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. 2025 Jun:216:107764.
doi: 10.1016/j.phrs.2025.107764. Epub 2025 May 10.

The host cell factor DDX3 mediates sex dimorphism in the IFNα response of plasmacytoid dendritic cells upon TLR activation

Sebastian Schloer  1 , Jana Hennesen  2 , Lena Rueschpler  3 , Mohamed Zamzamy  3 , Felix Flomm  2 , Wing Hang Ip  4 , Andrea Pirosu  2 , Thomas Dobner  4 , Marcus Altfeld  5
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Free article

The host cell factor DDX3 mediates sex dimorphism in the IFNα response of plasmacytoid dendritic cells upon TLR activation

Sebastian Schloer et al. Pharmacol Res. 2025 Jun.
Free article

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Abstract

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.

Keywords: DDX3; Innate immunity; Interferons; Plasmacytoid dendritic cells; Sex differences.

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Conflict of interest statement

Declaration of Competing Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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