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Is Oestradiol a Key Player in the Sex Differences in Innate Immunity Through Toll-like Receptor Activation?
Alexandros Popotas1,2,3,4, Anne Delbaere5, Georges Casimir1
1Laboratory of Pediatrics, Université Libre de Bruxelles (ULB), 1020 Brussels, Belgium.
Cells
|July 27, 2026
Summary
Estradiol has a limited impact on Toll-like receptor (TLR)-dependent immune responses. This suggests that X-linked genetic factors, not hormones, are the primary drivers of sex-based immune differences in inflammatory diseases.
Area of Science:
- Immunology
- Endocrinology
- Genetics
Background:
- Sex-specific immune responses are observed, with males often experiencing worse outcomes in inflammatory conditions.
- While sex hormones were initially implicated, X-linked genetic factors are increasingly recognized as significant contributors.
- Toll-like receptors (TLRs) and their signaling pathways, encoded on the X chromosome, may underlie these sex-based immune disparities.
Purpose of the Study:
- To investigate the influence of elevated circulating estradiol on Toll-like receptor (TLR)-dependent immune responses.
- To determine if hormonal changes during controlled ovarian hyperstimulation affect immune cell signaling and cytokine production.
Main Methods:
- Whole blood samples from 16 women undergoing in vitro fertilization were collected at three time points: before treatment, during stimulation, and at ovulation triggering.
- Blood was stimulated with ligands targeting TLR2/6, TLR1/2, TLR4, and TLR7/8.
- Measurements included TLR2, TLR4, CD99 expression, intracellular signaling (NF-κB, ERK1/2, p38 MAPK), and cytokine production.
Main Results:
- Estradiol levels significantly increased during ovarian stimulation (48.1 to 1819.5 pg/mL).
- Despite the rise in estradiol, minimal impact was observed on TLR2/4 expression, CD99 levels, and intracellular signaling pathways.
- Interleukin-6 (IL-6) and IL-10 production in response to TLR2/6 stimulation showed a significant increase, with IL-6 positively correlating with estradiol variation.
Conclusions:
- Elevated estradiol levels exert a limited influence on the overall TLR-dependent immune response.
- These findings support the hypothesis that genetic factors on the X chromosome play a more dominant role in sex-based immune differences than hormonal factors.
- The study highlights the complexity of sex-specific immune regulation, emphasizing the interplay between genetic and hormonal influences.
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