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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.
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Submitted on : Tuesday, September 10, 2019 - 12:46:44 PM
Last modification on : Friday, April 10, 2020 - 5:08:32 PM
Document(s) archivé(s) le : Saturday, February 8, 2020 - 12:12:22 AM

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Distributed under a Creative Commons Attribution - NonCommercial 4.0 International License

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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 , American Association for the Advancement of Science (AAAS), 2019, 5 (7), pp.eaav9019. ⟨10.1126/sciadv.aav9019⟩. ⟨pasteur-02282952⟩

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