Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells

Díaz, Fernando Erra; Ochoa, Valeria; Merlotti, Antonela; Dantas, Ezequiel; Mazzitelli, Ignacio; Polo, Virginia Gonzalez; Sabatté, Juan; Amigorena, Sebastián; Ségura, Elodie; Geffner, Jorge

doi:10.1016/j.celrep.2020.107613

Cited by 47 publications

(33 citation statements)

References 98 publications

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“…For comparison, the extracellular pH e of tumors typically ranges from 6.5 to 6.9 74 . Furthermore, extracellular acidification as low as 6.0 can occur during inflammation, which leads to direct effects on the metabolism and differentiation state of immune cells recruited to these acidified microenvironments 75 . Thus, although we do not know if this magnitude of acidification is directly responsible for glycolysis inhibition in this context, the impacts that KG analogs have on glycolysis and respiration occur independently of KG.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters

et al. 2021

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Abstractα-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.

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Section: Discussionmentioning

confidence: 99%

Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters

et al. 2021

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“…Lactic acidosis not only induces the differentiation of monocytes into dendritic cells with an immunosuppressive phenotype [ 61 , 62 ], but also promotes their differentiation into macrophages with an inflammatory protumour phenotype [63] . However, exorbitant lactate levels in the TME may also retard the differentiation of monocytes into dendritic cells [6] .…”

Section: Lactate In the Tmementioning

confidence: 99%

Lactate in the tumour microenvironment: From immune modulation to therapy

et al. 2021

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Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.

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“…When these cells are exposed to transient acidic conditions, they acquire a mature phenotype with an up-regulation of MHC class II molecules and the costimulatory molecules CD40 and CD86, as well as the ability to stimulate the secretion of IFNγ by CD4 + T cells, via the secretion of IL-12p70. By using the culture model of Mo-DC generated from monocytes incubated with M-CSF/TNFα/IL-4, which yields a heterogeneous population of cells including Mo-DC closer to the Mo-DC found in inflammatory fluids of patients, Diaz et al have found that low pH markedly promotes the differentiation of human monocytes into Mo-DC [34]. In these culture conditions and at pH 6.5, most of the cells differentiated into Mo-DC, whereas cells cultured at pH 7.3 differentiated into macrophages.…”

Section: Impact Of the Extracellular Acidosis On The Monocyte-to-dc Transitionmentioning

confidence: 99%

Shaping of Monocyte-Derived Dendritic Cell Development and Function by Environmental Factors in Rheumatoid Arthritis

Coutant

2021

IJMS

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Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In RA, the synovial fluid of patients is enriched by a subset of DC that derive from monocytes (Mo-DC), which promote deleterious Th17 responses. The characterization of environmental factors in the joint that impact on the development and the fate of human Mo-DC is therefore of great importance in RA. When monocytes leave the blood and infiltrate inflamed synovial tissues, the process of differentiation into Mo-DC can be influenced by interactions with soluble factors such as cytokines, local acidosis and dysregulated synoviocytes. Other molecular factors, such as the citrullination process, can also enhance osteoclast differentiation from Mo-DC, favoring bone damages in RA. Conversely, biotherapies used to control inflammation in RA, modulate also the process of monocyte differentiation into DC. The identification of the environmental mediators that control the differentiation of Mo-DC, as well as the underlying molecular signaling pathways, could constitute a major breakthrough for the development of new therapies in RA.

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Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells

Abstract: Highlights d Low pH promotes monocyte differentiation into dendritic cells (mo-DCs) d Low pH inhibits mTORC1 activity d mTORC1 inhibition promotes mo-DC differentiation at neutral pH d mTORC1 inhibition turns GM-CSF into a strong inducer of mo-DC differentiation

Cited by 47 publications

References 98 publications

Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters

Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters

Lactate in the tumour microenvironment: From immune modulation to therapy

Shaping of Monocyte-Derived Dendritic Cell Development and Function by Environmental Factors in Rheumatoid Arthritis

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