HSS Research Institute, Hospital for Special Surgery, New York, NY.
Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY.
J Exp Med. 2022 Jul 4;219(7). doi: 10.1084/jem.20212142. Epub 2022 May 31.
Chemokines control the migratory patterns and positioning of immune cells to organize immune responses to pathogens. However, many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signatures. We report that a series of chemokines, including CXCL4, CXCL10, CXCL12, and CCL5, can superinduce type I IFN (IFN-I) by TLR9-activated plasmacytoid DCs (pDCs), independently of their respective known chemokine receptors. Mechanistically, we show that chemokines such as CXCL4 mediate transcriptional and epigenetic changes in pDCs, mostly targeted to the IFN-I pathways. We describe that chemokines physically interact with DNA to form nanoparticles that promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two separate mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data reveal a noncanonical role for chemokines to serve as nucleic acid delivery vectors to modulate TLR signaling, with implications for the chronic presence of IFN-I by pDCs in autoimmune diseases.
趋化因子控制免疫细胞的迁移模式和定位，以组织对病原体的免疫反应。然而，许多趋化因子与具有慢性 IFN 特征的系统性自身免疫性疾病有关。我们报告了一系列趋化因子，包括 CXCL4、CXCL10、CXCL12 和 CCL5，可通过 TLR9 激活的浆细胞样树突状细胞（pDC）超诱导 I 型 IFN（IFN-I），而不依赖于它们各自已知的趋化因子受体。从机制上讲，我们表明趋化因子（如 CXCL4）在 pDC 中介导转录和表观遗传变化，主要针对 IFN-I 途径。我们描述了趋化因子与 DNA 物理相互作用形成纳米颗粒，促进网格蛋白介导的细胞摄取，并在 pDC 的早期内体中递送 DNA。使用两种不同的皮肤炎症小鼠模型，我们观察到体内存在与 DNA 结合的 CXCL4。这些数据揭示了趋化因子作为核酸递送载体的非典型作用，可调节 TLR 信号，这对 pDC 中 IFN-I 的慢性存在对自身免疫性疾病有影响。
