Histamine promotes mouse decidualization through stimulating epithelial amphiregulin release.

Area of Science:

• Reproductive Biology
• Immunology
• Cell Biology

Background:

• Inflammation plays a critical role in embryo implantation and decidualization.
• Histamine, a key inflammatory mediator, is essential for decidualization, but its precise mechanism is unclear.
• Histidine decarboxylase (HDC) synthesizes histamine by decarboxylating histidine.

Purpose of the Study:

• To elucidate the mechanism by which histamine influences decidualization.
• To investigate the role of blastocyst-derived factors in regulating histamine production.
• To determine the signaling pathway involved in histamine-mediated decidualization.

Main Methods:

• In vitro and in vivo mouse models.
• Analysis of histidine decarboxylase (HDC) protein levels during pregnancy and pseudopregnancy.
• Treatment with histamine, famotidine (H2R inhibitor), TPAI-1 (ADAM17 inhibitor), urocanic acid (HDC inhibitor), and amphiregulin (AREG).
• Assessment of implantation site counts and protein expression (HDC, AREG, ADAM17).

Main Results:

• Blastocyst-derived tumor necrosis factor α (TNFα) upregulates HDC in the uterine luminal epithelium.
• Histamine increases amphiregulin (AREG) and ADAM17 protein levels, a process inhibited by famotidine or TPAI-1.
• Inhibition of HDC with urocanic acid reduces implantation rates.
• TNFα-induced increases in HDC, AREG, and ADAM17 are blocked by urocanic acid.
• AREG treatment enhances in vitro decidualization.

Conclusions:

• Blastocyst-derived TNFα stimulates histamine production in the uterine epithelium.
• Histamine promotes decidualization through the ADAM17-mediated release of AREG.
• This pathway is critical for successful embryo implantation in mice.