Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus

Gina S. Garcia-Romo, Simone Caielli, Barbara Vega, John Connolly, Florence Allantaz, Zhaohui Xu, Marilynn Punaro, Jeanine Baisch, Cristiana Guiducci, Robert L. Coffman, Franck J. Barrat, Jacques Banchereau, Virginia Pascual

Research output: Contribution to journalArticlepeer-review

721 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFN production in this disease.

Original languageEnglish (US)
Article number73ra20
JournalScience translational medicine
Volume3
Issue number73
DOIs
StatePublished - Mar 9 2011

ASJC Scopus subject areas

  • Medicine(all)

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