The effect of HMGB1, a damage-associated molecular pattern molecule, on polymorphonuclear neutrophil migration depends on its concentration

J Innate Immun. 2012;4(1):41-58. doi: 10.1159/000328798. Epub 2011 Aug 19.


Polymorphonuclear neutrophils (PMN) play a key role in host defenses against invading microorganisms but also potentiate inflammatory reactions in case of excessive or misdirected responses. Release of the alarmin high-mobility group box 1 (HMGB1) by cells that die at an inflammatory site may act as an alert signal for the immune system. We studied the effect of HMGB1 on human PMN migration, using whole-blood samples to avoid cell activation associated with isolation procedures. HMGB1 50-100 ng/ml reduced baseline PMN migration as well as formyl-methionyl-leucyl-phenylalanine- and IL-8-induced PMN chemotaxis. This inhibitory effect was mediated by the RAGE receptor. In contrast, a higher HMGB1 concentration (5,000 ng/ml) had a chemoattractant effect on PMN through IL-8 production. This effect required the engagement of Toll-like receptors 2 and 4 in addition to the RAGE receptor. The A box component of HMGB1, which antagonizes the endogenous protein, reduced chemotaxis and also strongly inhibited the enhancement of PMN migration observed with the highest HMGB1 concentration. In contrast, the B box, reported to be the active form of HMGB1, exerted a chemoattractant effect. These results strongly point to a key regulatory role of HMGB1 in PMN recruitment to inflammatory tissues. The A box component could potentially serve to inhibit inappropriate PMN recruitment during chronic inflammatory disorders associated with excessive HMGB1 release.

MeSH terms

  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / immunology*
  • Chronic Disease
  • Dose-Response Relationship, Drug
  • HMGB1 Protein / immunology*
  • HMGB1 Protein / pharmacology
  • Humans
  • Inflammation / immunology
  • Interleukin-8 / immunology
  • Interleukin-8 / pharmacology
  • N-Formylmethionine Leucyl-Phenylalanine / immunology
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 4 / immunology


  • CXCL8 protein, human
  • HMGB1 Protein
  • Interleukin-8
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • N-Formylmethionine Leucyl-Phenylalanine