CNRS UMR-8601, CICB, 45 rue des Saints-Pères, 75006 Paris, France.
Team Chemistry & Biology, Modeling & Immunology for Therapy, CBMIT, Paris, France.
Sci Adv. 2019 Jul 10;5(7):eaav9019. doi: 10.1126/sciadv.aav9019. eCollection 2019 Jul.
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.
I 型干扰素是高度有效的细胞因子，对于保护机体免受肿瘤和感染至关重要。I 型干扰素信号的失调与多种疾病相关，这些疾病需要新的治疗选择。在这里，我们发现了小分子 IT1t，它是一种先前描述的 CXCR4 配体，是 Toll 样受体 7（TLR7）介导的炎症的高效抑制剂。IT1t 抑制化学（R848）和天然（HIV）TLR7 介导的来自血液和人扁桃体的纯化人浆细胞样树突状细胞的炎症。在 TLR7 依赖性狼疮样模型中，体内用 IT1t 治疗小鼠可显著降低全身性炎症和抗双链 DNA 自身抗体，并预防肾小球肾炎。此外，IT1t 控制炎症，包括来自系统性红斑狼疮患者静止和刺激细胞的干扰素 α 分泌。我们的研究结果强调了 CXCR4 信号的突破性免疫调节特性，为炎症和自身免疫性疾病的治疗提供了新的前景。
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