Abstract
SIGNIFICANCE: Inflammation is a complex biological process that represents the body's response to infection and/or injury. Endogenous molecules that induce inflammation are called death- or damage-associated molecular patterns (DAMPs). Among cellular constituents with DAMP activity, nuclear molecules can stimulate pattern recognition receptors, including toll-like receptors (TLRs). Current research is elucidating the translocation of nuclear molecules during cell death and identifying novel anti-inflammatory approaches to block their DAMP activity. RECENT ADVANCES: High mobility group box protein 1 (HMGB1), a non-histone nuclear protein, can translocate from cells during immune cell activation and cell death. Depending on redox state, HMGB1 can interact with TLR4 although it can bind to molecules such as cytokines to trigger other receptors. DNA and histones, which are bound together in the nucleus, also have important immunological activity. For DNA, DAMP activity may vary depending upon the binding to molecules that affect cell entry and intracellular location. The role of nuclear molecules in disease has been established in animal models using antibodies as inhibitors. CRITICAL ISSUES: Key issues about the DAMP activity of nuclear molecules relate to (i) the impact on function of biochemical modifications such as redox state and post-translational modification, and (ii) the composition and properties of complexes that nuclear molecules may form with other blood components to affect immunological activity. FUTURE DIRECTIONS: With the recognition of the immunological activity of the products of dead cells, future studies will define the diversity and properties of nuclear molecules in the extracellular space and develop strategies to block their activity during inflammation.