Endogenous HMGB1 prevents nuclear catastrophe and proinflammatory nucleosomal release (IRM9P.719)

Abstract

Abstract The mechanisms by which tissue injury alerts the immune system and drives a systemic inflammatory response syndrome remain unknown. Here we identify a high mobility group box 1 (HMGB1)-mediated nuclear regulatory mechanism for the control of the inflammatory response during tissue injury. We show that conditional knockout of HMGB1 within the pancreas, while benign without provocation, rendered mice dramatically more susceptible to experimental acute severe pancreatitis, as manifested by accelerated tissue injury and animal lethality. Deficiency of endogenous pancreatic HMGB1 led to exaggeration of L-arginine-induced nuclear catastrophe and nucleosome release, which then recruited and activated inflammatory cells with subsequent HMGB1 release locally and into the circulation. Serum levels of tissue enzymes (e.g., amylase, lactate dehydrogenase, and pancreatic myeloperoxidase) and pro-inflammatory cytokines were significantly higher in conditional pancreas-specific HMGB1 knockout mice compared to their wild-type control littermates. Moreover, neutralizing extracellular histone and HMGB1 conferred protection against acute pancreatitis in conditional pancreas-specific HMGB1 knockout mice. Thus, intracellular HMGB1 may serve as a previously underappreciated negative regulator of inflammation, shedding light on the role of the innate immune response in infection and tissue damage.