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

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Smith, Nikaïa | Rodéro, Mathieu | Bekaddour, Nassima | Bondet, Vincent | Ruiz-Blanco, Yasser | Harms, Mirja | Mayer, Benjamin | Badder-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

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

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