Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis

J. Xu, Y. Jiang*, J. Wang, X. Shi, Q. Liu, Z. Liu, Y. Li, M. J. Scott, G. Xiao, S. Li, L. Fan, T. R. Billiar, M. A. Wilson, J. Fan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), a highly conserved nuclear protein. Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4, and TLR9. Pyroptosis is a caspase-1-dependent programmed cell death, which features rapid plasma membrane rupture, DNA fragmentation, and release of proinflammatory intracellular contents. Pyroptosis can be triggered by various stimuli, however, the mechanism underlying pyroptosis remains unclear. In this study, we identify a novel pathway of HMGB1-induced macrophage pyroptosis. We demonstrate that HMGB1, acting through RAGE and dynamin-dependent signaling, initiates HMGB1endocytosis, which in turn induces cell pyroptosis. The endocytosis of HMGB1 triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. We further confirm that HMGB1-induced macrophage pyroptosis also occurs in vivo during endotoxemia, suggesting a pathophysiological significance for this form of pyroptosis in the development of inflammation. These findings shed light on the regulatory role of ligand-receptor internalization in directing cell fate, which may have an important role in the progress of inflammation following infection and injury.

Original languageEnglish
Pages (from-to)1229-1239
Number of pages11
JournalCell Death and Differentiation
Issue number8
StatePublished - Aug 2014
Externally publishedYes


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