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

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

doi:10.1038/s41467-019-09683-z

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

Journal Article · 01 May 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-09683-z · OSTI ID:1624151

Lande, Roberto ^[1];

^[2]; Palazzo, Raffaella ^[1]; Marinari, Barbara ^[3]; Pietraforte, Immacolata ^[1]; Santos, Giancarlo Santiago ^[2]; Mattenberger, Yves ^[4]; Spadaro, Francesca ^[1]; Stefanantoni, Katia ^[5]; Iannace, Nicoletta ^[5]; Dufour, Aleksandra Maria ^[6]; Falchi, Mario ^[1]; Bianco, Manuela ^[1]; Botti, Elisabetta ^[3]; Bianchi, Luca ^[3]; Alvarez, Montserrat ^[6]; Riccieri, Valeria ^[5]; Truchetet, Marie-Elise ^[7]; Wong, Gerard C. L. ^[2]; Chizzolini, Carlo ^[6] more »

Istituto Superiore di Sanità, Rome (Italy)
Univ. of California, Los Angeles, CA (United States)
Univ. of Tor Vergata, Rome (Italy)
Univ. of Geneva (Switzerland)
Univ. La Sapienza, Rome (Italy)
Univ. Hospital and School of Medicine, Geneva (Switzerland)
Univ. Hospital, Bordeaux (France)
Istituto Superiore di Sanità, Rome (Italy); Univ. Hospital and School of Medicine, Geneva (Switzerland)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); Swiss National Science Foundation (SNF); Ernst et Lucie Schmidheiny Foundation; Carlos et Elsie De Reuter Foundation; Fondazione Roma; Ricerca Finalizzata; National Institutes of Health (NIH); National Psoriasis Foundation

Grant/Contract Number:: AC02-76SF00515; 310030-159999; CO-2013-02356463; T32GM008185

OSTI ID:: 1624151

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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