High-Mobility Group Box 1 Protein Signaling in Painful Diabetic Neuropathy

Abstract

Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment.

HMGB1, the Next Predictor of Transcatheter Arterial Chemoembolization for Liver Metastasis of Colorectal Cancer?

“…Receptor for advanced glycation end products (RAGE) plays a role in tumor metastasis after binding to HMGB1 ( 43 , 44 ). The C-terminus of HMGB1 can specifically bind to RAGE binding, triggering cytoplasmic signaling required for cell movement regulation and opening the molecular switches that control cytoskeletal organization ( 45 ). HMGB1/RAGE cannot only regulate the cytoskeleton to achieve cell movement, but also attract and aggregate other cells, and enhance the ability of cell aggregation and adhesion, which plays an important role in the formation of new collateral circulation after TACE.…”

Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice

“…The clinical pathogenesis underlying diabetic neuropathic pain remains elusive, although several mechanisms have been proposed, including the involvement of hemodynamic factors and thalamic neuronal dysfunction [ 44 , 45 , 46 ]. On the other hand, multiple mechanisms have been proposed in studies using diabetic rodent models, including aldose reductase/AR [ 47 , 48 ], high mobility group box 1/HMGB1- receptor for advanced glycation end-product/RAGE signaling [ 49 , 50 ], protein kinase C/PKC [ 51 , 52 ], poly(ADP-ribose) polymerase/PARP [ 53 , 54 ] and oxidative stress [ 55 , 56 , 57 ]. These are all presumed to play critical roles in the activation through primary sensory neurons and the DRG.…”

The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders

“…Unfortunately, the study of the molecular mechanisms and, specifically, pathogenic mechanisms involving the inflammasome has lagged somewhat behind other complications of diabetes. To date, a handful of articles on the involvement of NLRP3 in some pathophysiological changes and clinical manifestations of diabetic neuropathy are found in the literature [ 153 , 154 , 155 , 156 , 157 ]. Though suggesting a contribution of the TXNIP [ 153 , 154 ], PR2X4 [ 155 ], and HMGB1/TLR4-NLRP3 signaling pathways [ 156 ], these studies do not provide conclusive evidence on the role of NLRP3 in diabetic neuropathy and need to be confirmed in larger controlled studies.…”