title: The effect of HMGB1, a damage-associated molecular pattern molecule, on polymorphonuclear neutrophil migration depends on its concentration.
abstract: 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.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872 et Université Paris Descartes, UMR S 872, INSERM, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Berthelot
authors.forename: Lakhdar
authors.initials: L
authors.lastname: Fattoum
authors.forename: Sarah
authors.initials: S
authors.lastname: Casulli
authors.forename: Joël
authors.initials: J
authors.lastname: Gozlan
authors.forename: Vincent
authors.initials: V
authors.lastname: Maréchal
authors.forename: Carole
authors.initials: C
authors.lastname: Elbim
mesh_terms: D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: C508606:CXCL8 protein, human; D024243:HMGB1 Protein; D016209:Interleukin-8; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D009240:N-Formylmethionine Leucyl-Phenylalanine