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
• 负责人: ReyesMoreno, Carlos
• 金额: $ 1.46万
• 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: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=481583
• 关键词: Studies; macrophage; behavior; changes; response

As mononuclear phagocytes, tissue macrophages (MØ) exhibit diverse and divergent activities in response to tissue damage. These functions are expected to be executed by at least two different subtypes of polarized MØ: pro-inflammatory M1 MØ, which express tissue-destructive activities, and anti-inflammatory M2 MØ, which exhibit tissue-reparative activities. However, although the initial MØ maturation process is well established, the regulating mechanisms involved in terminal MØ differentiation remain to be clearly elucidated. To address this question, we have chosen uterine MØ as experimental model because they are abundant within the endometrium and their number and phenotype are subjected to change in response to uterine or embryonic factors. During early pregnancy, uterine MØ are locally modified to exhibit an immunosuppressive phenotype and to perform pregnancy-associated functions. Of note, some key pregnancy-associated factors are also involved in MØ survival, activation and function. This suggests that uterine factors can also regulate stable MØ polarization during early gestation via activation of specific signalling pathways in MØ. The fundamental relevance of our studies is based on the fact that regulation of MØ polarization is required for normal physiological processes, mainly the onset and the resolution of inflammation, but also to avoid inappropriate MØ activation and thus lead to pathological functions. Using the mouse as a model, our long-term goal is to better understand and document the physiology of the uterine immune system by defining the molecular basis for physiological responses of resident and recruited leukocytes in the pregnant uterus. Specifically, we propose to determine the molecular mechanisms involved in MØ differentiation during early pregnancy by investigating the effects of pregnancy-associated factors on MØ polarization and plasticity in vivo and in vitro. It is hoped that the forthcoming information will generate new working hypothesis and concepts to better define the role of MØ-mediated activities in other physiological or pathological processes.

作为单核吞噬细胞，组织巨噬细胞（MØ）在对组织损伤的反应中表现出多种多样的活性。这些功能预计至少由两种不同的极化亚型MØ执行：促炎M1 MØ，表达组织破坏活性，抗炎M2 MØ，表现组织修复活性。然而，尽管最初的MØ成熟过程已经建立，但参与末梢MØ分化的调节机制仍有待明确阐明。为了解决这个问题，我们选择子宫MØ作为实验模型，因为它们在子宫内膜内丰富，它们的数量和表型会随着子宫或胚胎因素的变化而变化。在妊娠早期，子宫MØ被局部修饰，表现出免疫抑制表型，并执行妊娠相关功能。值得注意的是，一些关键的妊娠相关因素也参与MØ的存活、激活和功能。这表明子宫因子还可以通过激活MØ的特定信号通路，在妊娠早期调节稳定的MØ极化。我们研究的基本相关性是基于这样一个事实，即MØ极化的调节是正常生理过程所必需的，主要是炎症的发生和消退，但也是为了避免不适当的MØ激活从而导致病理功能。以小鼠为模型，我们的长期目标是通过定义妊娠子宫中常驻和募集白细胞的生理反应的分子基础，更好地了解和记录子宫免疫系统的生理学。具体来说，我们建议通过研究妊娠相关因素对体内和体外MØ极化和可塑性的影响，来确定妊娠早期MØ分化的分子机制。希望即将到来的信息将产生新的工作假设和概念，以更好地定义MØ-mediated活动在其他生理或病理过程中的作用。