Targeting HMGB1 in inflammation

Abstract

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types, is a necessary and sufficient mediator of inflammation during sterile and infection-associated responses. Elevated levels of HMGB1 in serum and tissues occur during sterile tissue injury and during infection, and targeting HMGB1 with antibodies or specific antagonists is protective in established preclinical inflammatory disease models including lethal endotoxemia or sepsis, collagen-induced arthritis, and ischemia-reperfusion induced tissue injury. Future advances in this field will stem from understanding the biological basis for the success of targeting HMGB1 to therapeutic improvement in the treatment of inflammation, infection and ischemia-reperfusion induced injury.

Fig. 1

Strategies targeting HMGB1 in inflammatory diseases. HMGB1 can be actively secreted by innate immune cells in response to exogenous microbial products from infection; or passively released from injured or necrotic cells. Exogenous HMGB1 can act via receptors (RAGE, TLR2, and TLR4) to stimulate the release of pro-inflammatory cytokines and elicit injurious inflammatory responses. Anti-HMGB1 treatment is beneficial in many preclinical disease models as described in the text by using anti-HMGB1 antibodies, specific HMGB1 antagonist A box, blockade of HMGB1 receptors, or other pharmacological agents partially through targeting HMGB1.