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

Nikaïa Smith (1, 2) , Mathieu Rodéro (2) , Nassima Bekaddour (2) , Vincent Bondet (3) , Yasser Ruiz-Blanco (4) , Mirja Harms (1) , Benjamin Mayer (5) , Brigitte Badder-Meunier (6, 7, 8) , Pierre Quartier (6, 7, 8) , Christine Bodemer (9) , Véronique Baudouin (10) , Yannick Dieudonné (11, 12, 13) , Frank Kirchhoff (1) , Elsa Sanchez Garcia (4) , Bruno Charbit (14) , Nicolas Leboulanger (7, 8) , Bernd Jahrsdörfer (15) , Yolande Richard (16, 8) , Anne-Sophie Korganow (13, 11, 12) , Jan Münch (1) , Sébastien Nisole (17) , Darragh Duffy (3, 14) , Jean-Philippe Herbeuval (2)

1 Universitätsklinikum Ulm - University Hospital of Ulm
2 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
3 Immunobiologie des Cellules dendritiques
4 Universität Duisburg-Essen [Essen]
5 Universität Ulm - Ulm University [Ulm, Allemagne]
6 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 CHU Necker - Enfants Malades [AP-HP]
8 UPD5 - Université Paris Descartes - Paris 5
9 AP-HP Hôpital universitaire Robert-Debré [Paris]
10 Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré]
11 CHU Strasbourg
12 UNISTRA - Université de Strasbourg
13 ICT - Immunopathologie et chimie thérapeutique
14 CRT - Centre de Recherche Translationnelle - Center for Translational Science
15 Institute of Transfusion Medicine and Immunogenetics
16 IC UM3 (UMR 8104 / U1016) - Institut Cochin
17 IRIM - Institut de Recherche en Infectiologie de Montpellier

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.

Domains: Immunology

Nikaïa Smith, Mathieu Rodéro, Nassima Bekaddour, Vincent Bondet, Yasser Ruiz-Blanco, et al.. Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement—A new target for lupus treatment. Science Advances , 2019, 5 (7), pp.eaav9019. ⟨10.1126/sciadv.aav9019⟩. ⟨pasteur-02282952⟩