Studies of macrophage behavior changes in response to pregnancy-associates factors

组织巨噬细胞（tissue macrophages，MMCs）作为单核巨噬细胞，对组织损伤的反应表现出多样性和差异性.预期这些功能由至少两种不同亚型的极化M1 M2执行：表达组织破坏活性的促炎性M1 M2和表现出组织修复活性的抗炎性M2 M2。然而，虽然最初的Mp45成熟过程是很好地建立，参与终端Mp45分化的调节机制仍有待明确阐明。为了解决这个问题，我们选择了子宫内膜作为实验模型，因为它们在子宫内膜中丰富，并且它们的数量和表型会随着子宫或胚胎因素而发生变化。在妊娠早期，子宫内膜局部发生改变，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了MMPs的存活、激活和功能。这表明子宫因素也可以通过激活MØ中的特定信号通路来调节妊娠早期稳定的MØ极化。我们的研究的基本相关性是基于以下事实：正常生理过程需要调节膜电极化，主要是炎症的发作和消退，但也要避免不适当的膜电极活化，从而导致病理功能。使用小鼠作为模型，我们的长期目标是通过定义妊娠子宫中驻留和招募的白细胞的生理反应的分子基础，更好地理解和记录子宫免疫系统的生理学。具体而言，我们建议通过研究妊娠相关因素对体内和体外Mp45极化和可塑性的影响，确定妊娠早期Mp45分化的分子机制。我们希望，即将到来的信息将产生新的工作假设和概念，以更好地定义在其他生理或病理过程中的作用，MMPs介导的活动。

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.