Galectin-9 Alleviates LPS-Induced Preeclampsia-Like Impairment in Rats via Switching Decidual Macrophage Polarization to M2 Subtype
Galectin-9 Alleviates LPS-Induced Preeclampsia-Like Impairment in Rats via Switching Decidual Macrophage Polarization to M2 Subtype
复制标题
Galectin-9 通过将蜕膜巨噬细胞极化切换为 M2 亚型来减轻 LPS 诱导的大鼠先兆子痫样损伤
DOI：
10.3389/fimmu.2018.03142
复制
发表时间：
2019-01-10
影响因子：
7.3
通讯作者：
Liao, Ai-Hua
中科院分区：
文献类型：
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作者：
Li, Zhi-Hui;Wang, Li-Ling;Liao, Ai-Hua
蜕膜巨噬细胞（DM）的功能障碍被认为是先兆子痫（PE）发病机制中的关键事件。T细胞免疫球蛋白粘蛋白3（Tim-3）是一种重要的负性调节分子，其通过与其配体半乳糖凝集素-9（Gal-9）相互作用而诱导免疫耐受，从而调节包括巨噬细胞在内的各种免疫细胞的功能。然而，Tim-3/Gal-9信号对DM极化的调节作用及其在PE中的作用仍不清楚。本研究采用脂多糖（lipopolysaccharide，LPS）1.0 μg/kg经尾静脉注射于胚胎5天（E5）的SD大鼠，建立PE样大鼠模型。除先兆子痫表现外，在母胎界面观察到M1亚型增加和M2亚型减少，以及促炎细胞因子（TNF-α和IL-1β）增加和抗炎细胞因子（TGF-β和IL-10）减少。此外，DM中Tim-3和母胎界面Gal-9的表达减少。重组半乳糖凝集素-9（rGal-9）蛋白给药后，我们发现肝和肾损伤和母胎胎盘功能缺陷，包括滋养层细胞浸润不足，螺旋动脉重塑受损和胎儿毛细血管发育，被逆转。此外，DM的极化倾向于M2亚型，这与对照组大鼠DM的极化相似，而与PE样大鼠相反。有趣的是，在E9时，在rGal-9蛋白干预组中，DM中Tim-3的表达和母胎界面处Gal-9的表达显著增加。综上所述，我们的研究结果表明，rGal-9蛋白的管理可以减轻由LPS诱导的PE样大鼠表现。这一发现可能与Tim-3/Gal-9信号通路的激活有关，该信号通路促进DM的极化主要向M2亚型转变。此外，Tim-3在DM中的上调和Gal-9在E9的母胎界面的上调表明Tim-3/Gal-9通路可能在早期妊娠甚至胚胎发育中发挥一些重要作用。
Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 μg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1β) and reduced anti-inflammatory cytokines (TGF-β and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.