Jessica Selim, Tilu Thomas, Rheanna Urrabaz-Garza, Glenmarie Angelica S Perias, Lauren S Richardson, Ourlad Alzeus Gaddi Tantengco, Ramkumar Menon
These findings identify PGRMC2 as an important regulator of decidual immune homeostasis; however, the translational relevance of this role remains limited, as neither our pregnancy nor labor models produced a physiologically meaningful downregulation of PGRMC2 expression. Instead, our data support a model in which parturition-associated changes in decidua are driven primarily by inflammatory cues rather than by loss of progesterone receptor signaling, demonstrating tissue-specific progesterone signaling.
PROBLEM: Preterm birth and dysregulated labor remain the leading causes of neonatal morbidity, yet the mechanisms governing progesterone (P4) signaling and inflammatory regulation within the decidua parietalis at the feto-maternal interface are poorly understood. In particular, the roles of progesterone receptor membrane components PGRMC1 and PGRMC2 in maintaining decidual immune homeostasis during pregnancy and labor remain undefined.
METHODS: of Study:Human decidua parietalis cells were cultured under pregnancy- and labor-like conditions, with and without immune cell co-culture. Expression of PGRMC1, PGRMC2, and PR-A/B and their interaction with P4 were assessed. Labor-associated inflammation was modeled using lipopolysaccharide (LPS). SiRNA targeted knockdown of PGRMC2 was performed to evaluate effects on progesterone receptor expression, cell-cycle progression, progesterone metabolism (AKR1C1/2) and inflammatory cytokine production.
RESULTS: PGRMC1, PGRMC2, and PR-A/B expression remained stable across gestational conditions, and P4 robustly interacted with PGRMCs. LPS-induced inflammation was not suppressed by P4 despite preserved receptor expression. PGRMC2 knockdown did not alter progesterone receptor expression, cell-cycle progression, or progesterone metabolism; however, it significantly increased baseline and stimulus-induced IL-6 and TNF levels. Under labor-like inflammatory conditions, loss of PGRMC2 markedly amplified cytokine production.
CONCLUSIONS: These findings identify PGRMC2 as an important regulator of decidual immune homeostasis; however, the translational relevance of this role remains limited, as neither our pregnancy nor labor models produced a physiologically meaningful downregulation of PGRMC2 expression. Instead, our data support a model in which parturition-associated changes in decidua are driven primarily by inflammatory cues rather than by loss of progesterone receptor signaling, demonstrating tissue-specific progesterone signaling.