Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis.
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.
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Pathophysiology, Southern Medical University, Guangzhou, China.
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J
Xu
Department of Pathophysiology, Southern Medical University, Guangzhou, China.
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Jiang
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Pathophysiology, Southern Medical University, Guangzhou, China.
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J
Wang
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Pharmacology, Medical College of Xi'an Jiaotong University, Xi'an, China.
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Shi
1] Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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Liu
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Pathophysiology, Southern Medical University, Guangzhou, China.
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Liu
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Y
Li
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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MJ
Scott
Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
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Xiao
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
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Li
University of Pittsburgh School of Arts and Science, Pittsburgh, PA, USA.
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Fan
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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Billiar
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
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Wilson
1] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA [3] Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
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Fan
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D014162:Transfection
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products