TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus.
The nucleosome is a major autoantigen in systemic lupus erythematosus (SLE); it can be detected as a circulating complex in the serum, and nucleosomes have been suggested to play a key role in disease development. In the present study, we show for the first time that physiological concentrations of purified nucleosomes trigger innate immunity. The nucleosomes are endocytosed and induce the direct activation of human neutrophils (polymorphonuclear leukocytes (PMN)) as revealed by CD11b/CD66b up-regulation, IL-8 secretion, and increased phagocytic activity. IL-8 is a neutrophil chemoattractant detected in high concentrations in the sera of patients, and IL-8 secretion might thus result in enhanced inflammation, as observed in lupus patients, via an amplification loop. Nucleosomes act as free complexes requiring no immune complex formation and independently of the presence of unmethylated CpG DNA motifs. Both normal and lupus neutrophils are sensitive to nucleosome-induced activation, and activation is not due to endotoxin or high-mobility group box 1 contamination. In mice, i.p. injection of purified nucleosomes induces neutrophil activation and recruitment in a TLR2/TLR4-independent manner. Importantly, neutrophils have been suggested to link innate and adaptive immunity. Thus, nucleosomes trigger a previously unknown pathway of innate immunity, which may partially explain why peripheral tolerance is broken in SLE patients.
Rönnefarth
Viktoria M
VM
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, D-72076 Tübingen, Germany.
Erbacher
Annika I M
AI
Lamkemeyer
Tobias
T
Madlung
Johannes
J
Nordheim
Alfred
A
Rammensee
Hans-Georg
HG
Decker
Patrice
P
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004705:Endocytosis / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018375:Neutrophil Activation / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000276:immunology; D009707:Nucleosomes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
D001324:Autoantigens; D039481:CD11b Antigen; D016209:Interleukin-8; D009707:Nucleosomes; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4