PAF, had only minor effects on immunosuppressive activity, but greatly increased cytotoxicity. These data establish that inhibition of activated T-cells is not a direct consequence of the cytotoxicity of these molecules, although some structural features that contribute to lytic activity, such as fatty acid chain length, overlap with the ability to confer immunosuppression. On the basis of these data, we propose that the effects of LPCs on T-cell proliferation may not be mediated by a specific lock-and-key receptor, but rather by a direct interaction with the cell membrane at concentrations significantly below their lytic concentrations.

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PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

Nature Communications ◽

10.1038/ncomms7692 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 394

Author(s):

Nikolaos Patsoukis ◽

Kankana Bardhan ◽

Pranam Chatterjee ◽

Duygu Sari ◽

Bianling Liu ◽

...

Keyword(s):

Fatty Acid ◽

T Cell ◽

Fatty Acid Oxidation ◽

Metabolic Reprogramming ◽

Acid Oxidation

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CD28 Regulates Metabolism In Multiple Myeloma For Cell Survival and Proliferation

Blood ◽

10.1182/blood.v122.21.5400.5400 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5400-5400

Author(s):

Adam T Utley ◽

Megan Murray ◽

Louise M Carlson ◽

Matthew R. Farren ◽

Jayakumar R Nair ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Cell Death ◽

Fatty Acid ◽

T Cell ◽

Cell Survival ◽

Fatty Acid Oxidation ◽

Myeloma Cell ◽

Acid Oxidation ◽

Myeloma Cells

Abstract Multiple myeloma is an incurable hematological malignancy of transformed plasma cells. Many cellular interactions and soluble factors have been demonstrated to play a role in myeloma pathogenesis; however, novel targets to enhance therapeutic intervention are needed. We have demonstrated that CD28 signaling in myeloma cells supports their survival during chemotherapeutic challenge in vitro and in vivo. However, the cellular mechanisms by which CD28 confers this survival advantage to myeloma cells are not completely understood. CD28 is best characterized as the canonical T cell co-stimulatory molecule. During T cell activation, CD28 signaling induces glycolysis, a metabolic program required for T cell proliferation and functional maturation. In the absence of glycolysis, T cells utilize fatty acid oxidation for energy production through the mitochondria. However, the way in which CD28 regulates metabolism in multiple myeloma is not well understood. Here we present evidence that CD28 signaling induces glut1 expression, and that poisoning the glycolytic pathway inhibits proliferation and survival of myeloma cells. AMPK, an energy sensitive kinase known to regulate metabolism by driving fatty acid oxidation, is normally activated when cellular energy levels are low. Interestingly, poisoning glycolysis with a glucose analogue that cannot be processed (2DG) leads to AMPK inhibition in myeloma cells. Furthermore, pharmacological activation of AMPK by AICAR, an AMP analogue, is not sufficient to rescue myeloma cell proliferation from glycolytic inhibition and in fact increases cell death (p<.01 from no treatment, p<.05 from 2DG). This evidence suggests that multiple myeloma cells are absolutely dependent upon CD28-mediated glycolysis for proliferation and survival, and that myeloma cells cannot utilize fatty acid oxidation as a subsidiary metabolic pathway for proliferation in the absence of glycolysis. This understanding will allow us to target metabolism in multiple myeloma as a novel therapeutic strategy through pharmacological targeting of the CD28 pathway. This approach can be quickly translated into the clinic, as there are FDA approved drugs which activate AMPK (Metformin) and block CD28 signaling (Abatacept). Disclosures: Off Label Use: Abatacept, purpose to prevent CD28-mediated cell survival in multiple myeloma Metformin, purpose to activate AMPK in driving multiple myeloma cell death.

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