An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies

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Abstract

HMGB1 (High-Mobility Group Box-1) is a nuclear protein that acts as an architectural chromatin-binding factor involved in the maintenance of nucleosome structure and regulation of gene transcription. It can be released into the extracellular milieu from immune and non-immune cells in response to various stimuli. Extracellular HMGB1 contributes to the pathogenesis of numerous chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), as well as cancer pathogenesis. Interaction of released HMGB1 with the cell-surface receptor for advanced glycation end products (RAGE) is one of the main signaling pathways triggering these diseases. It has been also demonstrated that the inhibition of the HMGB1–RAGE interaction represents a promising approach for the modulation of the inflammatory and tumor-facilitating activity of HMGB1.

In this review we describe various approaches recently proposed in the literature to inhibit HMGB1 and the related inflammatory processes, especially focusing on the block of RAGE–HMGB1 signaling. Several strategies are based on molecules which mainly interact with RAGE as competitive antagonists of HMGB1. As an alternative, encouraging results have been obtained with HMGB1-targeting, leading to the identification of compounds that directly bind to HMGB1, ranging from small natural or synthetic molecules, such as glycyrrhizin and gabexate mesilate, to HMGB1-specific antibodies, peptides, proteins as well as bent DNA-based duplexes. Future perspectives are discussed in the light of the overall body of knowledge acquired by a large number of research groups operating in different but related fields.

Section snippets

HMGB1 protein: physiological and pathological roles

High mobility group box (HMGB) is a family of three nuclear proteins present in mammals including HMGB1, HMGB2 and HMGB3 (Bustin, 1999, Bianchi and Beltrame, 2000). HMGB1 protein was first isolated almost 40 years ago as an abundant non-histone chromatin-associated protein with high electrophoretic mobility (Goodwin et al., 1973, Goodwin and Johns, 1977). Many other functions for this protein, depending on its location and synergizing partners, have been successively discovered. HMGB1 is present

The HMGB1-receptor RAGE

RAGE is a multiligand transmembrane receptor composed of three extracellular immunoglobulin-like domains – one variable-like (V) and two constant-like (C1 and C2) parts – a single transmembrane helix, and a short (41 residues) cytoplasmic tail (Fig. 3), critical for signal transduction (Koch et al., 2010, Park et al., 2010, Borsi et al., 2012). Interactions between RAGE and its ligands are mapped to the V/C1 domain, with the amino-terminal V domain providing the major contribution (Dattilo et

HMGB1 antagonists interacting with RAGE

An efficient strategy to inhibit RAGE–HMGB-1 signaling is based on the use of HMGB1-antagonists. In particular, recombinant box A (the truncated N-terminal domain of HMGB1) efficiently interacts with RAGE, competing with the binding of the full-length protein, but does not activate the receptor, lacking the proinflammatory cytokine activity localized on the B box (Li et al., 2003) (Fig. 4). The A box, as specific antagonist of HMGB1, is thus considered a potential anti-inflammatory agent (

Conclusions and perspectives

HMGB1 contributes to the pathogenesis of several chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), and cancer.

As far as sepsis is concerned, which is the most common cause of death in intensive care units, the syndrome is pathologically mediated by the release of various proinflammatory cytokines, such as the early mediator TNF and the late one HMGB1, from immune cells. Secreted

Dedication

In memory of Dr Silvano Fumero.

Conflict of interest

The authors declare that there are no potential conflicts of interest.

Acknowledgments

We acknowledge MIUR (PRIN protocol n. 2009J54YAP_002) and AIRC, Italian Association for Cancer Research (grant n. 11947) for the financial support.

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