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
基本信息
- 批准号:RGPIN-2014-06516
- 负责人:
- 金额:$ 1.89万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2016
- 资助国家:加拿大
- 起止时间:2016-01-01 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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其保护粘膜免受各种病原体侵害的能力方面是特殊的,同时支持发育中的半同种异体胚胎。然而,由宿主对感染的防御诱导的炎症过程是母体免疫系统成功妊娠结果的主要挑战。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,它们支持胚胎着床和胎盘分化。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激活组织MPh诱导的。因此,在小鼠实验模型和人类感染诱导的流产中,MPh中炎症通路的异常激活与早期胚胎丢失相关,这并不奇怪。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功能的关键调制器是子宫上皮细胞产生的信号传导因子。事实上,细胞因子是子宫内膜内响应感染和胚胎信号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,我们一直致力于研究细胞因子白血病抑制因子(LIF)对MPh分化的影响。LIF在小鼠子宫内膜上皮高度表达,是胚胎着床所必需的。事实上,LIF是局部和全身炎症反应的中心调节因子。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。在妊娠子宫中,LIF最有可能在孕激素对内毒素诱导的胎儿死亡的保护作用中作为介体分子发挥作用。此外,在响应LIF刺激,子宫/蜕膜组织表达抑瘤素M(OSM)和双调蛋白(AREG),这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物,而相反,AREG是急性期反应的负调节剂。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传导因子在生殖和免疫系统界面的局部和全身炎症反应中的作用。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,我们建议,这种免疫调节作用将在发情周期和早孕期波动的雌二醇和孕酮水平的反应。通过使用LIF基因敲除小鼠模型和分析周期和妊娠动物,我们提出了以下具体目标:1)调查LIF和女性性激素在调节内毒素介导的炎症过程中子宫MPh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。
项目成果
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ReyesMoreno, Carlos其他文献
ReyesMoreno, Carlos的其他文献
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{{ truncateString('ReyesMoreno, Carlos', 18)}}的其他基金
Role of gestational factors in the metabolic reprogramming of fetal and maternal immune cells
妊娠因素在胎儿和母体免疫细胞代谢重编程中的作用
- 批准号:
DDG-2020-00017 - 财政年份:2022
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Development Grant
Role of gestational factors in the metabolic reprogramming of fetal and maternal immune cells
妊娠因素在胎儿和母体免疫细胞代谢重编程中的作用
- 批准号:
DDG-2020-00017 - 财政年份:2021
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Development Grant
Role of gestational factors in the metabolic reprogramming of fetal and maternal immune cells
妊娠因素在胎儿和母体免疫细胞代谢重编程中的作用
- 批准号:
DDG-2020-00017 - 财政年份:2020
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Development Grant
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 - 财政年份:2018
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2017
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2015
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2014
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Studies of macrophage behavior changes in response to pregnancy-associates factors
巨噬细胞行为变化响应妊娠相关因素的研究
- 批准号:
327106-2008 - 财政年份:2012
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Studies of macrophage behavior changes in response to pregnancy-associates factors
巨噬细胞行为变化响应妊娠相关因素的研究
- 批准号:
327106-2008 - 财政年份:2011
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Studies of macrophage behavior changes in response to pregnancy-associates factors
巨噬细胞行为变化响应妊娠相关因素的研究
- 批准号:
327106-2008 - 财政年份:2010
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
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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
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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
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$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
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
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