Fig. 6. The control of HMGB1 secretion in professional inflammatory cells. In all cells, including resting inflammatory cells, HMGB1 shuttles between nucleus and cytoplasm; nuclear import is active, and the protein migrates back to the cytoplasm via passive diffusion and CRM1-mediated active export. When HMGB1 is underacetylated, the rate of nuclear import exceeds that of rediffusion plus export, and the protein appears predominantly or solely nuclear. Upon activation of inflammatory cells through binding of IL-1β, TNF-α, LPS or HMGB1 itself to their own receptors, the NF-κB and MAP kinase (MAPK) pathways are activated. Phosphorylated MAPKs migrate to the nucleus, where directly or via adaptor proteins they activate histone acetylases or inhibit deacetylases. This in turn promotes acetylation of HMGB1. Exported acetyl-HMGB1 cannot return to the nucleus. Myeloid cells are equipped with secretory lysosomes, a variety of lysosomes that can be secreted upon appropriate stimulation and that can accumulate IL-1β or HMGB1, presumably through specific transporters embedded in the lysosomal membrane. Upon binding of LPC (an inflammatory lipid) to its own receptor, the secretory lysosomes carrying HMGB1 fuse with the plasma membrane and secrete their cargo.