Department of Reproductive Immunology, Chengdu Xi'nan Gynecology Hospital, Chengdu 610066, Sichuan, China; Department of Reproductive Immunology, Chengdu Jinjiang Hospital for Maternal & Child Health Care, Chengdu 610066, Sichuan, China; Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Laboratory Animal Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Int Immunopharmacol. 2022 Sep;110:108930. doi: 10.1016/j.intimp.2022.108930. Epub 2022 Jun 25.
Unexplained recurrent spontaneous abortion (URSA) is one of the most challenging conditions in the reproductive field, and macrophage M1/M2 polarization disorder is involved in URSA pathogenesis, although the relevant mechanisms are undefined. miR-146a-5p possesses an immunoregulatory role and is expressed in decidual immune cells, and this study aims to investigate its effect on decidual macrophage polarization and therapeutic prospects in URSA, which has never been reported. The levels of M1/M2 markers in the deciduae and the miR-146a-5p expression in the decidual macrophages of URSA and healthy pregnant women were first detected and analyzed. Then, the in vitro effect of miR-146a-5p on the M1/M2 polarization and the secretion of inflammatory cytokines was investigated in Tamm-Horsfall protein-1 (THP-1)-induced macrophages. Finally, the in vivo immunotherapeutic effect of miR-146a-5p on embryo survival and the potential mechanisms were evaluated in a murine model of immune-based URSA. As a result, the abnormal M1/M2 polarization, which showed a shift towards the M1 phenotype and correlated with the decreased expression of miR-146a-5p, was verified in human URSA decidual macrophages. miR-146a-5p could inhibit M1 polarization, promote M2 polarization, and result in an anti-inflammatory microenvironment in THP-1-induced macrophages. The intravenous injection of exogenous miR-146a-5p in the first trimester of pregnant URSA mice significantly reduced the embryo resorption rate and promoted the M2 polarization of decidual macrophages. In conclusion, miR-146a-5p enhances embryo survival in URSA by promoting decidual macrophage polarization toward an M2 phenotype, giving new ideas and potential targets for subsequent research on the pathogenesis and immunotherapeutic strategies of URSA.
不明原因复发性自然流产（URSA）是生殖领域最具挑战性的病症之一，巨噬细胞 M1/M2 极化紊乱与 URSA 的发病机制有关，但其相关机制尚不清楚。miR-146a-5p 具有免疫调节作用，并在蜕膜免疫细胞中表达，本研究旨在探讨其对蜕膜巨噬细胞极化的影响及其在 URSA 中的治疗前景，这在以前的研究中从未报道过。首先检测并分析 URSA 和健康孕妇蜕膜中 M1/M2 标志物水平和 miR-146a-5p 的表达。然后，研究 miR-146a-5p 在 Tamm-Horsfall 蛋白-1（THP-1）诱导的巨噬细胞中对 M1/M2 极化和炎症细胞因子分泌的体外作用。最后，在免疫性 URSA 小鼠模型中评估 miR-146a-5p 对胚胎存活的体内免疫治疗效果及其潜在机制。结果表明，在人 URSA 蜕膜巨噬细胞中证实了异常的 M1/M2 极化，表现为向 M1 表型的转变，与 miR-146a-5p 的表达下调相关。miR-146a-5p 可抑制 M1 极化，促进 M2 极化，并在 THP-1 诱导的巨噬细胞中产生抗炎微环境。在妊娠早期 URSA 小鼠静脉注射外源性 miR-146a-5p 可显著降低胚胎吸收率，并促进蜕膜巨噬细胞 M2 极化。总之，miR-146a-5p 通过促进蜕膜巨噬细胞向 M2 表型极化来增强 URSA 中的胚胎存活，为 URSA 的发病机制和免疫治疗策略的后续研究提供了新的思路和潜在靶点。
