Tissue damage negatively regulates LPS-induced macrophage necroptosis

Cell Death Differ. 2016 Sep 1;23(9):1428-47. doi: 10.1038/cdd.2016.21. Epub 2016 Mar 4.


Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mφ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mφ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mφ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mφ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alarmins / metabolism
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects*
  • Cells, Cultured
  • Fractures, Bone / metabolism
  • Fractures, Bone / pathology*
  • HMGB1 Protein / metabolism
  • Lipopolysaccharides / toxicity*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Myeloid Differentiation Factor 88 / metabolism
  • Necrosis / physiopathology*
  • Neuroprotective Agents / pharmacology
  • Receptor for Advanced Glycation End Products / metabolism
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Up-Regulation


  • Alarmins
  • Amino Acid Chloromethyl Ketones
  • HMGB1 Protein
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • Neuroprotective Agents
  • Receptor for Advanced Glycation End Products
  • Toll-Like Receptor 4
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone