Suzuki Takuma, Iizuka Takashi, Kagami Kyosuke, Matsumoto Takeo, Yamazaki Rena, Daikoku Takiko, Horie Akihito, Ono Masanori, Hattori Akira, Fujiwara Hiroshi
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Division of Animal Disease Model, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan.
iScience. 2023 Aug 19;26(9):107692. doi: 10.1016/j.isci.2023.107692. eCollection 2023 Sep 15.
Human extravillous trophoblast (EVT) invades the maternal endometrium and reconstructs uterine spiral arteries cooperatively with maternal immune cells. Although EVT has allogeneic paternal antigens, the maternal immune system does not reject it. Here, we found that laeverin (LVRN), an EVT-specific cell surface peptidase, interacts with monocytes to produce indoleamine 2,3-dioxygenase-1 (IDO1). LVRN-transfected Swan71 cells, a cytotrophoblast-derived cell line, and increased IDO1 expression in PBMC under cell-to-cell interacting conditions. Soluble recombinant LVRN (r-LVRN) interacted with CD14-positive monocytes and induced their IDO1 expression without the intervention of other immune cell populations. LVRN-induced IDO1 production was promoted in PMA-activated monocyte-like THP-1 cells. Furthermore, r-LVRN decreased the tryptophan level and increased the kynurenine/tryptophan ratio in the culture media of the PMA-treated THP-1 cells. These findings suggest that LVRN is one of the key molecules that mediate the interaction between EVT and monocytes/macrophages and creates an immunosuppressive environment at the maternal-fetal interface in the uterus.
人绒毛外滋养层细胞（EVT）侵入母体子宫内膜，并与母体免疫细胞协同重建子宫螺旋动脉。尽管EVT具有同种异体父源抗原，但母体免疫系统并不排斥它。在此，我们发现了一种EVT特异性细胞表面肽酶laeverin（LVRN），它与单核细胞相互作用以产生吲哚胺2,3-双加氧酶-1（IDO1）。转染了LVRN的Swan71细胞（一种细胞滋养层来源的细胞系），在细胞间相互作用条件下可增加外周血单核细胞（PBMC）中IDO1的表达。可溶性重组LVRN（r-LVRN）与CD14阳性单核细胞相互作用，并在无其他免疫细胞群体干预的情况下诱导其IDO1表达。在经佛波酯（PMA）激活的单核细胞样THP-1细胞中，LVRN诱导的IDO1产生增加。此外，r-LVRN降低了经PMA处理的THP-1细胞培养基中的色氨酸水平，并提高了犬尿氨酸/色氨酸比值。这些发现表明，LVRN是介导EVT与单核细胞/巨噬细胞之间相互作用并在子宫母胎界面创造免疫抑制环境的关键分子之一。
