TY - JOUR
T1 - CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis
AU - Lande, Roberto
AU - Lee, Ernest Y
AU - Palazzo, Raffaella
AU - Marinari, Barbara
AU - Pietraforte, Immacolata
AU - Santos, Giancarlo Santiago
AU - Mattenberger, Yves
AU - Spadaro, Francesca
AU - Stefanantoni, Katia
AU - Iannace, Nicoletta
AU - Dufour, Aleksandra Maria
AU - Falchi, Mario
AU - Bianco, Manuela
AU - Botti, Elisabetta
AU - Bianchi, Luca
AU - Alvarez, Montserrat
AU - Riccieri, Valeria
AU - Truchetet, Marie-Elise
AU - C L Wong, Gerard
AU - Chizzolini, Carlo
AU - Frasca, Loredana
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Biopsy
KW - Case-Control Studies
KW - DNA, Bacterial/immunology
KW - Dendritic Cells/immunology
KW - Female
KW - Healthy Volunteers
KW - Humans
KW - Interferon-alpha/immunology
KW - Liquid Crystals
KW - Male
KW - Middle Aged
KW - Platelet Factor 4/immunology
KW - Receptors, CXCR3/immunology
KW - Scleroderma, Systemic/immunology
KW - Skin/cytology
KW - Toll-Like Receptor 9/immunology
U2 - 10.1038/s41467-019-09683-z
DO - 10.1038/s41467-019-09683-z
M3 - Article
C2 - 31043596
VL - 10
SP - 1731
JO - Nat. Commun.
JF - Nat. Commun.
SN - 2041-1723
IS - 1
ER -