PREreview del Constitutive Interferon Epsilon Expression Shapes Antiviral Epithelial States in the Female Reproductive Tract and Intestine

Major issues

• The mechanism underlying intracellular retention and autocrine signaling of IFNε remains insufficiently defined. While the authors demonstrate intracellular localization and biological activity, the molecular basis by which IFNε is retained and initiates signaling is not directly investigated.

• The study identifies ELF3 as one of the few transcription factors consistently associated with IFNε-expressing epithelial populations; however, no functional experiments were performed to determine whether ELF3 is required for constitutive IFNε expression. Validation through knockdown, knockout, or promoter-based approaches would strengthen the mechanistic conclusions.

• Although IFNβ is included in selected experiments, a broader functional comparison with other type I interferons is lacking. Such analyses would help establish whether the intracellular retention and constitutive antiviral functions described are unique features of IFNε or shared with other members of the type I interferon family.

Minor issues

• The generalizability of the findings to other mucosal barriers, particularly the respiratory epithelium, remains unclear and should be discussed in greater detail.

• Given the known influence of sex hormones on IFNε biology, the manuscript would benefit from additional discussion of potential sex-dependent effects and limitations associated with the use of different sexes in some infection models.

• The discussion could be expanded to address additional transcriptional regulators reported to influence IFNε expression, including GATA family factors, SOX2, and STAT1, which may contribute to tissue-specific regulation.

• Several conclusions regarding tissue-specific regulation of IFNε would benefit from clearer discussion of how reproductive and intestinal findings compare with previously reported observations in other epithelial tissues.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they used generative AI to come up with new ideas for their review.