Abstract
Endometrial stromal cells (EnSCs) are the major cell type of the human endometrium and they undergo dramatic differentiation, termed decidualization, every month that enables them to be receptive to implantation. Appropriate decidualization and EnSC function is key for a successful pregnancy. EnSC function may be affected when the uterus is exposed to bacterial and viral infection. However, how human EnSCs respond to viral and bacterial components have not been well-studied and it remains unclear whether uterine innate immune responses change during decidualization. This study demonstrated that viral double-stranded RNA [Poly(I:C)] and bacterial lipopolysaccharide (LPS) upregulated undecidualized human EnSC production of a large array of proinflammatory cytokines and chemokines, and revealed that these immune responses were significantly dampened during decidualization in vitro and in vivo. This dampened response was associated with increased NFKBIA transcription during decidualization that leads to the accumulation of this negative regulator in decidualizing EnSCs that can bind to NFκB p65 and prevents its nuclear translocation and downstream Toll-like receptor signaling. These findings highlight that endometrial responses to infection may vary at different stages of the menstrual cycle which may be important for preparing the endometrium to support the growth of the semi-allogenic blastocyst. This work emphasizes the need to consider menstrual cycle stage, sex hormone levels and the differentiation status of cells when examining inflammatory responses in the future.