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Abstract Number: 1090

CpG-Stimulated B Cells Require Glutaminolysis for Glycolysis, Mitochondrial Respiration, and Cytokine Production

Matthew Cheung1, Dongyue Huang1, Doujiao Wu2, Edward Pearce3 and Alfred Kim1, 1Rheumatology, Washington University School of Medicine, Saint Louis, MO, 2Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO, 3Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: B cells, cytokines and metabolism

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Session Information

Date: Monday, November 14, 2016

Session Title: B Cell Biology and Targets in Autoimmune Disease - Poster I: SLE and Sjögren's

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  B cells contribute to disease pathophysiology through several mechanisms, including cytokine secretion. A wide variety of stimuli can activate B cells to produce cytokines including B cell receptor and Toll-like receptor engagement. Recently, numerous observations have established the role of metabolic pathways in the diverse array of immune cell functions. It is unknown though how these metabolic pathways influence B cell cytokine production. We sought to elucidate the metabolic programs required for B cell cytokine production.

Methods:  B cells were isolated from the spleens of C57Bl/6J mice and activated overnight individually by the following agents: anti-μ antibody, anti-CD40 agonist antibody, poly(I:C), LPS, loxoribine, and CpG. Supernatants were collected and analyzed for the quantification of cytokines using the Milliplex cytokine kit (EMD Millipore). Real-time analysis of extracellular acidification rates and oxygen consumption rates of activated B cells were performed using the XF-96 Extracellular Flux Analyzer (Seahorse Bioscience). Three or more consecutive measurements were obtained under basal conditions and after the sequential addition of 1 μM oligomycin, to inhibit mitochondrial ATP synthase; 1.5 μM FCCP (fluoro-carbonyl cyanide phenylhydrazone), a protonophore that uncouples ATP synthesis from oxygen consumption by the electron-transport chain; and 100 nM rotenone plus 1 μM antimycin A, which inhibit the electron transport chain. To assess 3-carbon sources for oxidative phosphorylation, inhibitors to fatty acid oxidation (etomoxir, which irreversibly inhibits carnitine palmitoyltransferase-1), pyruvate transfer to mitochondria (UK-5099), and glutamine usage (BPTES, which inhibits mitochondrial glutaminases) were used.

Results:  CpG stimulation of mouse splenic B cells increased both glycolysis and mitochondrial respiration to a larger extent that by other stimuli such as LPS or B cell receptor alone. These processes are highly dependent on glutamine, as inhibition of glutaminolysis with BPTES significantly reduced both processes. Importantly, production of TNF-α, IL-6, and IL-10 by CpG-stimulated B cells also heavily relied on glutaminolysis.

Conclusion: B cells undergo metabolic reprogramming when stimulated with CpG, requiring glutaminolysis. Cytokine production is intrinsically linked with this reprogramming. These data are the among first to demonstrate a relationship between B cell effector function and metabolic reprogramming, and suggest that B cell cytokine secretion can be manipulated by altering the local metabolic environment. Manipulating metabolic pathways may represent an interesting therapeutic approach for modulating B cells in autoimmune diseases.


Disclosure: M. Cheung, None; D. Huang, None; D. Wu, None; E. Pearce, None; A. Kim, Kypha, Inc., 2,Amgen, 5,Janssen Pharmaceutica Product, L.P., 5,Pfizer Inc, 5.

To cite this abstract in AMA style:

Cheung M, Huang D, Wu D, Pearce E, Kim A. CpG-Stimulated B Cells Require Glutaminolysis for Glycolysis, Mitochondrial Respiration, and Cytokine Production [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/cpg-stimulated-b-cells-require-glutaminolysis-for-glycolysis-mitochondrial-respiration-and-cytokine-production/. Accessed February 27, 2021.
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