Disulfide High‐Mobility Group Box 1 Drives Ischemia‐Reperfusion Injury in Human Liver Transplantation

Abstract

Background and Aims Sterile inflammation is a major clinical concern during ischemia‐reperfusion injury (IRI) triggered by traumatic events, including stroke, myocardial infarction, and solid organ transplantation. Despite high‐mobility group box 1 (HMGB1) clearly being involved in sterile inflammation, its role is controversial because of a paucity of patient‐focused research. Approach and Results Here, we examined the role of HMGB1 oxidation states in human IRI following liver transplantation. Portal blood immediately following allograft reperfusion (liver flush; LF) had increased total HMGB1, but only LF from patients with histopathological IRI had increased disulfide‐HMGB1 and induced Toll‐like receptor 4–dependent tumor necrosis factor alpha production by macrophages. Disulfide HMGB1 levels increased concomitantly with IRI severity. IRI+ prereperfusion biopsies contained macrophages with hyperacetylated, lysosomal disulfide‐HMGB1 that increased postreperfusion at sites of injury, paralleling increased histone acetyltransferase general transcription factor IIIC subunit 4 and decreased histone deacetylase 5 expression. Purified disulfide‐HMGB1 or IRI+ blood stimulated further production of disulfide‐HMGB1 and increased proinflammatory molecule and cytokine expression in macrophages through a positive feedback loop. Conclusions These data identify disulfide‐HMGB1 as a mechanistic biomarker of, and therapeutic target for, minimizing sterile inflammation during human liver IRI.

Endogenous Interleukin-33 Acts as an Alarmin in Liver Ischemia-Reperfusion and Is Associated With Injury After Human Liver Transplantation

“…High mobility group box 1 (HMGB1), which is generally accepted as the archetype of alarmin, has recently been documented in human LT. Indeed, Sosa et al (39) showed that disulfide HMGB1 levels increased concomitantly with I/R tissue lesions. Further studies are needed to assess the possible association of HMGB1 with general consequences of I/R and to refine its role in predicting graft function recovery compared with IL-33.…”

HMGB1, the Next Predictor of Transcatheter Arterial Chemoembolization for Liver Metastasis of Colorectal Cancer?

“…Due to their stability and specificity in most bodily fluids, HMGB1 provides a high potential to serve as a liquid biopsy tool for some cancers and sterile inflammation ( 18 ). Some researchers performed proteomic analyses to the clinical significance of HMGB1 in serum-purified exosomes from malignant mesothelioma cancer patients and identified it as potential biomarkers in diagnosis and prognosis ( 19 , 20 ).…”

“…HMGB1 plays an important role in the process of ischemia–reperfusion after TACE, and its acetylation and release are mainly regulated by four main modes ( 18 ). Firstly, large amounts of hypoxanthine accumulated converted to xanthine during anaerobic respiration after the interruption of blood supply, and the resulting ROS prompt cells to release acetylated HMGB1 ( 26 , 27 ).…”

Integrated Analysis of Prognostic Genes Associated With Ischemia–Reperfusion Injury in Renal Transplantation

“…Their expression levels were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the mouse RIRI model. Moreover, their roles in renal and other solid organ transplantations (liver and lung) were explored (26)(27)(28). Additionally, we conducted gene set enrichment and single-cell analyses for these novel genes.…”