Role of oxidative stress on the biology of HMGB1.
Excess ROS/RNS promote cell necrosis, leading to the passive release of intracellular HMGB1 into the extracellular milieu. HMGB1 can interact with multiple molecules, including LPS, DNA, lipoteichoic acid (LPT), and IL-1, to elicit inflammatory responses through distinct TLRs. Alternatively, HMGB1 can undergo various cysteine modifications depending on the local concentrations of oxidants. In the absence of ROS, HMGB1 is in the all thiol conformation, owing to reduced forms of Cys23, Cys45, and Cys106. All thiol HMGB1 interacts with the receptor for advanced glycation end-product (RAGE) to promote autophagic responses, and with the chemokine receptor CXCR4, triggering chemotactic responses. In the presence of increasing amounts of ROS, HMGB1 occurs either in the disulfide conformation (oxidation of Cys23 and Cys45), which targets TLR4 to initiate inflammatory responses, or in the fully oxidized conformation, due to oxidation to sulfonic acid of its three redox active cysteines. This latter form cannot activate inflammatory cells and thus promotes immune tolerance.