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TLR2/TLR4-Independent Neutrophil Activation and Recruitment upon Endocytosis of Nucleosomes Reveals a New Pathway of Innate Immunity in Systemic Lupus Erythematosus¹

Viktoria M. Rönnefarth^*, Annika I. M. Erbacher^*, Tobias Lamkemeyer, Johannes Madlung, Alfred Nordheim, Hans-Georg Rammensee^* and Patrice Decker^2,*

^* Department of Immunology and Proteom Center Tübingen, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Deutsche Forschungsgemeinschaft Grant DE 879/1-1, as well as Forschungsprogramm der Tübinger Medizinischen Fakultät fortüne Grant 1451-0-0), and Fritz Thyssen Stiftung Grant Az. 10.03.2.123 (to P.D.). The Proteom Centrum Tübingen is supported by the Ministerium für Wissenschaft und Kunst, Landesregierung Baden-Württemberg.

² Address correspondence and reprint requests to Dr. Patrice Decker, Department of Immunology, Institute for Cell Biology, Auf der Morgenstelle 15, D-72076 Tübingen, Germany. E-mail address: patrice.decker{at}uni-tuebingen.de

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; 7-AAD, 7-aminoactinomycin D; FITC-nucleosomes, FITC-conjugated nucleosomes; HMGB1, high-mobility group box 1; KO, knockout; MS, mass spectrometry; pI, isoelectric point; PMN, polymorphonuclear leukocyte.

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