Abstract B08: HMGB1 regulates natural killer (NK) cell metabolism and cross-talk with dendritic cells (DCs)
Authors: Li Guanqiao , Vernon Philip J. , Houten Bennett van , Liang Xiaoyan , Lotze Michael T. 
Published: May 2015

HMGB1 is an evolutionarily ancient, highly abundant and conserved chromatin-associated protein which regulates transcription factor access to DNA in the nucleus. Within the cytosol, it promotes autophagy, and when extracellular promotes chemotaxis and induces inflammation. Under conditions of cellular stress, it translocates to the cytosol where it enhances autophagy and can be actively or passively secreted and serve as a damage associated molecular pattern (DAMP) molecule. HMGB1 is a critical regulator of metabolism in murine embryonic fibroblasts and tumor cells lacking the receptor for advanced glycation endproducts (RAGE) by modulation of autophagy and promotion of mitochondrial quality control. To determine if HMGB1 also plays a role in NK and DC metabolic regulation, NKp46-Cre and CD11c-Cre mice were crossed with HMGB1 flox/flox mice to generate NK- or DC-specific HMGB1-KO mice (NKH and DCH respectively). NK and DC derived from such mice were evaluated for metabolic flux using real time assessment of oxidative phosphorylation (OCR) and glycolysis (ECR) at basal levels and following sequential addition of oligomycin, FCCP, 2-deoxyglucose, and rotenone. DCH demonstrated depressed basal and CD40L-stimulated OCR. NKH cells similarly were significantly less metabolically active in response to IL-2 stimulation. Since HMGB1 secreted from NK cells play a critical role in DC maturation, wildtype DCs were briefly co-cultured with NK cells, markedly increasing their metabolic activity. This was substantially less in DCs cocultured with NKH. These findings suggest that NK HMGB1 enhances DC metabolic activity, promoting NK:DC crosstalk.

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Citation Format: Guanqiao Li, Philip J. Vernon, Bennett van Houten, Xiaoyan Liang, Michael T. Lotze. HMGB1 regulates natural killer (NK) cell metabolism and cross-talk with dendritic cells (DCs). [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B08. doi:10.1158/1538-7445.CHTME14-B08