Stimuli for secretion of HMGB1 from immune cells are diverse and include PAMPs, cytokines, and certain states of cellular stress. Macrophages release HMGB1 starting approximately 8 h following exposure to LPS (10,31-33) but do not demonstrate the same response to CpG DNA (34) . It is notable that release due to LPS is dependent, at least partially, on TNFα (31) . HMGB1 also can be released in response to polyinosinicpolycytidylic acid (a model of viral infection) (33, 35) , while in vitro viral stimulation has demonstrated only passive release of HMGB1 due to cytokines or necrotic cells (36) . In addition to these PAMPs that result in the release of HMGB1, endogenous molecules such as cytokines released during other states of injury can result in secretion of HMGB1. While first demonstrated with IFNγ, macrophages also release HMGB1 in response to stimulation with TNFα, IL-1, and oxidative stress (35, (37) (38) (39) (40) . Interestingly, the PAMPs and cytokine stimuli for HMGB1 secretion from macrophages occurs through distinct pathways (35) . For example, while LPS regulates HMGB1 release by hyper-acetylation, TNFα-induced secretion is mediated through phosphorylation, which directs it to the cytoplasm for release (30) .