The nuclear protein HMGB1 is secreted by monocytes via a non‐classical, vesicle‐mediated secretory pathway

Abstract

HMGB1, a non-histone nuclear factor, acts extracellularly as a mediator of delayed endotoxin lethality, which raises the question of how a nuclear protein can reach the extracellular space. We show that activation of monocytes results in the redistribution of HMGB1 from the nucleus to cytoplasmic organelles, which display ultrastructural features of endolysosomes. HMGB1 secretion is induced by stimuli triggering lysosome exocytosis. The early mediator of inflammation interleukin (IL)-1β is also secreted by monocytes through a non-classical pathway involving exocytosis of secretory lysosomes. However, in keeping with their respective role of early and late inflammatory factors, IL-1β and HMGB1 respond at different times to different stimuli: IL-1β secretion is induced earlier by ATP, autocrinally released by monocytes soon after activation; HMGB1 secretion is triggered by lysophosphatidylcholine, generated later in the inflammation site. Thus, in monocytes, non-classical secretion can occur through vescicle compartments that are at least partially distinct.

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

“…2A, lower row). In activated monocytes this phenomenon has been shown to precede secretion of HMGB1 in the extracellular environment [35,52]. We then checked if HMGB1 is (Fig.…”

“…HMGB1 is abundantly expressed in the nuclei of mammalian cells (>10 6 molecules/nucleus), facilitating interaction of chromatin with various nuclear proteins [32,33]. HMGB1 reaches the extracellular environment when monocytes/macrophages actively secrete it following acetylation and transfer to secretory endolysosomal compartments [34][35][36] or by passive release from necrotic cells [37]. Once in the extracellular milieu, HMGB1 has been shown to activate the receptor for advanced glycation end-products (RAGE) [38][39][40] and possibly TLR2 in neutrophils and macrophages [41].…”

High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis

“…HMGB-1 lacks a classic signal sequence, but large amounts of HMGB-1 are released into the extracellular milieu by activated monocyte/macrophages (14). The mechanism of HMGB-1 secretion is largely unknown, but recent evidence suggests that HMGB-1 can be released via cytoplasmic organelles that exhibit features of endolysosomes (15). Following activation with inflammatory stimuli, monocytes can release large amounts of HMGB-1, but only after a lag or delay of 12-16 hours.…”

Successful treatment of collagen‐induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity

“…The interaction of HMGB-1 with RAGE activates several intracellular signal transduction pathways, including mitogenactivated protein kinases, Cdc42, Rac, and a nuclear translocation of nuclear factor B (13), the transcription factor classically linked to inflammatory processes. Stimulated monocyte/macrophages actively secrete HMGB-1 through lysosomal exocytosis (14). The molecule is released as a late mediator during acute inflammation and participates in an important way in the pathogenesis of systemic inflammation in sepsis, after the early mediator response has resolved (9).…”