Abstract
High-mobility group box 1 (HMGB1) is a leaderless cytokine, like the IL-1 and FGF family members, that has primary roles within the nucleus and the cytosol. Within the nucleus, it serves as another guardian of the genome, protecting it from oxidant injury and promoting access to transcriptional complexes such as nuclear hormone/nuclear hormone receptors and p53/p73 complexes. Within the cytosol it promotes autophagy and recruitment of the myddosome to Toll-like receptor (TLR) 9 vesicular compartments. Outside of the cell, it can either bind to specific receptors itself, or with high affinity to DNA, nucleosomes, IL-1β, lipopolysaccharide, and lipoteichoic acid to mediate responses in specific physiological or pathological conditions. Currently identified receptors include TLR2, TLR4, the receptor for advanced glycation end products, CD24-Siglec G/10, chemokine CXC receptor 4, and TIM-3. In terms of its effects or functions within lymphoid cells, HMGB1 is principally secreted from mature dendritic cells (DCs) to promote T-cell and B-cell reactivity and expansion and from activated natural killer cells to promote DC maturation during the afferent immune response. Some studies suggest that its primary role in the setting of chronic inflammation is to promote immunosuppression. As such, HMGB1 is a central cytokine for all lymphoid cells playing a role complementary to its better studied role in myeloid cells.