Targeting HMGB1 in Acute Pancreatitis

High Mobility Group Box 1 (HMGB1) is normally a non-histone nuclear protein that acts as a DNA chaperone with DNA binding and bending activity. Besides its intracellular function, extracellular HMGB1 is an inducer, sensor, mediator, and effect or in the innate immune response to infection and sterile inflammation. We recently demonstrated that HMGB1 is an important regulator of the links between local tissue injuries and the systemic inflammatory response in acute pancreatitis. Deficiency of endogenous pancreatic HMGB1 in experimental acute pancreatitis leads to oxidative stress-mediated nuclear catastrophe and nucleosome (including histone and DNA) release, which then recruits and activates macrophages, with subsequent HMGB1 release locally and into the circulation. Neutralizing extracellular histone and HMGB1 protects against acute pancreatitis in conditional pancreas-specific HMGB1 knockout mice. Thus, HMGB1 has a dual role in the pathogenesis of pancreatitis, shedding light on the role of the innate immune response in infection and tissue damage.