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.

Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

“…This fact correlates to the previous information as soluble RAGE acts differently from cellular RAGE preventing immunostimulatory effects rather than promoting them, i.e. functioning as a decoy receptor (34).…”

“…In late tumor stages, high levels of sHMGB1 are associated with poor prognosis due to chronic adaptation. In fact, this would be occurring due to the reason that chronic ICD could lead to adaptation and down-regulation of the immune response, while acute ICD -also induced by some chemotherapeutic agentsleads to immune stimulation and better patient outcome (34).…”

Autologous minced muscle grafts improve endogenous fracture healing and muscle strength after musculoskeletal trauma

“…Beyond the local traumatized skeletal muscle tissue, we interrogated if VML injury heightens systemic immune responses and damps systemic growth factor concentrations in a manner that may potentially deleteriously impact healing of other tissues (e.g., fractured bone); and, whether augmentation of traumatized musculature with minced grafts normalized these responses. As an initial step in provoking a systemic immune response to local tissue trauma, alarmins, such as soluble RAGE and HMGB1, are released from the traumatized tissue and initiates sterile immune responses through binding to TLR4 and RAGE receptor (Magna and Pisetsky ; Pilzweger and Holdenrieder ). OST + VML injury elevated circulating protein levels of soluble RAGE (31%) compared to OST, which returned to OST levels with graft repair of the VML injury (Fig.…”

WONOEP appraisal: Molecular and cellular biomarkers for epilepsy

“…A pilot study in patients with drug‐resistant focal epilepsy suggests that HMGB1 isoforms may be candidate biomarkers for stratification in epilepsy (Walker et al, unpublished data). HMGB1 is, however, by no means specific for epilepsy, and has in fact shown promise as a sensitive and specific biomarker for stratification of subpopulations of patients in many conditions, including autoimmune and malignant diseases …”