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Review
. 2010 Mar;9(1):60-72.
doi: 10.2174/187152810791292872.

High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation

Shu Zhu  1 , Wei Li, Mary F Ward, Andrew E Sama, Haichao Wang
Affiliations
Review

High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation

Shu Zhu et al. Inflamm Allergy Drug Targets. 2010 Mar.

Abstract

In response to infection or injury, a ubiquitous nucleosomal protein, HMGB1 is secreted actively by innate immune cells, and / or released passively by injured/damaged cells. Subsequently, extracellular HMGB1 alerts, recruits, and activates various innate immune cells to sustain a rigorous inflammatory response. A growing number of HMGB1 inhibitors ranging from neutralizing antibodies, endogenous hormones, to medicinal herb-derived small molecule HMGB1 inhibitors (such as nicotine, glycyrrhizin, tanshinones, and EGCG) are proven protective against lethal infection and ischemic injury. Here we review emerging evidence that support extracellular HMGB1 as a proinflammatory alarmin(g) danger signal, and discuss a wide array of HMGB1 inhibitors as potential therapeutic agents for sepsis and ischemic injury.

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Conflict of interest statement

Conflict of interest: A.E.S. and H.W. are co-inventors of patent applications related to HMGB1 inhibitors as potential therapeutic agents for sepsis.

Figures

Figure 1
Figure 1. Amino acid sequence of human HMGB1
The N-terminus of HMGB1 comprises two repeats of a positively charged domain of about 80 amino acids (termed HMG box A and B) (shown in box). The cytokine-stimulating motif (“Cytokine Domain”, shown in bold text) does not overlap with its RAGE-binding site (bold textg), supporting the potential involvement of other cell surface receptors (such as TLR4) in HMGB1-mediated inflammatory responses.
Figure 2
Figure 2. Mechanisms underlying the regulation of endotoxin-induced HMGB1 release
The potential involvement of several signaling molecules (receptors and MAP kinases) and proinflammatory mediators in endotoxin-induced HMGB1 release is summarized.
Figure 3
Figure 3. Extracellular HMGB1 functions as an alarmin signal
HMGB1 is actively secreted by innate immune cells and passively released by damaged cells, and orchestrates an inflammatory response by: 1) stimulating cell migration; 2) facilitating innate recognition of bacterial products; 3) activating various innate immune cells; and 4) suppressing phagocytosis of apoptotic cells. Consequently, HMGB1 functions as an alarmin signal to recruit, alert and activate innate immune cells, thereby sustaining potentially injurious inflammatory response during infection or injury.
Figure 4
Figure 4. HMGB1 functions as late of sepsis, but an early mediator of ischemic injury
A). HMGB1 as a late mediator of experimental sepsis. Mice subjected to experimental sepsis (such as cecal ligation and puncture, CLP) succumb at latencies of up to 1–3 days, long after early proinflammatory cytokines (such as TNF) reach plateau levels in the circulation. In contrast, HMGB1 reach peak levels in the circulation in a delayed fashion, which parallels with septic lethality, thereby providing HMGB1 with a wider therapeutic window. B). HMGB1 as an early mediator of ischemic injury. Immediately following ischemic insult, HMGB1 is rapidly released by injured cells, and accumulates in the circulation within a few hours. Consequently, the therapeutic window for HMGB1-targeting strategies is relatively narrower as opposed to experimental sepsis.
See this image and copyright information in PMC

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