Schloer Sebastian, Hennesen Jana, Rueschpler Lena, Zamzamy Mohamed, Flomm Felix, Ip Wing Hang, Pirosu Andrea, Dobner Thomas, Altfeld Marcus
Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg 20251, Germany; Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg 20251, Germany.
Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg 20251, Germany.
Pharmacol Res. 2025 Jun;216:107764. doi: 10.1016/j.phrs.2025.107764. Epub 2025 May 10.
During the course of viral infections, IFN-I producing pDCs are fundamental in establishing antiviral defense. However, little is known about the molecular mechanisms by which biological sex contributes to differences in IFN-I production by pDCs. Here, we aimed to identify X-chromosome-encoded proteins as a source of sex differences in IFN-I responses by pDCs. We identified the host-cell factor DDX3 as a key mediator for the sex dimorphism in the IFNα response. DDX3 was significantly higher expressed in female pDCs and was translocated together with IRF7 to the nucleus to orchestrate IFN-I transcription. DDX3 as driver of sex differences in the initial and chronic IFN-I response might serve as a novel target to limit IFN-I-mediated hyperactivation of immune cells.
在病毒感染过程中，产生I型干扰素（IFN-I）的浆细胞样树突状细胞（pDCs）对于建立抗病毒防御至关重要。然而，关于生物性别导致pDCs产生IFN-I差异的分子机制，我们了解甚少。在此，我们旨在确定X染色体编码的蛋白质是pDCs对IFN-I反应存在性别差异的一个来源。我们确定宿主细胞因子DDX3是IFNα反应中性别二态性的关键调节因子。DDX3在雌性pDCs中表达显著更高，并与IRF7一起转运至细胞核以协调IFN-I转录。DDX3作为初始和慢性IFN-I反应中性别差异的驱动因素，可能成为限制IFN-I介导的免疫细胞过度激活的新靶点。
