Figure 1

The relationship between HMGB1 release mechanism and HMGB1 isoforms. As this figure illustrates, the various release mechanisms (necrosis, pyroptosis, macrophage activation and apoptosis) can lead to the release of different redox forms of HMGB1. Necrotic cells and pyroptotic cells release the all-thiol or completely reduced form; this form can bind the chemokine CXC12 and signal through the CXCR4 receptor to induce chemotaxis. Pyroptosis, in association with stimulation by a TLR4 ligand, causes release of both fully reduced HMGB1 and HMGB1 with a disulfide bond between C23 and C45 and C106 in the thiol form. This form of HMGB1 can induce cytokine production by signaling through TLR4. Activated macrophages also release the cytokine-inducing form of HMGB1 upon TLT4 activation. Apoptotic cells release HMGB1 that is partially oxidized or completely oxidized at the critical cysteine residues. Completely oxidized HMGB1, with cysteines in the form of sulfonates, is unable to stimulate cytokines or induce chemotaxis; apoptotic cells expressing this form of oxidized HMGB1 can induce tolerance.