Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor

Sharkia, Israa; Erlich, Tal Hadad; Landolina, Nadine; Assayag, Miri; Motzik, Alex; Rachmin, Inbal; Kay, Gillian; Porat, Ziv; Tshori, Sagi; Berkman, Neville; Levi‐Schaffer, Francesca; Razin, Ehud

doi:10.1016/j.jaci.2016.09.047

Cited by 27 publications

(36 citation statements)

References 39 publications

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“…We have previously shown that oxidative phosphorylation (OXPHOS)‐mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase is activated following immunological stimulation of mast cells to produce NADH and FADH2 via the Krebs cycle . These cofactors are necessary for the electron transport chain (ETC), which is positively regulated by mitochondrial signal transducer and activator of transcription 3 (STAT3) during mast cell activation to produce more ATP for the degranulation process …”

Section: Introductionmentioning

confidence: 99%

Modulation of allergic responses by mitochondrial STAT3 inhibitors

Erlich

Sharkia

Landolina

et al. 2018

Allergy

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Section: Introductionmentioning

confidence: 99%

Modulation of allergic responses by mitochondrial STAT3 inhibitors

Erlich

Sharkia

Landolina

et al. 2018

Allergy

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“…Finally, direct inhibition of OXPHOS using rotenone blocked degranulation and lowered IL‐6 production in BMMCs . It is likely that OXPHOS fuelled by glucose oxidation rather than FAO is required for mast cell effector functions, as inhibition of pyruvate dehydrogenase (PDH) with CPI‐613 lowered β‐hexosaminidase release and cytokine production in RBL cells and human cord blood‐derived mast cells , while blockade of FAO using the CTP1a inhibitor etomoxir did not affect mast cell functions . As a whole, these studies suggest that glucose‐fuelled OXPHOS is important for mast cell function.…”

Section: Metabolism Of Cells Involved In the Effector Phase Of Type 2mentioning

confidence: 82%

“…In the same model, blocking the entry of glycolysis‐derived pyruvate into the TCA cycle using CPI‐613 decreased airway resistance, which was associated with a reduction in the release of histamine by mast cells. However, CPI‐613 also promoted the infiltration of eosinophils, macrophages, neutrophils, and lymphocytes into the BAL fluid . Finally, the finding that ILC2s might rely on arginine metabolism for their function sheds interesting new mechanistic light on the long‐appreciated beneficial effects of the arginase inhibitor nor‐NOHA on asthma pathophysiology .…”

Section: Conclusion and Future Perspectivementioning

confidence: 94%

Metabolic control of type 2 immunity

Pelgrom

Everts

2017

Eur J Immunol

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Type 2 immune responses play key roles in protection against parasitic worm infections, whole-body metabolic homeostasis, wound healing, and the development of allergies. As a result, there is considerable interest in understanding the pathways that regulate type 2 immunity in order to identify strategies of targeting and controlling these responses. In recent years, it has become increasingly clear that the functional properties of immune cells, including those involved in type 2 immune responses, are dependent on the engagement of specific metabolic pathways such as aerobic glycolysis and fatty acid oxidation (FAO). We here discuss the latest insights in the metabolic regulation of immune cells that initiate type 2 immune responses, such as dendritic cells and innate lymphoid cells, as well as immune cells involved in the effector phase, like T helper 2 (Th2) cells, B cells and alternatively activated macrophages (M2 macrophages). Finally, we consider whether these findings may provide new prospects for the treatment of type 2 immune response-associated diseases.Keywords: Cellular metabolism r Glycolysis r M2 macrophage r Oxidative phosphorylation r Th2 response r Type 2 immunity IntroductionType 2 immune responses are initiated by dendritic cells (DCs) that promote the differentiation of naïve CD4+ T cells towards a T helper 2 (Th2) phenotype, which is characterized by the production of the prototypical type 2 cytokines: interleukin-4 (IL-4), . In some settings, type 2 innate lymphoid cells (ILC2s) and basophils contribute to this process by also presenting antigens to naïve T cells and by producing type 2 cytokines. IL-4, IL-5, and IL-13 play a central role in driving the humoral and cellular arms of type 2 immunity. IL-4 released in B-cell follicles by a specialized subset of Th2 cells, termed T follicular helper (Tfh) cells, promotes B cells to induce antibody class switching towards immunoglobulin E (IgE) as well as toward IgG4 in humans and IgG1 in mice [2]. Local release of IL-5 at the site of inflammation leads to the recruitment and activation of eosinophils which, similar to basophils and mast cells, release preformed granules with toxic proteins, histamine, and other vasoactive amines upon engagement of their high-affinity IgE receptorsCorrespondence: Dr. Bart Everts e-mail: b.everts@lumc.nl (FC epsilon receptor [FcεR]) by immune complexes of IgE [1]. In addition, these granulocytes produce bio-active lipids such as leukotrienes and prostaglandins, and a wide variety of cytokines. Finally, local release of both IL-4 and IL-13 induces the alternative activation of macrophages (M2 macrophages), a subset of macrophages that is known to assist in the killing of parasites, resolution of inflammation and repair of any tissue damage that has occurred [3]. However, these responses are also the main driver of allergic reactions that result in diseases such as asthma, rhinitis, and atopic dermatitis [1]. Given the vital contributions of each of these cells in the outcome of type 2 immune response-associated d...

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“…Enolase, the ninth enzyme of the glycolytic pathway, has been related with mast cell differentiation, and Chakravarty saw in his studies that treatment with fluoride, an enolase inhibitor, diminished the glucose‐supported histamine release . Moreover, inhibition of pyruvate dehydrogenase (PDH), the clue enzyme for the TCA, inhibits mast cell degranulation and cytokine secretion . These last pieces of evidence indicate a glucose‐depending mast cell function.…”

Section: Metabolism Of Cells At the Tumor Microenvironmentmentioning

confidence: 99%

Metabolism within the tumor microenvironment and its implication on cancer progression: An ongoing therapeutic target

Ocaña

Martínez‐Poveda

Quesada

et al. 2018

Medicinal Research Reviews

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Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment (TME).Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the TME and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that TME is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with

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Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor

Abstract: The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.

Cited by 27 publications

References 39 publications

Modulation of allergic responses by mitochondrial STAT3 inhibitors

Modulation of allergic responses by mitochondrial STAT3 inhibitors

Metabolic control of type 2 immunity

Metabolism within the tumor microenvironment and its implication on cancer progression: An ongoing therapeutic target

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