Succinate/SUCNR1-mediated regulation of macrophage polarization reduces trophoblast apoptosis: A potential cause of retained placenta in peripartal dairy cows.

Retained placenta (RP) is recognized as a multifactorial postpartal reproductive disorder in dairy cows. Trophoblast dysfunction and abnormal macrophage activation at the maternal-fetal interface are associated with occurrence of RP. Our previous work demonstrated that caruncle tissue from cows with RP had lower macrophage numbers together with predominance of macrophages expressing markers associated with immunoregulatory macrophages (M2). However, the mechanisms underlying macrophage alterations and the potential interactions between macrophages and trophoblasts remain unclear. Succinate acts as a signaling metabolite that is detected extracellularly by succinate receptor 1 (SUCNR1), and plays an essential role in modulating macrophage activation states. This study aimed to characterize succinate accumulation, macrophage activation states, and trophoblast apoptosis in RP, and to assess the potential role of succinate-SUCNR1 signaling in these processes. A total of 80 multiparous Holstein dairy cows were screened at calving. Blood samples were obtained from the coccygeal vein at calving and at 12 h after parturition, and placental tissues were collected within 30 min after parturition from all screened cows. Based on whether placental expulsion occurred within 12 h, 6 cows with RP (RP group) and 6 healthy control cows (control group) were selected from this cohort for inclusion in downstream studies. The RP cows exhibited reduced apoptosis in placental cotyledon tissue and aberrant M2-like macrophage polarization in caruncle tissue compared with healthy controls. Metabolomics profiling identified a significant accumulation of succinate within caruncle tissue of RP-affected cows. In vitro, under M2-polarized conditions, succinate enhanced M2-associated marker expression in bovine macrophage (BoMac) cells in association with SUCNR1 and PI3K signaling. In addition, trophoblast cells exposed to conditioned medium from BoMac cells under different stimuli showed that M2-polarized macrophage medium suppressed trophoblast apoptosis and that succinate modestly enhanced this anti-apoptotic effect, whereas SUCNR1 knockdown attenuated it. These findings suggest that enhanced succinate/SUCNR1 signaling may contribute to persistence of an anti-inflammatory and pro-remodeling immune environment at the maternal-fetal interface in RP cows.