Journal Article

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

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

2019

Overview

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. CXCL4 is an inflammatory chemokine signaling through CXCR3 receptor. Here the authors show a CXCR3-independent function of CXCL4: it forms liquid crystals with DNA, potentiating mammalian and bacterial DNA recognition by TLR9, thereby amplifying interferon-a production in systemic sclerosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/6 / 13 / 13/21 / 13/31 / 14 / 14/19 / 631/250/262/2106/2108 / 631/250/38 / 631/250/98 / 692/4023/1670/122/1801 / Adult / Aged / Amplification / Antigen-antibody complexes / Autoimmune diseases / autoimmunity / BASIC BIOLOGICAL SCIENCES / Biomarkers / Biopsy / Case-Control Studies / Chemokines / Crystal structure / Crystallinity / Crystals / CXCR3 protein / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Deoxyribonucleic acid / DNA / DNA, Bacterial - immunology / DNA, Bacterial - metabolism / Female / Fibrosis / Healthy Volunteers / Humanities and Social Sciences / Humans / Interferon / Interferon-alpha - immunology / Interferon-alpha - metabolism / Liquid Crystals / Male / Microorganisms / Middle Aged / multidisciplinary / Pathogenesis / Platelet Factor 4 - immunology / Platelet Factor 4 - metabolism / Receptors / Receptors, CXCR3 - immunology / Receptors, CXCR3 - metabolism / Science / science & technology - other topics / Science (multidisciplinary) / Scleroderma / Scleroderma, Systemic - immunology / Scleroderma, Systemic - microbiology / Scleroderma, Systemic - pathology / Skin / Skin - cytology / Skin - immunology / Skin - microbiology / Skin - pathology / Systemic sclerosis / TLR9 protein / Toll-Like Receptor 9 - immunology / Toll-Like Receptor 9 - metabolism / Toll-like receptors / Vascular diseases / α-Interferon