Glucose metabolism controls disease-specific signatures of macrophage effector functions

Watanabe, Ryu; Hilhorst, Marc; Zhang, Hui; Zeisbrich, Markus; Berry, Gerald J.; Wallis, Barbara B.; Harrison, David G.; Giacomini, John C.; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1172/jci.insight.123047

Cited by 70 publications

(64 citation statements)

References 53 publications

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“…By flow cytometric analysis they confirmed the same difference in surface induction of GLUT1. Serum glucose levels in the CVD group were higher than in the GCA group [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Negative associations for fasting blood glucose, cholesterol and triglyceride levels with the development of giant cell arteritis

et al. 2020

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Objectives To investigate metabolic features that may predispose to GCA in a nested case–control study. Methods Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Preventive Medicine Project; N = 33 346) were identified and validated through a structured review of medical records. Four controls for every validated case were selected from the database. Results A total of 76 cases with a confirmed incident diagnosis of GCA (61% female, 65% biopsy positive, mean age at diagnosis 70 years) were identified. The median time from screening to diagnosis was 20.7 years (range 3.0–32.1). Cases had significantly lower fasting blood glucose (FBG) at baseline screening compared with controls [mean 4.7 vs 5.1 mmol/l (s.d. overall 1.5), odds ratio (OR) 0.35 per mmol/l (95% CI 0.17, 0.71)] and the association remained significant when adjusted for smoking [OR 0.33 per mmol/l (95% CI 0.16, 0.68)]. Current smokers had a reduced risk of GCA [OR 0.35 (95% CI 0.18, 0.70)]. Both cholesterol [mean 5.6 vs 6.0 mmol/l (s.d. overall 1.0)] and triglyceride levels [median 1.0 vs 1.2 mmol/l (s.d. overall 0.8)] were lower among the cases at baseline screening, with significant negative associations with subsequent GCA in crude and smoking-adjusted models [OR 0.62 per mmol/l (95% CI 0.43, 0.90) for cholesterol; 0.46 per mmol/l (95% CI 0.27, 0.81) for triglycerides]. Conclusion Development of GCA was associated with lower FBG and lower cholesterol and triglyceride levels at baseline, all adjusted for current smoking, suggesting that metabolic features predispose to GCA.

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“…By flow cytometric analysis they confirmed the same difference in surface induction of GLUT1. Serum glucose levels in the CVD group were higher than in the GCA group [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Negative associations for fasting blood glucose, cholesterol and triglyceride levels with the development of giant cell arteritis

et al. 2020

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“…Understanding why GCA patients have a defect in PD-L1 expression should yield important insights. PD-L1 expression is dependent on glucose uptake and intracellular glycolytic activity (66,91,92). Large epidemiological studies demonstrate that body mass index and fasting blood glucose levels were negatively associated with the development of GCA (93,94), supporting the concept that low glycolytic activity promotes low PD-L1 expression, enabling uncontrolled autoimmunity.…”

Section: T Cell-dendritic Cell Interactionsmentioning

confidence: 92%

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

et al. 2020

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Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumenstenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.

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“…M1 macrophages use glycolysis as their primary energy source and M2 macrophage use OXPHOS as primary source for long and sustained response [112,113]. increased glucose utilization and cytokine production as compared to healthy controls and GCA patients [114].…”

Section: Monocyte Metabolic Profile/signatures In Autoimmune Diseasesmentioning

confidence: 99%

Metabolic Targets for Treatment of Autoimmune Diseases

2020

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There is a considerable unmet demand for safe and efficacious medications in the realm of autoimmune and inflammatory diseases. The fate of the immune cells is precisely governed by control of various metabolic processes such as mitochondrial oxidative phosphorylation, glycolysis, fatty acid synthesis, beta-oxidation, amino acid metabolism, and several others including the pentose phosphate pathway, which is a unique source of metabolites for cell proliferation and maintenance of a reducing environment. These pathways are tightly regulated by the cytokines, growth factors, availability of the nutrients and host-microbe interaction. Exploring the immunometabolic pathways that govern the fate of cells of the innate and adaptive immune system, during various stages of activation, proliferation, differentiation and effector response, is crucial for new development of new treatment targets. Identifying the pathway connections and key enzymes will help us to target the dysregulated inflammation in autoimmune diseases. The mechanistic target of rapamycin (mTOR) pathway is increasingly recognized as one of the key drivers of proinflammatory responses in autoimmune diseases. In this review, we provide an update on the current understanding of the metabolic signatures noted within different immune cells of many different autoimmune diseases with a focus on selecting pathways and specific metabolites as targets for treatment.

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Glucose metabolism controls disease-specific signatures of macrophage effector functions

Cited by 70 publications

References 53 publications

Negative associations for fasting blood glucose, cholesterol and triglyceride levels with the development of giant cell arteritis

Negative associations for fasting blood glucose, cholesterol and triglyceride levels with the development of giant cell arteritis

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

Metabolic Targets for Treatment of Autoimmune Diseases

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