Role of leukemia inhibitory factor (LIF) in the orchestration of local and systemic inflammatory responses at the interface of immune and reproductive systems

白血病抑制因子（LIF）在协调免疫和生殖系统界面局部和全身炎症反应中的作用

• 批准号: RGPIN-2014-06516
• 负责人: ReyesMoreno, Carlos
• 金额: $ 1.89万
• 依托单位: Université du Québec à Trois-Rivières
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=663256
• 关键词: Role; leukemia; inhibitory; factor; LIF

The immune system of the uterine endometrium is exceptional in its ability to protect the mucosa from a variety of pathogens while being supportive to a developing semiallogeneic embryo. Inflammatory processes induced by host defense to infection, however, are a major challenge for the maternal immune system to successful pregnancy outcome. Tissue macrophages (MPhs) represent one of the most abundant populations of inflammatory cells in the human and the mouse uterus. In normal pregnancies, they support embryo implantation and placental differentiation. On the other hand, many effects of bacterial endotoxins in tissue injury are known to be induced through activation of tissue MPhs. Thus, it is not surprising that aberrant activation of inflammatory pathways in MPhs has been associated with early embryo loss in murine experimental models and in infection-induced abortion in humans. Because MPhs play such important functions in the uterine tissues, the cellular and molecular mechanisms underlying their differentiation and adaptation during gestation and infection need to be investigated in depth. *We propose that the key modulators of uterine MPh functions are signaling factors produced by uterine epithelial cells. In fact, cytokines are the main inflammatory mediators produced within the uterine endometrium in response to infectious and embryonic signals. They act in complex networks to orchestrate local and systemic inflammatory responses required to protect the embryo from maternal immune rejection and invading pathogens. In the recent years, we have focused our efforts on studying the effect of the cytokine leukemia inhibitory factor (LIF) on MPh differentiation. LIF is highly expressed in the endometrial epithelium and is essential to embryo implantation in mice. In fact, LIF is a central regulator of local and systemic inflammatory responses. LIF provides protection against endotoxin-induced tissue pathology by enhancing the expression of hepatic acute-phase proteins. In the pregnant uterus, LIF is most likely playing a role as a mediator molecule in the protective effect of progesterone against endotoxin-induced fetal demise. Moreover, in response to LIF stimulation, uterine/decidual tissues express oncostatin M (OSM) and amphiregulin (AREG), which are key mediators of the acute-phase protein synthesis regulation. Indeed, in the liver, LIF and OSM are among the major inducers of the hepatic acute-phase gene expression while, in contrast, AREG is a negative regulator of the acute-phase reaction. However, the roles of LIF, OSM and AREG in modulating endotoxin-mediated MPh activation and the acute-phase response to endotoxins during pregnancy remain to be elucidated.*Thus, the overall research program of my laboratory is to investigate and understand the role of uterine signaling factors in the orchestration of local and systemic inflammatory responses at the interface of reproductive and immune systems. On the basis of above observations, our general working hypothesis is that, in order to protect the uterus and the developing embryo, LIF is critical to direct the spatiotemporal differentiation of tissue MPhs in the uterus and the acute-phase response in the liver. In addition, we propose that this immune-modulating effect will vary during the estrous cycle and early pregnancy in response to fluctuating estradiol and progesterone levels. By using the LIF knockout mouse model and analyzing cycling and pregnant animals, we propose the following specific objectives: 1) Investigate the role of LIF and female sex hormones in regulating the process of uterine MPh activation during endotoxin-mediated inflammation; and 2) Determine the mechanisms by which LIF protects the host and the embryo against endotoxin-mediated tissue injury.

子宫内膜的免疫系统在支持发育中的半异基因胚胎的同时，具有保护粘膜免受各种病原体侵袭的能力。然而，宿主对感染的防御所诱导的炎症过程是母体免疫系统成功妊娠结局的主要挑战。组织巨噬细胞(MPHS)是人类和小鼠子宫中最丰富的炎性细胞群之一。在正常妊娠中，它们支持胚胎植入和胎盘分化。另一方面，细菌内毒素在组织损伤中的许多作用是通过激活组织MPHS来诱导的。因此，在小鼠实验模型和人类感染诱导流产中，MPHS中炎症通路的异常激活与早期胚胎丧失有关并不令人惊讶。由于MPHS在子宫组织中发挥着如此重要的功能，其在妊娠和感染过程中的分化和适应的细胞和分子机制需要深入研究。*我们认为子宫MPH功能的关键调节因子是子宫上皮细胞产生的信号因子。事实上，细胞因子是子宫内膜对感染性和胚胎信号做出反应时产生的主要炎症介质。它们在复杂的网络中协调局部和全身炎症反应，以保护胚胎免受母体免疫排斥和入侵病原体的侵袭。近年来，我们致力于研究细胞因子白血病抑制因子(LIF)在MPH分化中的作用。LIF在小鼠子宫内膜上皮细胞中高表达，对小鼠胚胎着床是必不可少的。事实上，LIF是局部和全身炎症反应的中央调节因子。LIF通过增强肝脏急性时相蛋白的表达，对内毒素诱导的组织病理起到保护作用。在妊娠子宫中，LIF很可能在孕酮对内毒素诱导的胎儿死亡的保护作用中起着中介分子的作用。此外，作为对LIF刺激的响应，子宫/蜕膜组织表达抑癌素M(OSM)和两端调节素(AREG)，这是急性时相蛋白质合成调节的关键介质。事实上，在肝脏中，LIF和OSM是肝脏急性期基因表达的主要诱导者，而AREG则相反，是急性期反应的负调控因子。然而，LIF、OSM和AREG在调节内毒素介导的MPH激活和妊娠期对内毒素的急性时相反应中的作用仍有待阐明。因此，我的实验室的总体研究计划是调查和了解子宫信号因子在生殖和免疫系统界面上协调局部和全身炎症反应中的作用。在上述观察的基础上，我们的一般工作假设是，为了保护子宫和发育中的胚胎，LIF在指导子宫组织MPHS的时空分化和肝脏的急性时相反应方面起着关键作用。此外，我们认为这种免疫调节作用在发情周期和早孕期间会随着雌二醇和孕酮水平的波动而变化。通过建立LIF基因敲除小鼠模型，通过对周期动物和妊娠动物的分析，我们提出了以下具体目标：1)研究LIF和雌性激素在内毒素介导的炎症过程中调节子宫PMH激活过程中的作用；2)确定LIF保护宿主和胚胎免受内毒素介导的组织损伤的机制。