Topic Overview:
Activation of the innate immune system is fundamental in the antimicrobial response to invading pathogens. However, noninfectious inflammatory insults (e.g., ischemia, surgery, trauma) also engage innate immunity, leading to inflammation and organ injury. While foreign pathogens and their products, pathogen-associated molecular pattern (PAMP) molecules, have been shown to activate the innate immune system, the mechanisms by which damaged tissues “notify” the immune system remain to be fully elucidated. The recognition of a group of endogenous damage-associated molecular pattern (DAMP) molecules, which serve a similar function to PAMPs, has provided a framework for understanding the overlap between the inflammatory responses activated by pathogens and injury. It appears that certain pattern recognition receptors, such as the family of toll-like receptors, serve as a common pathway for immune recognition of microbial invasion and tissue injury. By recognizing either PAMP or DAMP molecules, these receptors alert the host to tissue damage by activating the innate immune system. Initially, this process is manifested by the production of inflammatory mediators, which allow the host to respond appropriately to infectious or noninfectious insults.  When excessive, however, this inflammatory response can contribute to severe organ damage and dysfunction.

High mobility group box-1 (HMGB1) is an evolutionarily conserved protein present in the nucleus of almost all eukaryotic cells, where it stabilizes nucleosomes and acts as a transcription factor. Its proinflammatory properties were highlighted in experiments showing that HMGB1 is actively secreted by activated macrophages, serving as a late mediator of lethality in sepsis models. Whereas HMGB1 is involved in the late systemic inflammatory response to sepsis, Tsung was among the first to demonstrate that HMGB1 is also a central and necessary mediator following “sterile” inflammation, using a model of hepatic ischemia and reperfusion. His studies also point to toll-like receptor-4 as a key surface receptor in HMGB1 recognition following acute liver injury. These findings demonstrate that the release of endogenous HMGB1 is a key link between the initial damage to ischemic cells and the activation of innate immune responses.