An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages
An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages
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IL-33/ST2-AXL-胞吞作用轴的不平衡通过蜕膜巨噬细胞的代谢重编程诱导流产
DOI：
10.1007/s00018-022-04197-2
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发表时间：
2022-03
影响因子：
8
通讯作者：
Xiao‑Yong Zhu
中科院分区：
文献类型：
--
作者：
Yan‑Ran Sheng;Wen‑Ting Hu;Hui-Hui Shen;Chun‑Yan Wei;Yu‑Kai Liu;Xiao-Qian Ma;Ming-Qing Li;Xiao‑Yong Zhu
胚胎着床过程中，细胞凋亡是不可避免的。这些凋亡细胞(ACS)通过吞噬作用被去除，在吞噬作用中，巨噬细胞充满了几乎等于吞噬细胞本身的代谢物负荷。一个及时的问题与蜕膜巨噬细胞(DM、Φ、S)的吐痰相关代谢和免疫行为的关系及其对妊娠结局的影响有关。在此，我们报道了通过DMΦS代谢重编程导致IL-33/ST2-AX1吞噬导致妊娠失败的正反馈。我们比较了正常妊娠和不明原因反复妊娠丢失患者的血清IL-33和ST2水平，以及DMΦS的吞噬和代谢。我们发现糖尿病患者ΦS的IL-33/ST2轴被破坏，细胞凋亡率增加，吞噬功能增强。吞噬大量凋亡细胞的DMΦS分泌较多的Sst2和较少的转化生长因子-β，使DMΦS向M1表型分化。此外，升高的sst2使ΦS的胞吐相关代谢偏向氧化磷酸化，加剧了IL-33/st2信号通路的破坏。代谢紊乱还会导致胞吐功能障碍，导致更多未清除的凋亡细胞和继发性坏死。我们还筛选了受IL-33/ST2调节的泡吞噬分子Axl。IL-33/ST2-Ax1-胞吐正反馈轴导致妊娠失败。IL-33基因敲除小鼠表现出不良的妊娠结局，外源补充小鼠IL-33可以减少胚胎损失。这些发现突显了一种新的病因机制，即DMΦS利用免疫代谢来维持母胎界面微环境的动态平衡。
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.
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DOI：
10.1111/j.1600-0897.2004.00156.x
发表时间：
2004-04-01
影响因子：
3.6
作者：
Abrahams, VM;Kim, YM;Mor, G
通讯作者：
Mor, G
妊娠和先兆子痫的ST2和IL-33。
影响因子：
3.7
作者：
Granne I;Southcombe JH;Snider JV;Tannetta DS;Child T;Redman CW;Sargent IL
通讯作者：
Sargent IL
DOI：
10.1186/s12964-020-00542-9
发表时间：
2020-05
期刊：
Cell Communication and Signaling : CCS
影响因子：
--
作者：
Yunxiang Zhou;Yihan Yao;Yongchuan Deng;Anwen Shao
通讯作者：
Yunxiang Zhou;Yihan Yao;Yongchuan Deng;Anwen Shao
影响因子：
3.4
作者：
Kaitu'u-Lino, Tu'uhevaha J.;Tuohey, Laura;Tong, Stephen
通讯作者：
Tong, Stephen
AhR 激活通过减少 M1 巨噬细胞极化和促进 M2 巨噬细胞极化来减轻草酸钙肾钙质沉着症
影响因子：
12.4
作者：
Yang X;Liu H;Ye T;Duan C;Lv P;Wu X;Liu J;Jiang K;Lu H;Yang H;Xia D;Peng E;Chen Z;Tang K;Ye Z
通讯作者：
Ye Z