Triggering the succinate receptor GPR91 on dendritic cells enhances immunity

Rubic, Tina; Lametschwandtner, Günther; Jost, Sandra; Hinteregger, Sonja; Kund, Julia; Carballido‐Perrig, Nicole; Schwärzler, Christoph; Junt, Tobias; Voshol, Hans; Meingassner, Josef G.; Mao, Xiaohong; Werner, Gudrun; Rot, Antal; Carballido, José M.

doi:10.1038/ni.1657

Cited by 402 publications

(452 citation statements)

References 28 publications

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“…A recent study showed that succinate acts as a chemokine, inducing MoDC migration in vitro [8]. DCs treated in the presence of succinate displayed enhanced migration to draining lymph nodes, demonstrating its chemotactic function.…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 98%

“…For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been demonstrated to possess signaling capacity and to influence immunity [4,8,9]. These somewhat surprising findings allow for metabolic changes occurring in inflammatory cells to serve as signals to which cells respond and can contribute to the inflammatory process ( Figure 2).…”

Section: Metabolic Alterations Influence the Immune Responsementioning

confidence: 99%

“…This indicates that succinate has a signaling role beyond HIF-1a stabilization [27,28]. SUCNR1 is highly expressed in mouse kidney, liver, spleen, small intestine [27], and on DCs [8]. The signaling cascade activated by SUCNR1 has only recently emerged [29] (Figure 3).…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

“…Calcium-dependent NO and prostaglandin E2 (PGE2) production was also observed following stimulation of SUCNR1 with succinate. In addition to HEK293 cells, succinate induces calcium mobilization and ERK1/2 phosphorylation in human monocyte-derived DCs (MoDCs) [8], suggesting SUCNR1 signaling is also functional in immune cells.…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

“…Succinate also influences inflammatory cytokine production in DCs. Succinate was found to act in synergy with the TLR3 ligand poly(I:C) and the TLR7 ligand imiquimod, increasing tumor necrosis factor a (TNF-a) production and expression [8]. Furthermore, IL-1b expression was enhanced in murine bone marrow-derived dendritic cells (BMDCs) treated with succinate and LPS simultaneously.…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

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Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

517

445

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 98%

Section: Metabolic Alterations Influence the Immune Responsementioning

confidence: 99%

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

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Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

517

445

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Krebs cycle rewired for macrophage and dendritic cell effector functions

2017

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Edited by Laszlo NagyThe Krebs cycle is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms. In response to proinflammatory stimuli, macrophages and dendritic cells undergo profound metabolic remodelling to support the biosynthetic and bioenergetic requirements of the cell. Recently, it has been discovered that this metabolic shift also involves the rewiring of the Krebs cycle to regulate cellular metabolic flux and the accumulation of Krebs cycle intermediates, notably, citrate, succinate and fumarate. Interestingly, a new role for Krebs cycle intermediates as signalling molecules and immunomodulators that dictate the inflammatory response has begun to emerge. This review will discuss the latest developments in Krebs cycle rewiring and immune cell effector functions, with a particular focus on the regulation of cytokine production.

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Nutritional and metabolic signalling through GPCRs

et al. 2022

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Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and b-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.

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Triggering the succinate receptor GPR91 on dendritic cells enhances immunity

Cited by 402 publications

References 28 publications

Succinate: a metabolic signal in inflammation

Succinate: a metabolic signal in inflammation

Krebs cycle rewired for macrophage and dendritic cell effector functions

Nutritional and metabolic signalling through GPCRs

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