von Hippel-Lindau Protein Maintains Metabolic Balance to Regulate the Survival of Naive B Lymphocytes

Xu, Shengli; Huo, Jianxin; Huang, Yuhan; Aw, Melissa; Chen, Shuwen; Mak, Shiya; Yip, Lian Yee; Ho, Ying Swan; Ng, Sze Wai; Tan, Andy Hee-Meng; Lee, Alison; Ou, Xijun; Lam, Kong-Peng

doi:10.1016/j.isci.2019.07.002

Cited by 18 publications

(25 citation statements)

References 46 publications

(56 reference statements)

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“…NK cells were treated with IL-10 in the presence or absence of rapamycin for 16 h as indicated. Real-time analyses of ECAR and OCR of treated and non-treated NK cells were performed using XF-24 Extracellular Flux Analyzer (Seahorse Bioscience) as described previously ( 31 ). Briefly, NK cells were resuspended in XF base and assay medium (Agilent Technologies) for ECAR and OCR analysis, respectively.…”

Section: Methodsmentioning

confidence: 99%

IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling

et al. 2021

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Cell metabolism plays a pivotal role in regulating the effector functions of immune cells. Stimulatory cytokines, such as interleukin (IL)-2 or IL-12 and IL-15, activate glycolysis and oxidative phosphorylation in natural killer (NK) cells to support their enhanced effector functions. IL-10, a pleiotropic cytokine, is known to suppress macrophage activation but stimulate NK cells. However, it remains unclear if IL-10 has an effect on the metabolism of human NK cells and if so, what metabolic mechanisms are affected, and how these metabolic changes are regulated and contribute to the effector functions of NK cells. In this study, we demonstrate that IL-10 upregulates both glycolysis and oxidative phosphorylation in human NK cells, and these metabolic changes are crucial for the enhanced effector functions of NK cells. Mechanistically, we unravel that IL-10 activates the mammalian target of rapamycin complex 1 (mTORC1) to regulate metabolic reprogramming in human NK cells.

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Section: Methodsmentioning

confidence: 99%

IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling

et al. 2021

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“…In accordance, we observed a stabilization of HIF1in DNT B cells at d3 of LPS stimulation under normoxic conditions (Figure 9a, b). The increased HIF1 protein abundance suggested increased reductive decarboxylation of -ketoglutarate to citrate and the generation of long chain acylcarnitines (Xu et al, 2019), but our measurements indicated that citrate was not increased (Figure 8 f, g). Therefore, we reasoned that the driving force of the intact SDH complex II shifts the equilibrium of the TCA cycle away from citrate generated through reductive carboxylation of -ketoglutarate towards the conversion of -ketoglutarate to succinate (see Figure S5 for illustration).…”

Section: The Mitochondrial Respiratory Chain In Plasmablasts Coordinamentioning

confidence: 67%

“…This would increase HIF1 abundance without concomitantly increasing citrate. Since HIF1 normally increases lipid synthesis in B cells via citrate (Xu et al, 2019), de novo lipid biosynthesis should be altered in DNT-expressing B cells.…”

Section: The Mitochondrial Respiratory Chain In Plasmablasts Coordinamentioning

confidence: 99%

“…On the other hand, mature plasma cells depend on glucose uptake for Ab glycosylation and import of pyruvate into mitochondria . The metabolism of mature plasma cells is distinct from resting B cells which primarily consume fatty acids (FA) to support OxPhos in mitochondria (Caro-Maldonado et al, 2014) and depend on continuous degradation of hypoxia inducible factor 1 (HIF1) (Xu et al, 2019). Yet, resting B cells increase OxPhos, glucose uptake and glycolysis when activated by the B cell receptor (BCR) or the innate stimulus lipopolysaccharide (LPS) already within 6h, switching to glucose and glutamine catabolism (Caro-Maldonado et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

Urbanczyk

Baris

Hofmann

et al. 2021

Preprint

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The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1α, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells.

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“…Unlike glomerulonephritis, erythropoietin production may be elevated in RCC [ 94 ] and B cells are not commonly detected in RCC [ 95 ]. These latter inverse manifestations between the diseases may be associated with the differential expression of hypoxic cell signals that induce the production of erythropoietin [ 94 ] and promote B cell apoptosis [ 96 ].…”

Section: Introductionmentioning

confidence: 99%

PD-1 immunobiology in glomerulonephritis and renal cell carcinoma

Curran

Kopp

2021

BMC Nephrol

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Background Programmed cell death protein (PD)-1 receptors and ligands on immune cells and kidney parenchymal cells help maintain immunological homeostasis in the kidney. Dysregulated PD-1:PD-L1 binding interactions occur during the pathogenesis of glomerulopathies and renal cell carcinoma (RCC). The regulation of these molecules in the kidney is important to PD-1/PD-L1 immunotherapies that treat RCC and may induce glomerulopathies as an adverse event. Methods The expression and function of PD-1 molecules on immune and kidney parenchymal cells were reviewed in the healthy kidney, PD-1 immunotherapy-induced nephrotoxicity, glomerulopathies and RCC. Results PD-1 and/or its ligands are expressed on kidney macrophages, dendritic cells, lymphocytes, and renal proximal tubule epithelial cells. Vitamin D3, glutathione and AMP-activated protein kinase (AMPK) regulate hypoxic cell signals involved in the expression and function of PD-1 molecules. These pathways are altered in kidney disease and are linked to the production of vascular endothelial growth factor, erythropoietin, adiponectin, interleukin (IL)-18, IL-23, and chemokines that bind CXCR3, CXCR4, and/or CXCR7. These factors are differentially produced in glomerulonephritis and RCC and may be important biomarkers in patients that receive PD-1 therapies and/or develop glomerulonephritis as an adverse event Conclusion By comparing the functions of the PD-1 axis in glomerulopathies and RCC, we identified similar chemokines involved in the recruitment of immune cells and distinct mediators in T cell differentiation. The expression and function of PD-1 and PD-1 ligands in diseased tissue and particularly on double-negative T cells and parenchymal kidney cells needs continued exploration. The possible regulation of the PD-1 axis by vitamin D3, glutathione and/or AMPK cell signals may be important to kidney disease and the PD-1 immunotherapeutic response.

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von Hippel-Lindau Protein Maintains Metabolic Balance to Regulate the Survival of Naive B Lymphocytes

Cited by 18 publications

References 46 publications

IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling

IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling

Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

PD-1 immunobiology in glomerulonephritis and renal cell carcinoma

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