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

• Published in: Science advances Vol. 5; no. 7; p. eaav9019
• Main Authors: Smith, Nikaïa, Rodero, Mathieu P., Bekaddour, Nassima, Bondet, Vincent, Ruiz-Blanco, Yasser B., Harms, Mirja, Mayer, Benjamin, Bader-Meunier, Brigitte, Quartier, Pierre, Bodemer, Christine, Baudouin, Véronique, Dieudonné, Yannick, Kirchhoff, Frank, Sanchez Garcia, Elsa, Charbit, Bruno, Leboulanger, Nicolas, Jahrsdörfer, Bernd, Richard, Yolande, Korganow, Anne-Sophie, Münch, Jan, Nisole, Sébastien, Duffy, Darragh, Herbeuval, Jean-Philippe
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 01.07.2019; American Association for the Advancement of Science
• Subjects: Animals; Cytokines - biosynthesis; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Disease Progression; Disease Susceptibility; Gene Expression Profiling; Humans; Immunology; Interferon Type I - metabolism; Life Sciences; Ligands; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - etiology; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Mice; Protein Binding; Receptors, CXCR4 - metabolism; SciAdv r-articles; Signal Transduction; Toll-Like Receptor 7 - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aav9019

CXCR4 engagement by amines leads to the control of IFN signaling in pDCs and opens new therapeutic perspectives in Lupus patients. 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.