The mechanism of HMGB1 secretion and release

Abstract

High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA chaperone that maintains the structure and function of chromosomes. In the cytoplasm, HMGB1 can promote autophagy by binding to BECN1 protein. After its active secretion or passive release, extracellular HMGB1 usually acts as a damage-associated molecular pattern (DAMP) molecule, regulating inflammation and immune responses through different receptors or direct uptake. The secretion and release of HMGB1 is fine-tuned by a variety of factors, including its posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, and methylation) and the molecular machinery of cell death (e.g., apoptosis, pyroptosis, necroptosis, alkaliptosis, and ferroptosis). In this minireview, we introduce the basic structure and function of HMGB1 and focus on the regulatory mechanism of HMGB1 secretion and release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases and tissue damage.

The Fatal Circle of NETs and NET-Associated DAMPs Contributing to Organ Dysfunction

“…Partially reduced HMGB1, also termed disulfide-HMGB1, carries a disulfide bond between C23 and C45, and can trigger inflammatory responses [ 111 ]. Once released into the extracellular space, reduced HMGB1 potentiates the inflammatory response through different mechanisms [ 112 , 113 ]. It is able to induce neutrophil recruitment to the site of injury [ 114 ], bind directly to PRRs such as RAGE, TLR2, TLR4, TLR9, and triggering receptor expressed in myeloid cells 1 (TREM1) [ 59 , 62 , 63 , 64 , 65 , 66 ], but also bind to PAMPs such as LPS [ 115 ], DNA [ 116 ] or lipoteichoic acid [ 117 ].…”

“…Following ischemia–reperfusion of the kidney, neutrophils infiltrate the lung, increasing cytokine secretion, and NET formation, which was ameliorated upon PAD4 inhibition, thereby reducing ischemia–reperfusion-consecutive lung injury [ 159 ]. Doi and colleagues [ 160 ] revealed that ALI following AKI depends on HMGB1, which is further underlined by a recently published study demonstrating that acute lung injury following intestinal ischemia–reperfusion depends on HMGB1-induced NET formation, associated with tissue inflammation, and pathological injury in the lung [ 112 , 161 ]. In line with this, histones have detrimental effects on alveolar cells in vitro and in vivo during transfusion-related lung injury [ 75 , 162 ].…”

High Mobility Group Proteins in Sepsis

“…The activity of extracellular HMGB1 is regulated not only by the receptor, but also by its redox state and structure. In addition to the nuclear and extracellular roles of HMGB1, cytoplasmic HMGB1 could bind many proteins involved in autophagy, cancer evolution and unconventional secretory pathways ( 35 ).…”

Schizophrenia Hypothesis: Autonomic Nervous System Dysregulation of Fetal and Adult Immune Tolerance

“…Rather than reducing their immune response to DAMPs over time, their immune system may have a prolonged inflammatory activation by DAMPs such as HMGB1 and therefore release pro-inflammatory cytokines in response to chronic stress (Figure 1). Inflammatory cytokines and LPS also upregulate HMGB1 expression and secretion from macrophages, further increasing circulating HMGB1 (Chen et al, 2022). This may not cause much damage during a short stressful experience, but if a patient is producing pro-inflammatory cytokines such as TNF-α over a long period of chronic stress lasting months or years, it is possible that significant damage could be caused.…”