Format

Send to

Choose Destination
Sci Adv. 2019 Jul 10;5(7):eaav9019. doi: 10.1126/sciadv.aav9019. eCollection 2019 Jul.

Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement-A new target for lupus treatment.

Author information

1
CNRS UMR-8601, CICB, 45 rue des Saints-Pères, 75006 Paris, France.
2
Team Chemistry & Biology, Modeling & Immunology for Therapy, CBMIT, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany.
5
Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
6
INSERM U1223, Paris, France.
7
Computational Biochemistry and Center of Medical Biotechnology, University of Duisburg-Essen, 45141 Essen, Germany.
8
Institute for Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
9
Imagine Institute, Paris, France.
10
Paediatric Haematology-Immunology and Rheumatology Department, Hôpital Universitaire Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.
11
INSERM UMR 1163, Laboratory of Immunogenetics of Paediatric Autoimmunity, Paris, France.
12
Department of Paediatric Dermatology, Reference Centre for Rare Skin Disorders (MAGEC), Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
13
Hôpital Universitaire Robert Debré, Néphrologie pédiatrique, Paris, France.
14
CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Médalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France.
15
Department of Clinical Immunology and Internal Medicine, National Reference Center for Rare Autoimmune Diseases, University Hospital, Strasbourg, France.
16
UFR Medicine, University of Strasbourg, Strasbourg, France.
17
Centre for Translational Research, Institut Pasteur, Paris, France.
18
Pediatric Otolaryngology Department, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
19
Institute of Transfusion Medicine and Immunogenetics (IKT) Ulm, Helmholtzstr. 10, 89081 Ulm, Germany.
20
INSERM U1016, Institut Cochin, Paris, France.
21
CNRS UMR 8104, Paris, France.
22
IRIM, Université de Montpellier, CNRS UMR, 9004 Montpellier, France.

Abstract

Type I interferons are highly potent cytokines essential for self-protection against tumors and infections. Deregulations of type I interferon signaling are associated with multiple diseases that require novel therapeutic options. Here, we identified the small molecule, IT1t, a previously described CXCR4 ligand, as a highly potent inhibitor of Toll-like receptor 7 (TLR7)-mediated inflammation. IT1t inhibits chemical (R848) and natural (HIV) TLR7-mediated inflammation in purified human plasmacytoid dendritic cells from blood and human tonsils. In a TLR7-dependent lupus-like model, in vivo treatment of mice with IT1t drives drastic reduction of both systemic inflammation and anti-double-stranded DNA autoantibodies and prevents glomerulonephritis. Furthermore, IT1t controls inflammation, including interferon α secretion, in resting and stimulated cells from patients with systemic lupus erythematosus. Our findings highlight a groundbreaking immunoregulatory property of CXCR4 signaling that opens new therapeutic perspectives in inflammatory settings and autoimmune diseases.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center