Cell death in the pathogenesis of immune-mediated diseases: the role of HMGB1 and DAMP-PAMP complexes

Abstract

Cell death is a ubiquitous process whose immunological consequences can influence the course of infectious, autoimmune and inflammatory diseases. While cell death has long been dichotomised in terms of apoptosis and necrosis, other forms of death can occur and they vary in their capacity to stimulate as well as inhibit inflammation. The pro-inflammatory activity of dead cells results from a wide variety of intracellular molecules that are released as cell permeability increases during death. These molecules have been termed as DAMPs (damage associated molecular patterns) or alarmins. Among these DAMPs, HMGB1, a non-histone nuclear protein, serves as the prototype. Although HMGB1 was originally thought to act alone as a cytokine, recent studies suggest that its immunological effects result from complexes of HMGB1 with either other DAMPs or with PAMPs (pathogen associated molecular patterns). Studies on the role of HMGB1 in pathogenesis suggest that the formation of extracellular complexes is an important mechanism for generating pro-inflammatory signals during cell death and therefore could be a potential target of new therapy.

Figure 1

The structure of HMGB1. The figure illustrates the molecular structure of HMGB1, demonstrating the presence of two boxes (A and B) and the C-terminal tail.

Figure 2

The formation of DAMP-PAMP complexes with HMGB1. The figure depicts a model by which HMGB1 can form complexes with DAMPs, PAMPs and cytokines following cell death. During necrosis in the setting of infection, both HMGB1 and DNA (illustrated by the double helix) can exit cells, alone or as a complex. Once in the extracellular milieu, HMGB1 can bind to molecules such as IL-1 and LPS and, depending on its interactions with DNA, can form complexes varying structure and the number of components. The large complex illustrated is hypothetical although experimental data have demonstrated complexes of HMGB1 with DNA, IL-1 and LPS. This model allows the generation of many types of complexes that could vary depending on the components and the stoichiometry. For simplicity, the array of such complexes is not illustrated.