Skip to main content
. Author manuscript; available in PMC: 2015 Aug 14.
Published in final edited form as: Annu Rev Immunol. 2011;29:139–162. doi: 10.1146/annurev-immunol-030409-101323

Figure 4.

Figure 4

HMGB1 signals by binding to TLR4 to activate macrophage/monocyte cytokine release (left) and by binding to RAGE to modulate endothelial and tumor cell function (right). In monocytes/macrophages, HMGB1 binds TLR4 in the context of MD2 through a mechanism that requires cysteine in position 106. The addition of dithiothreitol (DTT) to HMGB1 denatures this interaction. HMGB1-TLR4 signaling activates MyD88-dependent nuclear translocation of NF-κB, which upregulates the expression of cytokine and other inflammatory mediators. In endothelial cells and other somatic cells, e.g., tumors and smooth muscle, HMGB1 interacts with RAGE. This signaling, which is not sensitive to DTT, is transduced by mechanisms that are incompletely known but culminate on Cdc42 and Rac. Other binding partners may be required, but RAGE signaling has been implicated in cell growth, differentiation, migration, and expression of cell surface proteins. HMGB1 interaction with CD24 and Siglec-10 can mediate a signal that inhibits activation of NF-κB and prevents cytokine release mediated by HMGB1-TLR4 signaling.