HMGB1 is released passively during cellular necrosis by almost all cells which have a nucleus and signals neighboring cells of ongoing damage (25) . However, HMGB1 also is secreted actively by immune cells such as monocytes, macrophages, and dendritic cells (10, 16, 26) . Active secretion of HMGB1 is generally through non-traditional, leaderless pathways which are not routed through the endoplasmic reticulum or Golgi apparatus, similar to IL-1 (27) . During normal cellular homeostasis the dynamic relationship of HMGB1 with the nucleus and cytoplasm heavily favors the nucleus. However, HMGB1 localizes in secretory lysosomes when hyper-acetylated on lysine residues and then is released upon appropriate signaling stimuli (21, 28) . When HMGB1 is not acetylated, it remains localized to the nucleus and is not secreted or released, such as during apoptosis (25) . How the acetylation of HMGB1 is regulated is yet to be determined but is surmised to in-volve deacetylases in the nucleus (16, 21, 29) . In other studies, specifically with TNFα stimulated macrophages, the secretion of HMGB1 is dependent upon phosphorylation (30) . While these modifications are clearly important in the release of HMGB1, it currently is unclear how these specific modifications differ.