Reappraisal of Oxidized HMGB1 As a Mediator and Biomarker

Abstract

HMGB1 is a dual-function protein that acts as a chromatin-binding protein and as a danger-associated molecular pattern (DAMP) when released from activated immune cells or injured tissue. In much of the HMGB1 literature, immunomodulatory effects of extracellular HMGB1 are proposed to depend on its oxidation state. However, many of the foundational studies for this model have been retracted or flagged with expressions of concern. The literature on HMGB1 oxidation reveals a diversity of redox proteoforms of HMGB1 that are inconsistent with current models of redox modulation regulating HMGB1 secretion. A recent study of acetaminophen toxicity has identified previously unrecognized HMGB1 oxidized proteoforms. HMGB1 undergoes oxidative modifications that could serve as pathology-specific biomarkers and drug targets.

Cisplatin Dependent Secretion of Immunomodulatory High Mobility Group Box 1 (HMGB1) Protein from Lung Cancer Cells

“…Using this approach, we were unable to detect acetylation on K-3, K-7, or K-12 residues using a highly specific nanoLC-PRM/HRMS method ( Scheme 1 ). There is also substantial evidence suggesting that HMGB1 NLS1 and NLS2 acetylation is required to facilitate its secretion [ 31 , 32 , 41 , 61 ], although many of the key studies have been retracted or statements of concern issued [ 28 ]. Consequently, it is perhaps not surprising that we were unable to detect any acetylated forms of HMGB1 secreted after treatment of A549 lung cells with cisplatin.…”

“…HMGB1 secretion during the treatment of NSCLC has been reported, although the studies were flawed by the analysis of HMGB1 in serum instead of plasma [ 26 , 27 ]. Regrettably, a significant number of studies of HMGB1 secretion have been conducted using serum instead of plasma [ 28 ] Our study utilizing matched plasma and serum samples from twenty healthy control subjects revealed that HMGB1 is released when blood is allowed to clot and form serum [ 15 ]. The process of clotting led to a substantial 30-fold increase in HMGB1 concentrations, escalating from 0.2 ng/mL in plasma to 6 ng/mL in serum [ 15 ].…”

“…Similarly, secretion of the HMGB1 proteoform with an intramolecular disulfide between Cys-23 and Cys-45 ( Figure 1 ) has been associated with inflammation and oxidative stress, whereas reduced HMGB1 with no intramolecular disulfide bond has been associated with passive release from necrotic cells [ 36 , 37 ]. However, many of the studies supporting this conceptual framework have been discredited or retracted [reviewed in [ 28 ]]. Therefore, we considered that it was important to definitively characterize distinct patterns of HMGB1 PTMs arising from chemotherapy-induced HMGB1 secretion.…”

A Review of Temporomandibular Joint (TMJ) Synovitis and the Important Role of the Nuclear Protein, High Mobility Group Box 1 (HMGB1)

“…However, as TMJ disorders involving traumatic synovitis are usually promoted by sterile inflammation, the biomarkers identified should be similar. 52,53 As targeted biologics, such as anti-HMGB1-mc/pc AB, are being developed to antagonize the actions of proinflammatory cytokines, there is a need to improve these compounds' pharmacokinetics and half-life. To this end, a myriad of drug delivery vehicles are being developed to circumvent the harsh environment that exists in the oral facial area for biotherapeutics.…”

“…However, as TMJ disorders involving traumatic synovitis are usually promoted by sterile inflammation, the biomarkers identified should be similar. 52,53…”