Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review

Abstract

High mobility group box 1 (HMGB1) is an evolutionarily conserved protein, and is constitutively expressed in virtually all types of cells. Infection and injury converge on common inflammatory responses that are mediated by HMGB1 secreted from immunologically activated immune cells or passively released from pathologically damaged cells. Herein we review the emerging molecular mechanisms underlying the regulation of pathogen-associated molecular patterns (PAMPs)-induced HMGB1 secretion, and summarize many HMGB1-targeting therapeutic strategies for the treatment of infection- and injury-elicited inflammatory diseases. It may well be possible to develop strategies that specifically attenuate damage-associated molecular patterns (DAMPs)-mediated inflammatory responses without compromising the PAMPs-mediated innate immunity for the clinical management of infection- and injury-elicited inflammatory diseases.

Keywords::

• damage-associated molecular patterns
• herbal components
• high mobility group box 1
• infection
• injury
• pathogen-associated molecular patterns
• signaling

Acknowledgements

The authors are grateful to the peer reviewers for their critical and constructive comments.

Financial & competing interests disclosure

Work in the authors’ laboratory was supported by grants from the National Center of Complementary and Alternative Medicine (NCCAM, R01AT005076) and the National Institute of General Medical Sciences (NIGMS, R01GM063075). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Pathogen-associated molecular patterns stimulate immune cells to sequentially release early proinflammatory cytokines and late proinflammatory mediators (e.g., high mobility group box 1 [HMGB1]).

• The secretion of HMGB1 from immunologically activated immune cells is regulated by specific molecular mechanisms: JAK/STAT1 regulates cytoplasmic translocation, and protein kinase R/inflammasomes-dependent pyroptosis regulates cellular secretion.

• HMGB1 can be passively released from necrotic cells following ischemia-reperfusion, trauma and injury; in this context, it is a damage-associated molecular pattern, which orchestrates injury-elicited inflammatory responses by interacting with a family of receptors.

• Early proinflammatory cytokines (e.g., TNF, IFN-β or IFN-γ) also induce a highly regulated cell death process, termed necroptosis, which may contribute to HMGB1 release.

• Extracellular HMGB1 functions as a damage-associated molecular pattern molecule to alert, recruit and activate immune cells, thereby serving as a mediator of lethal infection and injury.

• A number of endogenous macromolecules (e.g., intravenous immunoglobulin, anti-coagulants, acute phase proteins and hormones) have been proven effective in inhibiting HMGB1 release, and protecting against lethal infection and injury.

• Many herbal extracts and components have been proven effective in inhibiting HMGB1 release and protective against lethal infection and injury.

• Different herbal components (e.g., epigallocatechin gallate, tanshinone IIA sodium sulfonate and carbenoxolone) inhibit active HMGB1 secretion through divergently distinct mechanisms, ranging from inducing autophagic degradation, stimulating endocytic uptake, to preventing protein kinase R activation.

• Many agents capable of inhibiting HMGB1 secretion are also proven protective in various animal models of injury, but the protective mechanisms remains poorly elucidated.

Notes