Department of Biomedicine, Aarhus University, Aarhus DK-8000, Denmark;
J Immunol. 2014 Mar 1;192(5):2395-404. doi: 10.4049/jimmunol.1302120. Epub 2014 Jan 31.
Keratinocytes are involved in protecting the body from infections and environmental challenges, but also in inflammatory conditions like psoriasis. DNA has emerged as a potent stimulator of innate immune responses, but there is largely no information of how keratinocytes respond to cytosolic DNA. In this study, we report that human keratinocytes are tolerant to cytoplasmic DNA. However, if treated with inflammatory cytokines, keratinocytes gained the capacity to respond to DNA through a mechanism antagonized by the antimicrobial peptide LL37, proposed to be involved in activation and regulation of skin inflammation. The DNA sensor IFN-inducible protein 16 (IFI16) colocalized with DNA and the signaling molecule stimulator of IFN genes (STING) in the cytoplasm only in cytokine-stimulated cells, correlating with recruitment of the essential kinase TANK-binding kinase 1. Moreover, IFI16 was essential for DNA-driven innate immune responses in keratinocytes. Finally, IFI16 was upregulated in psoriasis skin lesions and localized to the cytoplasm in a subpopulation of cells. Collectively, this work suggests that inflammatory environments in the skin can lead to breakdown of tolerance for DNA in keratinocytes, which could contribute to the development of inflammatory diseases.
角质形成细胞参与保护身体免受感染和环境挑战，但也参与银屑病等炎症情况。DNA 已成为先天免疫反应的有效刺激物，但对于角质形成细胞如何对细胞质 DNA 作出反应，我们知之甚少。在这项研究中，我们报告说，人角质形成细胞对细胞质 DNA 具有耐受性。然而，如果用炎性细胞因子处理，角质形成细胞通过一种被抗菌肽 LL37 拮抗的机制获得了对 DNA 的反应能力，该机制被认为参与了皮肤炎症的激活和调节。DNA 传感器干扰素诱导蛋白 16（IFI16）仅在细胞因子刺激的细胞中与 DNA 和信号分子干扰素基因刺激物（STING）在细胞质中共定位，与必需激酶 TANK 结合激酶 1 的募集相关。此外，IFI16 对于角质形成细胞中的 DNA 驱动的先天免疫反应是必不可少的。最后，IFI16 在银屑病皮损中上调，并在细胞的亚群中定位于细胞质。总的来说，这项工作表明，皮肤中的炎症环境可能导致角质形成细胞对 DNA 的耐受性丧失，这可能导致炎症性疾病的发展。
