Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200080, China.
Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, 200032, China.
Cell Mol Life Sci. 2022 Mar 4;79(3):173. doi: 10.1007/s00018-022-04197-2.
During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the relationship between efferocytosis-related metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here, we report positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum levels of IL-33 and sST2, along with IL-33 and ST2, efferocytosis and metabolism of dMΦs, from patients with normal pregnancies and unexplained recurrent pregnancy loss (RPL). We revealed disruption of the IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from patients with RPL. The dMΦs that engulfed many apoptotic cells secreted more sST2 and less TGF-β, which polarized dMΦs toward the M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis-related metabolism of RPL dMΦs toward oxidative phosphorylation and exacerbated the disruption of the IL-33/ST2 signaling pathway. Metabolic disorders also lead to dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and secondary necrosis. We also screened the efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback axis of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation with mouse IL-33 reduced the embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for homeostasis of the microenvironment at the maternal-fetal interface.
在胚胎植入过程中，细胞凋亡是不可避免的。这些凋亡细胞 (ACs) 通过噬作用被清除，其中巨噬细胞充满了几乎与吞噬细胞本身相等的代谢物负荷。一个及时的问题涉及到与噬作用相关的代谢与蜕膜巨噬细胞 (dMΦs) 的免疫行为及其对妊娠结局的影响之间的关系。在这里，我们报告了 IL-33/ST2-AXL 噬作用的正反馈通过 dMΦs 的代谢重编程导致妊娠失败。我们比较了正常妊娠和不明原因复发性妊娠丢失 (RPL) 患者的血清 IL-33 和 sST2 水平，以及 IL-33 和 ST2、dMΦs 的噬作用和代谢。我们发现 RPL 患者的 IL-33/ST2 轴中断，凋亡细胞增加，dMΦs 的噬作用增加。吞噬了许多凋亡细胞的 dMΦs 分泌更多的 sST2 和更少的 TGF-β，这将 dMΦs 极化到 M1 表型。此外，升高的 sST2 使 RPL dMΦs 的噬作用相关代谢向氧化磷酸化倾斜，并加剧了 IL-33/ST2 信号通路的中断。代谢紊乱也导致噬作用功能障碍，导致未清除的凋亡细胞增多和继发性坏死。我们还筛选了受 IL-33/ST2 调节的噬作用分子 AXL。IL-33/ST2-AXL 噬作用的这种正反馈轴导致妊娠失败。IL-33 敲除小鼠表现出不良的妊娠结局，而外源性补充小鼠 IL-33 减少了胚胎丢失。这些发现强调了一种新的病因机制，即 dMΦs 利用免疫代谢来维持母体-胎儿界面的微环境稳态。
