Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release

Abstract

Injury can trigger an acute inflammatory response, even in the absence of concomitant infection."Sterile" inflammation is also associated with several types of cancer.Two events are key for the development of sterile inflammation: the recruitment of leukocytes, especially neutrophils and monocytes, and their activation to release proinflammatory cytokines.High-mobility group box 1 (HMGB1) is a nuclear protein that signals tissue damage when released into the extracellular medium, and thus works as a damage-associated molecular pattern (DAMP;Bianchi, 2007).Extracellular HMGB1 can act both as a chemoattractant for leukocytes and as a proinflammatory mediator to induce both recruited leukocytes and resident immune cells to release TNF, IL-1, IL-6, and other cytokines.Notably, immune cells secrete HMGB1 when activated by infection or tissue damage (Andersson and Tracey, 2011); mesothelioma and other cancer cells secrete HMGB1 constitutively (Jube et al., 2012).Recent studies have shown that the proinflammatory cytokine-stimulating activity of HMGB1 depends on the redox state of three cysteines: C23 and C45 must form a disulfide bond within the first HMG-box domain of HMGB1, BoxA, whereas the unpaired C106 within BoxB must be in the thiol state (Yang et al., 2012).