High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies

Abstract

High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.

Keywords: HMGB1; cardiovascular diseases; receptor for advanced glycation end products (RAGE); renal dysfunction.

Figure 1

Molecular structure and functional correlation of HMGB1 domains. The Box-A chiefly exhibits anti-HMGB1 effects through specific intradomain regions, regulating heparin binding and proteolytic cleavage. The Box-B chiefly mediates pro-inflammatory functions. The acidic C-terminal regulates DNA-bending capabilities, chromosomal derotation, and the interactive potential of HMGB1 with core and linker histones [1,51,52,53].

Figure 2

Schematic representation of HMGB1-induced signaling cascades culminating to atherosclerosis. Extracellularly released HMGB1 augments expression of cytokines (TNF-α), cell adhesion molecules (ICAM-1 and VCAM-1), and other signaling receptors (RAGE) to induce TNF-α pro-inflammatory signaling, monocyte, macrophage aggregation, NF-κB signaling. HMGB1-induced inflammation and concomitant decrease in anti-coagulant proteins like thrombomodulin lead to atherosclerotic plaque formation [51,53].

Figure 3

HMGB1-associated NF-κB signaling activation, G1 cell cycle arrest, and the augmentation of EMT (via RAGE signaling) culminates to kidney damage, attributing to subsequent renal dysfunctions [51,53].

Figure 4

HMGB1 binds to α-synuclein aggregates in Lewy bodies, inhibits microglial phagocytosis, and upregulates NADPH oxidase levels (chiefly via NF-κB signaling) to mediate neurodegeneration [51,53].

Figure 5

Polyclonal- and monoclonal-antibody-mediated HMGB1 targeting attenuates the onset and progression of varied dysfunctions, viz., arthritis, drug-induced pulmonary fibrosis, hepatic injury, and BBB defects [51,53].

Figure 6

Synthetically derived SMIs, viz., nafamostat mesylate, gabexate mesylate, and silvestat prevent extracellular HMGB1 release, downregulate NF-κB and TNF-α pro-inflammatory signaling, and attenuate vascular inflammation and atherosclerosis progression [51,53,225].