GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis

Littlewood‐Evans, Amanda; Sarret, Sophie; Apfel, Verena; Loesle, Perrine; Dawson, Janet; Zhang, Juan; Muller, Alban; Tigani, Bruno; Kneuer, Rainer; Patel, Saijel; Valeaux, Stephanie; Gommermann, Nina; Rubic-Schneider, Tina; Junt, Tobias; Carballido, José M.

doi:10.1084/jem.20160061

Cited by 369 publications

(373 citation statements)

References 29 publications

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“…C-AR reduced succinate accumulation by attenuating synovial hypoxia and then inhibited inflammation and fibrosis by preventing NLRP3 inflammasome activation. Consistent with the published studies which show that succinate accumulated in the synovial fluids from RA patients (32, 33), the finding of the role of succinate/NLRP3 inflammation signaling not only provides insight into the connection between inflammation and fibroblast activation but also reveals therapeutic targets for RA treatment. Moreover, our work presented a potential therapeutic strategy for the application of C-AR in the management of RA.…”

Section: Discussionsupporting

confidence: 86%

Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis

Zheng

Liu

et al. 2016

Front. Immunol.

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Clematichinenoside AR (C-AR) is a triterpene saponin isolated from the root of Clematis manshurica Rupr., which is a herbal medicine used in traditional Chinese medicine for the treatment of arthritis. C-AR exerts anti-inflammatory and immunosuppressive properties, but little is known about its action in the suppression of fibroblast activation. Low oxygen tension and transforming growth factor-β (TGF-β1) induction in the synovium contribute to fibrosis in arthritis. This study was designed to investigate the effect of C-AR on synovial fibrosis from the aspects of hypoxic TGF-β1 and hypoxia-inducible transcription factor-1α (HIF-1α) induction. In the synovium of rheumatoid arthritis (RA) rats, hypoxic TGF-β1 induction increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction. In response to NLRP3 inflammasome activation, the released IL-1β further increased TGF-β1 induction, suggesting the forward cycle between inflammation and fibrosis in myofibroblast activation. In the synovium of RA rats, C-AR inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome activation by inhibiting SDH activity, and thereby prevented myofibroblast activation by blocking the cross-talk between inflammation and fibrosis. Taken together, these results showed that succinate worked as a metabolic signaling, linking inflammation with fibrosis through NLRP3 inflammasome activation. These findings suggested that synovial succinate accumulation and HIF-1α induction might be therapeutical targets for the prevention of fibrosis in arthritis.

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Section: Discussionsupporting

confidence: 86%

Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis

Zheng

Liu

et al. 2016

Front. Immunol.

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“…It is tempting to speculate that accumulation of extracellular itaconate, which may occur following macrophage death, could provide an amplification signal to enhance the inflammatory activity of local macrophages. Indeed, a recent study has found that succinate release into the extracellular fluid in a model of antigen-induced arthritis can increase macrophage production of IL-␤, in a GPR91-dependent manner (12).…”

Section: Resultsmentioning

confidence: 99%

Dimethyl Itaconate Is Not Metabolized into Itaconate Intracellularly

El-Azzouny

Tom

Evans

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillItaconic acid is an important metabolite produced by macrophages after stimulation with LPS. the cell culture medium leads to elevated intracellular levels of unlabeled succinate, with no evidence of intracellular uptake. The goal of this study is to encourage the development of effective pro-drug strategies to increase the intracellular levels of itaconate, which will enable more conclusive analysis of its action on macrophages and other cell and tissue types.Itaconic acid is a dicarboxylic acid polar metabolite originally characterized in Aspergillus terreus, but is also produced in mammalian cells (1). After LPS stimulation, itaconic acid is secreted by macrophages, where it can inhibit bacterial cell growth (1). In macrophages, itaconate synthesis is catalyzed by the immune-responsive gene 1 (IRG1) protein, which mediates the decarboxylation of cis-aconitate to itaconate (2). Metabolomic and fluxomic analysis of LPS-stimulated macrophages demonstrated reduced Isocitrate dehydrogenase-1 (IDH1) expression and increased IRG1 expression, resulting in a diversion of citrate from the TCA cycle 2 toward itaconate production (3). This metabolic remodeling results in glutamate serving as the anaplerotic substrate to maintain or elevate succinate levels (3). Moreover, elevated succinate acts as an inflammatory signal that induces secretion of IL-1␤ and stabilization of HIF-1␣ (4). Based on the similarity between itaconate (methylene succinic acid) and succinate, recent investigations have focused on the link between itaconate synthesis and succinate accumulation. Two complementary studies reported that itaconate inhibits succinate dehydrogenase and drives succinate accumulation (5, 6). Studying the role of itaconate requires either lowering its intracellular concentration by using IRG1 knock-out mouse models (5, 6) or increasing its intracellular concentration by using either itaconate (5) or a "cell-permeable" analog, dimethyl itaconate (DMI) (6). However, there is no direct evidence that itaconate or DMI can cross cell membranes and increase intracellular itaconate. Without direct evidence of intracellular delivery, it remains unclear whether itaconate-mediated metabolic and inflammatory effects are induced by increasing intracellular itaconate or by an extracellular mechanism.Here we synthesized isotopically labeled [ 13 C]itaconate and dimethyl [13 C]itaconate ([ 13 C]DMI) to directly profile itaconate metabolism and uptake (Fig. 1). This analysis suggests that exogenous itaconate is not taken up into cells and [13 C]DMI is not metabolized into [13 C]itaconate in bone marrow-derived macrophages. We also report that [13 C]itaconate in the cell culture medium leads to elevated intracellular levels of unlabeled succinate, yet there is no evidence of intracellular uptake. Overall, this study highlights current limitations in intracellular itaconate delivery, and emphasizes the development of effective pro-drug strategies to conclusively define its action on macrophages and other cell and tissue t...

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“…Reflective of the hypermetabolic status of RA Mø, glutamate is enriched in arthritic joints and stimulation of glutamate receptors regulates IL-6 release [60]. Similarly, succinate has been identified as a highly pro-inflammatory mediator [61,62]. GPR91-expressing Mø sense the succinate content in their environment, which triggers inflammasome activation and thus serves as an inflammatory amplification loop.…”

Section: Ra Macrophages – Glucose-intoxicated Hyperinflammatory Effementioning

confidence: 99%

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Weyand

Zeisbrich

Goronzy

2017

Current Opinion in Immunology

117

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In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATPlow, NADPHhigh, ROSlow T-cells hyperproliferate and are forced into premature senescence. ATPhigh, ROShigh macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.

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GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis

Abstract: Littlewood-Evans et al. demonstrate that extracellular succinate leads to the propagation of inflammatory macrophage activation, providing translational evidence to support the development of GPR91 antagonists for the treatment of rheumatoid arthritis.

Cited by 369 publications

References 29 publications

Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis

Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis

Dimethyl Itaconate Is Not Metabolized into Itaconate Intracellularly

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

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