An Immunogenic Peptide in the A-box of HMGB1 Reverses Apoptosis-Induced Tolerance Through RAGE [Molecular Bases of Disease]

January 28th, 2014 by LeBlanc, P. M., Doggett, T. A., Choi, J., Hancock, M. A., Durocher, Y., Frank, F., Nagar, B., Ferguson, T. A., Saleh, M.

Apoptotic cells trigger immune tolerance in engulfing phagocytes. This poorly understood process is believed to contribute to the severe immunosuppression and increased susceptibility to nosocomial infections observed in critically ill sepsis patients. Extracellular high-mobility group box 1 (HMGB1) is an important mediator of both sepsis lethality and the induction of immune tolerance by apoptotic cells. We have found that HMGB1 is sensitive to processing by caspase-1, resulting in the production of a fragment within its N-terminal DNA-binding domain (the A-box) that signals through RAGE to reverse apoptosis-induced tolerance. In a two-hit mouse model of sepsis, we show that tolerance to a secondary infection and its associated mortality were effectively reversed by active immunization with DCs treated with HMGB1 or the A-box fragment, but not a non-cleavable form of HMGB1. These findings represent a novel link between caspase-1 and HMGB1, with potential therapeutic implications in infectious and inflammatory diseases.