IL-33/ST2通过调控蜕膜巨噬细胞efferocytosis诱导早孕期母胎界面促/抑炎免疫平衡的分子机制

Recurrent spontaneous abortion (RSA) is a disease that constitutes a serious threat to women's reproductive health. Although it is found that the immunity imbalance of pro/anti inflammatory was an important reason of RSA, the molecular mechanism of maintaining the aforementioned balance remain unknown. We have demonstrated the expression of IL-33 decreased in patient with RSA, therefore induced decidual macrophage (dMφ) to differentiate into M1 phenotype with high level expression of inflammatory factors. Meanwhile, the ability of dMφ to eliminate apoptotic cell (efferocytosis) could be promoted by the soluble receptor of IL-33, but the mechanism of IL-33 regulating dMφ is incompletely understood. Current findings have revealed that efferocytosis could contribute to the polariztion of dMφ to anti-inflammatory M2 macrophage, and IL-33 could also shift the balance from Mφ to M2 macrophage differentiation. Hence, we speculate that IL-33/ST2 works in maintaining pro/anti inflammatory balance at maternal-fetal interface by regulating dMφ efferocytosis and promoting anti-inflammatory cytokine secretion. To confirm the hypothesis, we take advantage of RSA animal model, intend to study the molecular mechanism by which IL-33 modulates dMφ efferocytosis in vivo and in vitro with molecular biology technology, flow cytometer and so on.

反复自然流产（RSA）是严重危害女性生殖健康的疾病。尽管目前已发现母胎界面的促/抑炎失衡是导致RSA的重要原因，但维持上述平衡的分子机制并不明确。申请人前期研究发现IL-33在RSA患者蜕膜中表达下降，进而导致蜕膜巨噬细胞（dMφ）向M1型转化，炎性因子释放增加，同时IL-33的可溶性受体可促进dMφ对凋亡细胞的清除（efferocytosis），而IL-33对dMφ的调控机制尚不明确。根据文献报道Mφ对凋亡细胞的清除增强有助于Mφ向M2型转化，抑炎因子增多，而IL-33也有促进Mφ向M2型转化的特点。因此，我们推测IL-33可能是通过促进dMφ清除凋亡细胞的能力而发挥其维持促/抑炎平衡和免疫稳态的作用。为证实这一假说，我们将在体内/体外两个水平，借助自然流产动物模型，采用分子生物学、流式细胞仪等技术，揭示IL-33对dMφ的调控途径，阐明IL-33在维持母胎界面促/抑炎平衡中的分子机制。

本研究聚焦在IL-33-ST2-efferocytosis轴对母胎界面促/抑炎免疫平衡的调控，复发性流产（RPL）患者母胎界面 IL-33/ST2 轴出现紊乱，凋亡细胞增多，蜕膜巨噬细胞（dMΦs）efferocytosis代偿性增强，分泌更高水平的sST2及较低水平的TGF-β,使dMΦs向M1促炎表型偏倚；同时更高水平的 sST2使efferocytosis下降，代谢向氧化磷酸化偏倚，对凋亡细胞的清除减少，这样一个正反馈环路导致母胎界面微环境的稳态被打破，不利于妊娠维持。通过给 IL-33-/-孕鼠外源性补充 mIL-33 能够部分改善胚胎丢失的命运。同时，IL-33/ST2 轴的正常激活能够通过激活 PI3K/AKT 和 ERK1/2 信号通路抑制AXL 的表达并抑制efferocytosis，使代谢向糖酵解偏倚，dMΦs进行efferocytosis后，表型依旧为耐受表型，维持妊娠的正常进行。因此IL-33/ST2/efferocytosis 轴对母-胎界面微环境的代谢、免疫稳态维持发挥着重要作用，本课题为解析复发性流产等病理性妊娠的发病机制提供了理论补充以及实验室研究依据，同时也为临床探索复发性流产的诊疗方案提供了新的思路。项目资助发表SCI论文2篇，待发表1篇。培养博士生1名，已取得博士学位。项目投入经费22万元，支出18.1854万元，各项支出基本与预算相符。剩余经费3.8146万元，剩余经费计划用于本项目研究后续支出。