CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis

Roberto Lande, Ernest Y Lee, Raffaella Palazzo, Barbara Marinari, Immacolata Pietraforte, Giancarlo Santiago Santos, Yves Mattenberger, Francesca Spadaro, Katia Stefanantoni, Nicoletta Iannace, Aleksandra Maria Dufour, Mario Falchi, Manuela Bianco, Elisabetta Botti, Luca Bianchi, Montserrat Alvarez, Valeria Riccieri, Marie-Elise Truchetet, Gerard C L Wong, Carlo ChizzoliniLoredana Frasca

Research output: Contribution to journalArticlepeer-review


Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy. CXCL4 represents an early serum biomarker of severe SSc and likely contributes to inflammation via chemokine signaling pathways, but the exact role of CXCL4 in SSc pathogenesis is unclear. Here, we elucidate an unanticipated mechanism for CXCL4-mediated immune amplification in SSc, in which CXCL4 organizes "self" and microbial DNA into liquid crystalline immune complexes that amplify TLR9-mediated plasmacytoid dendritic cell (pDC)-hyperactivation and interferon-α production. Surprisingly, this activity does not require CXCR3, the CXCL4 receptor. Importantly, we find that CXCL4-DNA complexes are present in vivo and correlate with type I interferon (IFN-I) in SSc blood, and that CXCL4-positive skin pDCs coexpress IFN-I-related genes. Thus, we establish a direct link between CXCL4 overexpression and the IFN-I-gene signature in SSc and outline a paradigm in which chemokines can drastically modulate innate immune receptors without being direct agonists.

Original languageEnglish
Pages (from-to)1731
JournalNat. Commun.
Issue number1
Publication statusPublished - May 1 2019


  • Adult
  • Aged
  • Biopsy
  • Case-Control Studies
  • DNA, Bacterial/immunology
  • Dendritic Cells/immunology
  • Female
  • Healthy Volunteers
  • Humans
  • Interferon-alpha/immunology
  • Liquid Crystals
  • Male
  • Middle Aged
  • Platelet Factor 4/immunology
  • Receptors, CXCR3/immunology
  • Scleroderma, Systemic/immunology
  • Skin/cytology
  • Toll-Like Receptor 9/immunology


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