Therapeutic Potential of Targeting the HMGB1/RAGE Axis in Inflammatory Diseases

Abstract

High mobility group box 1 (HMGB1) is a nuclear protein that can interact with a receptor for advanced glycation end-products (RAGE; a multi-ligand immunoglobulin receptor) and mediates the inflammatory pathways that lead to various pathological conditions, such as cancer, diabetes, neurodegenerative disorders, and cardiovascular diseases. Blocking the HMGB1/RAGE axis could be an effective therapeutic approach to treat these inflammatory conditions, which has been successfully employed by various research groups recently. In this article, we critically review the structural insights and functional mechanism of HMGB1 and RAGE to mediate inflammatory processes. More importantly, current perspectives of recent therapeutic approaches utilized to inhibit the communication between HMGB1 and RAGE using small molecules are also summarized along with their clinical progression to treat various inflammatory disorders. Encouraging results are reported by investigators focusing on HMGB1/RAGE signaling leading to the identification of compounds that could be useful in further clinical studies. We highlight the current gaps in our knowledge and future directions for the therapeutic potential of targeting key molecules in HMGB1/RAGE signaling in the pathophysiology of inflammatory diseases.

Keywords: HMGB1; RAGE; TLRs; inflammation; inhibitors.

Figure 2

Active and passive secretion of HMGB1 and its interactions with RAGE, TLR2, and TLR4 to regulate the inflammatory cascade.

Figure 1

(left) Structure of HMGB1 and various ligand binding domains (PDB: 1HME); (right) Structure of full-length RAGE and various ligands that can bind to their respective binding domains (PDBs: 4LP5, 6VXG).

Figure 3

Molecules useful for the treatment of neuro-degenerative disorders acting through the HMGB1/RAGE axis.

Figure 4

Molecules for the treatment of various inflammatory diseases acting via the HMGB1/RAGE axis.