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

被引：118

作者：

Lande, Roberto ^{[1
]}

Lee, Ernest Y. ^{[2
,3
]}

Palazzo, Raffaella ^{[1
]}

Marinari, Barbara ^{[4
]}

Pietraforte, Immacolata ^{[5
]}

Santos, Giancarlo Santiago ^{[2
,3
]}

Mattenberger, Yves ^{[6
]}

Spadaro, Francesca ^{[7
]}

Stefanantoni, Katia ^{[8
]}

Iannace, Nicoletta ^{[8
]}

Dufour, Aleksandra Maria ^{[9
,10
]}

Falchi, Mario ^{[11
]}

Bianco, Manuela ^{[1
]}

Botti, Elisabetta ^{[4
]}

Bianchi, Luca ^{[4
]}

Alvarez, Montserrat ^{[9
,10
]}

Riccieri, Valeria ^{[8
]}

Truchetet, Marie-Elise ^{[12
,13
]}

Wong, Gerard C. L. ^{[2
,3
]}

Chizzolini, Carlo ^{[9
,10
]}

Frasca, Loredana ^{[1
,9
,10
]}

机构：

[1] ISS, Natl Ctr Drug Res & Evaluat, Pharmacol Res & Expt Therapy UNIT, I-00161 Rome, Italy

[2] Univ Calif Los Angeles, Dept Chem & Biochem, Dept Bioengn, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA

[4] Univ Tor Vergata, Dept Syst Med, Dermatol Unit, I-00133 Rome, Italy

[5] Ist Super Sanita, Dept Oncol & Mol Med, I-00161 Rome, Italy

[6] Univ Geneva, Dept Microbiol & Mol Med, CH-1211 Geneva, Switzerland

[7] Ist Super Sanita, Confocal Microscopy Unit, Core Facil, I-00161 Rome, Italy

[8] Univ Roma La Sapienza, Div Rheumatol Internal Med & Med Specialties, I-00161 Rome, Italy

[9] Univ Hosp & Sch Med, Immunol & Allergy, CH-1211 Geneva, Switzerland

[10] Univ Hosp & Sch Med, Immunol & Pathol, CH-1211 Geneva, Switzerland

[11] Natl AIDS Ctr, Ist Super Sanita, I-00161 Rome, Italy

[12] Univ Hosp, Div Rheumatol, F-33076 Bordeaux, France

[13] Univ Hosp, ImmunoConcept, F-33076 Bordeaux, France

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

瑞士国家科学基金会;

关键词：

PLASMACYTOID DENDRITIC CELLS; I INTERFERON; PROTEOMIC ANALYSIS; POSSIBLE MARKER; SELF; EXPRESSION; CLASSIFICATION; CHEMOKINES; INHIBITOR; INDUCTION;

D O I：

10.1038/s41467-019-09683-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-a 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.

引用

页数：14

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