High-mobility group box 1 protein (HMGB1) in ischaemic heart disease: beneficial or deleterious?

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High-mobility group box 1 (HMGB1; also known as amphoterin) protein was identified more than 30 years ago as a non-chromosomal nuclear protein that maintains the nucleosome structure and regulates gene transcription.¹ HMGB1 is highly conserved among species, has over 98% identity among all mammals, and is ubiquitously expressed in almost all types of cells. HMGB1-deficient mice are viable but die shortly after birth due to hypoglycaemia, suggesting that its nuclear functions are essential for survival. In 1999, Wang et al.² discovered that HMGB1 functions as a delayed mediator in inflammatory responses in sepsis and showed that the inhibition of HMGB1 confers significant protection against the lethal effects of endotoxin, indicating the importance of extracellular HMGB1 in inflammation.

HMGB1 is released into the extracellular milieu by two different routes: passive release from necrotic cells and active secretion from activated innate immune cells such as monocytes and macrophages. In necrotic cells, HMGB1 leaks into the extracellular environment via disrupted plasma membranes. In contrast, apoptotic cells retain chromatin-bound HMGB1. Therefore, HMGB1 is thought to contribute to the inflammation elicited by necrosis. Active secretion of HMGB1 from monocytes or macrophages occurs in response to proinflammatory stimuli, such as lipopolysaccharide, tumour necrosis factor-α, and interleukin-1β. HMGB1 has been reported to transduce its signals by interacting with at least three receptors: receptor for advanced glycation end products (RAGE), Toll-like receptor-2 (TLR2), and TLR4. RAGE signalling induces the activation of the nuclear factor-κB (NF-κB) pathway as well as signal transduction mediated by extracellular-regulated protein kinase-1/2 (ERK1/2) and p38, which promotes cytokine production and cell survival. In contrast, TLR2 and TLR4 signalling activate the NF-κB pathway via a myeloid differentiation primary response protein 88 (MyD88)-dependent mechanism. The recent discovery of extracellular HMGB1 as a proinflammatory mediator has opened up avenues to help study the role of HMGB1 in inflammatory diseases.