Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury

Abstract

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.

Keywords: LPS; Toll-like receptor; high mobility group box 1; inflammation; sepsis.

Fig. 1. Release of HMGB1 and its intracellular and extracellular function in LPS-mediated infection and sepsis.

LPS uptake into hepatocytes via TLR4 can activate the caspase-11-mediated pathway to stimulate HMGB1 mobilization from the nucleus and release from hepatocytes. Extracellular HMGB1 can deliver LPS to macrophages. Subsequently, endosomal and lysosomal rupture in macrophages leads to the release of HMGB1 and LPS into the cell cytosol and activates caspase-11 and caspase-1 signaling. Consequently, HMGB1 induces a systemic inflammatory response through TNF, IL-1, and IL-6 and triggers cell apoptosis, autophagy, and pyroptosis. LPS lipopolysaccharide, HMGB1 high mobility group box 1, TLR4 Toll-like receptors.