Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement—A new target for lupus treatment
SCIENCE ADVANCES. 2019. | JULY 10, 2019
Smith N, Rodero MP, Bekaddour N, Bondet V, Ruiz-Blanco YB, Harms M, Mayer B, Badder-Meunier B, Quartier P, Bodemer C, Baudouin V, Dieudonné Y, Kirchhoff F, Sanchez Garcia E, Charbit B, Leboulanger N, Jahrsdörfer B, Richard Y, Korganow A-S, Münch J, Nisole S, Duffy D and Herbeuval J-P.
Sci Adv. 2019 Jul 10;5(7):eaav9019. doi: 10.1126/sciadv.aav9019.
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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