Figure 1.

The effects of high-mobility group box protein 1 (HMGB1) are dependent on complex formation with different ligands. The figure depicts a possible, highly simplified scenario for the mechanisms for the various functions of HMGB1. During initiation of inflammation from infection, the abundant presence of Toll-like receptor (TLR) ligands will induce signaling through TLR, resulting in strong, proinflammatory cytokine production. The limited presence of HMGB1 at this stage will lead to weak signaling through receptor for advanced glycation endproducts (RAGE), thereby inducing only limited cell migration, proliferation, and differentiation. During the expansion phase of inflammation, an increased concentration of HMGB1, released from both activated and dead cells, occurs at the same time that TLR ligands are still present. Immune complexes formed between HMGB1 and TLR ligands can induce signaling through RAGE and TLR receptors in close proximity to each other. This signaling can increase and possibly prolong cytokine production as well as enhance cell migration, proliferation, and differentiation. During the regeneration/repair phase of inflammation, TLR ligands decrease in amount while HMGB1 is still abundant. This situation will cause signaling primarily through RAGE alone, leading to cell migration, proliferation, and differentiation while cytokine production diminishes. The illustration above shows complex formation between HMGB1 and TLR ligands. It is also possible that endogenous, non-TLR signaling, danger molecules can form complexes with HMGB1 and affect HMGB1 function in a similar way. HMGB1 can also enhance cytokine production when complexed to either lipopolysaccharide or interleukin-1β. The scenario described for the regeneration and repair phase of inflammation would also pertain to the function of HMGB1 during nerve sprouting, muscle cell regeneration, and other non-inflammatory circumstances in which the presence of HMGB1 has been described.