Estrogen-sensitive activation of SGK1 induces M2 macrophages with anti-inflammatory properties and a Th2 response at the maternal-fetal interface.
Level 4 - case-series / case-control
Case-control clinical tissue/serum comparisons combined with preclinical mechanistic experiments (in vitro cell lines and animal models).
PubMed 37226177 · doi:10.1186/s12958-023-01102-9
What was done
The authors evaluated the mechanism of estradiol (E2)-sensitive SGK1 regulation of macrophage polarization at the maternal-fetal interface. First-trimester serum E2 and progesterone were measured in women with threatened miscarriage resulting in live birth (n = 448) versus early miscarriage (n = 68). SGK1 expression was analyzed via immunofluorescence and western blotting in decidual tissue from recurrent pregnancy loss (RPL, n = 93) versus normal early pregnancies (n = 66). Mechanistic pathways were examined in LPS-stimulated human THP-1-derived macrophages (using E2, pathway inhibitors, and siRNA) and in ovariectomized (OVX) hormone-treated mice.
What was found
Serum E2 concentrations and their rate of increase from weeks 4 to 12 were lower in pregnancies ending in miscarriage. Decidual macrophages from women with RPL showed downregulated SGK1 expression. In cell culture, LPS exposure suppressed SGK1 activity while promoting M1 polarization and Th1 cytokines; E2 pretreatment rescued and amplified SGK1 activation through estrogen receptor beta (ERβ) and the PI3K pathway. SGK1 activation induced ARG1 and IRF4 transcription, driving M2 macrophage polarization and Th2 immune responses. In contrast, pharmacological inhibition or knockdown of SGK1, as well as E2 inhibition in OVX mice, increased NF-κB nuclear translocation and pro-inflammatory cytokine secretion. The abstract reported directional biological findings without exact numerical effect sizes or p-values.
Why it matters
This study identifies an E2/ERβ/PI3K/SGK1 signaling axis that promotes anti-inflammatory M2 macrophage polarization at the maternal-fetal interface. Disruptions in this pathway are linked to the pro-inflammatory decidual environment seen in recurrent pregnancy loss, highlighting potential therapeutic targets for pregnancy maintenance.
Limits
Human data were cross-sectional and observational, preventing determination of whether low E2 and reduced SGK1 are causes or downstream consequences of non-viable pregnancies. Exact numerical data, effect sizes, and mouse sample sizes were not reported in the abstract. Much of the mechanistic evidence relied on an immortalized human monocytic cell line (THP-1) rather than primary human decidual macrophages.
Cited by
- contradicts Estrogen increases the body's inflammatory response during pregnancy.