Cells have evolved rather sophisticated mechanisms to deal with stress positively and efficiently. Accumulation of reactive oxygen species (ROS), release of damage-associated molecular pattern molecule (DAMPs), and autophagy induction, are three inter-related processes occurring during most if not all cellular adaptations to stress. They influence each other reciprocally, initiating individual pathways, mediating and/or inducing effector mechanisms and modifying cellular function. High-mobility group box 1 (HMGB1), is a prototypic DAMP molecule, with various roles depending on its compartmental localization (nuclear, cytosolic, extracellular), well-defined but rather promiscuous binding partners, and the redox status within or without the cell. Typically, HMGB1 serves as a redox sensor, where redox modification also defines its translocation, release and activity, illustrative of the coordinate and multiply determined paths involved in the response to cell stress. Since DAMPs, redox and autophagy are essential and multifaceted in their roles in host defense, inflammation, and homeostasis, understanding how they interact and coordinate various signaling pathways to adjust to the stressful environment is important in the development of various potential therapeutic strategies, including application to patients with cancer.

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. References. 1: Hou W, Zhang Q, Yan Z, Chen R, Zeh Iii HJ, Kang R, Lotze MT, Tang D. Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell Death Dis. 2013 Dec 12;4:e966. 2: Rubartelli A, Lotze MT, Latz E, Manfredi A. Mechanisms of sterile inflammation. Front Immunol. 2013 Nov 22;4:398. doi: 10.3389/fimmu.2013.00398. 3: Li G, Tang D, Lotze MT. Ménage à Trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol. 2013 Oct;23(5):380-90. 4: Kang R, Tang D, Schapiro NE, Loux T, Livesey KM, Billiar TR, Wang H, Van Houten B, Lotze MT, Zeh HJ. The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene. 2013 Jan 14. doi: 10.1038/onc.2012.631 5: Tang D, Billiar TR, Lotze MT. A Janus tale of two active high mobility group box 1 (HMGB1) redox states. Mol Med. 2012 Dec 20;18:1360-2. 6: Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012 Sep;249(1):158-75. 7: Kang R, Loux T, Tang D, Schapiro NE, Vernon P, Livesey KM, Krasinskas A, Lotze MT, Zeh HJ 3rd. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc Natl Acad Sci U S A. 2012 May 1;109(18):7031-6. doi: 10.1073/pnas.1113865109 8: Buchser WJ, Laskow TC, Pavlik PJ, Lin HM, Lotze MT. Cell-mediated autophagy promotes cancer cell survival. Cancer Res. 2012 Jun 15;72(12):2970-9. doi: 10.1158/0008-5472.CAN-11-3396. 9: Liang X, De Vera ME, Buchser WJ, Romo de Vivar Chavez A, Loughran P, Beer Stolz D, Basse P, Wang T, Van Houten B, Zeh HJ 3rd, Lotze MT. Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Res. 2012 Jun 1;72(11):2791-801. 10: Weiner LM, Lotze MT. Tumor-cell death, autophagy, and immunity. N Engl J Med. 2012 Mar 22;366(12):1156-8. 11: Livesey KM, Kang R, Vernon P, Buchser W, Loughran P, Watkins SC, Zhang L, Manfredi JJ, Zeh HJ 3rd, Li L, Lotze MT, Tang D. p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res. 2012 Apr 15;72(8):1996-2005. 12: Kang R, Livesey KM, Zeh HJ 3rd, Lotze MT, Tang D. Metabolic regulation by HMGB1-mediated autophagy and mitophagy. Autophagy. 2011 Oct;7(10):1256-8. 13: Tang D, Kang R, Livesey KM, Kroemer G, Billiar TR, Van Houten B, Zeh HJ 3rd, Lotze MT. High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab. 2011 Jun 8;13(6):701-11. 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