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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=589061
• 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具有特殊的能力，能够保护粘膜免受多种病原体的侵害，同时支持发育中的半同种异体胚胎。然而，宿主对感染的防御引起的炎症过程是母体免疫系统成功妊娠的主要挑战。组织巨噬细胞 (MPh) 是人类和小鼠子宫中最丰富的炎症细胞群之一。在正常妊娠中，它们支持胚胎植入和胎盘分化。另一方面，已知细菌内毒素在组织损伤中的许多作用是通过组织 MPh 的激活引起的。因此，MPhs 中炎症途径的异常激活与小鼠实验模型中的早期胚胎丢失和人类感染引起的流产有关，这一点并不奇怪。由于 MPh 在子宫组织中发挥着如此重要的功能，因此需要深入研究其在妊娠和感染期间分化和适应的细胞和分子机制。 我们认为子宫 MPh 功能的关键调节剂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响应感染和胚胎信号而产生的主要炎症介质。它们在复杂的网络中发挥作用，协调保护胚胎免受母体免疫排斥和入侵病原体所需的局部和全身炎症反应。近年来，我们重点研究细胞因子白血病抑制因子（LIF）对MPh分化的影响。 LIF 在子宫内膜上皮中高表达，对于小鼠胚胎植入至关重要。事实上，LIF 是局部和全身炎症反应的中央调节剂。 LIF 通过增强肝脏急性期蛋白的表达来提供针对内毒素诱导的组织病理学的保护。在怀孕的子宫中，LIF 最有可能在黄体酮对内毒素引起的胎儿死亡的保护作用中发挥介质分子的作用。此外，响应 LIF 刺激，子宫/蜕膜组织表达制瘤素 M (OSM) 和双调蛋白 (AREG)，它们是急性期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剂，而相反，AREG 是急性期反应的负调节因子。然而，LIF、OSM 和 AREG 在调节内毒素介导的 MPh 激活和妊娠期间对内毒素的急性期反应中的作用仍有待阐明。 因此，我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局部和全身炎症反应的协调中的作用。基于上述观察，我们的一般工作假设是，为了保护子宫和发育中的胚胎，LIF对于指导子宫中组织MPh的时空分化和肝脏中的急性期反应至关重要。此外，我们认为这种免疫调节作用在动情周期和妊娠早期会因雌二醇和黄体酮水平的波动而变化。通过使用LIF敲除小鼠模型并分析循环和怀孕动物，我们提出以下具体目标：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MPh激活过程的作用； 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。