Fig. 7.

Graphical summary of proposed ERα-ERβ-GILZ signaling axis in Tregs. (Left) In the healthy, noninflamed intestinal mucosae, ERα and ERβ are expressed at physiological levels by immune cells including Tregs. Soluble E2 diffuses across the plasma membrane and binds ERα and ERβ in the cytoplasm, after which ERα/ERβ heterodimers form. These dimers then translocate to the nucleus and bind estrogen response elements (EREs) in target gene promoters. ERβ-containing dimers inhibit the transcriptional activation of Tsc22d3 (GILZ) in Tregs under noninflamed conditions. (Right) In the chronically inflamed intestine, expression of ERβ is significantly reduced in Tregs. Additional signals from cytokines such as IL-6 and IFN-γ contribute to a chronic inflammatory environment and may interact with ER signaling to influence target gene transcription. In the absence of ERβ, ERα/ERα homodimers permit Tsc22d3 transcription in Tregs, leading to loss of functional Treg suppression. Figure was created using BioRender.