Circulating HMGB1 and RAGE as Clinical Biomarkers in Malignant and Autoimmune Diseases

Abstract

High molecular group box 1 (HMGB1) is a highly conserved member of the HMG-box-family; abundantly expressed in almost all human cells and released in apoptosis; necrosis or by activated immune cells. Once in the extracellular space, HMGB1 can act as a danger associated molecular pattern (DAMP), thus stimulating or inhibiting certain functions of the immune system; depending on the "combinatorial cocktail" of the surrounding milieu. HMGB1 exerts its various functions through binding to a multitude of membrane-bound receptors such as TLR-2; -4 and -9; IL-1 and RAGE (receptor for advanced glycation end products); partly complex-bound with intracellular fragments like nucleosomes. Soluble RAGE in the extracellular space, however, acts as a decoy receptor by binding to HMGB1 and inhibiting its effects. This review aims to outline today's knowledge of structure, intra- and extracellular functions including mechanisms of release and finally the clinical relevance of HMGB1 and RAGE as clinical biomarkers in therapy monitoring, prediction and prognosis of malignant and autoimmune disease.

Keywords: DAMP; HMBG1; RAGE; autoimmune disease; biomarkers; circulation; prognosis; therapy response; tumor.

Figure 1

Origin and functions of sRAGE: sRAGE can derive from alternative splicing or proteolytic cleavage of the outer membrane domain of the full-length transmembrane receptor. In the extracellular space, sRAGE can act as decoy receptor for HMGB1 and other ligands.

Figure 2

Overview: functions of HMGB1 and sRAGE. HMGB1 is released as single molecule during necrosis while it is set free as complex bound to nucleosomes in apoptosis/secondary necrosis. In the extracellular space, HMGB1 binds to various receptors like TLR-2, TLR-4 and RAGE on the surface of macrophages, dendritic cells (DC) and other antigen presenting cells (APC), leading to inhibited fusion of phagosomes and lysosomes within these cells. This, in turn, promotes presentation of phagocyted antigens with effective specific T-cell response. sRAGE derived from alternative splicing or proteolytic cleavage can act as a decoy receptor for HMGB1. As circulating biomarkers, high levels of HMGB1 and low levels of sRAGE correlate with poor prognosis (adapted from [103] with permission from De Gruyter).

Figure 3

Receptors for HMGB1 and following pathways (adapted from [103] with permission from De Gruyter).

Figure 4

Tumor-promoting abilities of HMGB1 (adapted from [103] with permission from De Gruyter).