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

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.

• Authors: Nikaïa Smith, Mathieu P Rodero, Nassima Bekaddour, Vincent Bondet, Yasser B Ruiz-Blanco, Mirja Harms, Benjamin Mayer, Brigitte Bader-Meunier, Pierre Quartier, Christine Bodemer, Véronique Baudouin, Yannick Dieudonné, Frank Kirchhoff, Elsa Sanchez Garcia, Bruno Charbit, Nicolas Leboulanger, Bernd Jahrsdörfer, Yolande Richard, Anne-Sophie Korganow, Jan Münch, Sébastien Nisole, Darragh Duffy, Jean-Philippe Herbeuval
• Journal: Science advances (Sci Adv) Vol. 5 Issue 7 Pg. eaav9019 (07 2019) ISSN: 2375-2548 [Electronic] United States
• PMID: 31309143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, human
• Cytokines
• Interferon Type I
• Ligands
• Receptors, CXCR4
• TLR7 protein, human
• Toll-Like Receptor 7

Topics

• Animals
• Cytokines (biosynthesis)
• Dendritic Cells (immunology, metabolism)
• Disease Models, Animal
• Disease Progression
• Disease Susceptibility
• Gene Expression Profiling
• Humans
• Interferon Type I (metabolism)
• Ligands
• Lupus Erythematosus, Systemic (drug therapy, etiology, metabolism, pathology)
• Mice
• Protein Binding
• Receptors, CXCR4 (metabolism)
• Signal Transduction
• Toll-Like Receptor 7 (metabolism)