Fig. 11.

Schematic summary of the proposed interactions between UA and HMGB1 and their local and systemic effects. Release of UA by stressed cells activates TLR4 on endothelial cells. Once TLR4 is activated, nuclear HMGB1 becomes acetylated, translocates to the cytoplasm, and is released by mechanisms that are sensitive to blockade by TMB-8, U0126, and EP. Once released, HMGB1 can act as an autocrine signal or as a paracrine signal on distant cells to enhance release of HMGB1, increase exocytosis of Weibel-Palade bodies (WPB) and ANG 2, and increase NF-κB activity.